Microstructure and function of

the lungs

Professor Tracy Hussell

Director of the Manchester

Collaborative Centre for

Inflammation Research

1

Outline

bull Cellular composition of healthy airways

bull Control of airflow

bull Tolerance of the Environment

bull Diseases affecting airflow

ndash Asthma

ndash Chronic Obstructive Pulmonary Disease (COPD)

ndash Infection

2

Essential function of the airways

Gas exchange system

bull Conducts O2 into the body

bull Remove CO2 from the body

Facilitated by

bull mechanical stability

bull control of calibre

bull filtering and

cleansing

3

Lungs are susceptible to many

diseases that may reduce function

Asthma

Chronic obstructive

pulmonary disease

(COPD)

Mesothelioma

Acute respiratory

distress syndrome

(ARDS)

Idiopathic pulmonary

fibrosis

Sarcoidosis

Pulmonary

hypertension Cystic fibrosis

Infection

Bronchitis

Pneumonia Pleurisy

Trachea

Bronchi

Alveoli

4

Structure of a healthy airway

5 Advantages of a multi-lobed structure

Why are there different cells at different locations

Trachea

Primary bronchus

Secondary bronchus

Tertiary bronchus

Smaller bronchi

Bronchioles

Terminal bronchioles

Respiratory bronchioles

Alveolar sacs (150 million)

Ciliated epithelium Basal cell Goblet cell Club cell Serous cell Brush cell Alveolar type I Alveolar type II

BeacuteruBeacute K et al ATLA 37 89ndash141 2009

C

O

N

D

U

C

T

I

N

G

6

Specialised cellular function of epithelial cells

Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant

7

Proximal region - trachea

C-shaped rings of hyaline cartilage support trachea mucosa and

prevent tube collapse during inspiration

Lumen

Epithelium

Cartilage

8

Basic structure of the conducting airway

Cartilage

9

Airway associated cells ndash different roles

Categoryfunction Cell type ndash over 40 different types

Lining cells Ciliated intermediate brush basal epithelium

Contractile cells Smooth muscle

Secretory cells Goblet (epithelium) mucous serous (glands)

Connective tissue Fibroblast interstitial cell produce

elastin collagen proteoglycans cartilage

Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial

bodies

Vascular cells Endothelial smooth muscle pericyte

Immune cells Mast cell dendritic cell lymphocyte eosinophil

macrophage neutrophil

10

The epithelium is not simply a barrier

11

Functions of the conducting airway epithelium

bull Protection by secretion and movement

of mucus by cilia towards the pharynx ndash

mucociliary clearance

bull Physical barrier to pathogens ndash

junctional components between cells (tight adherens

desmosomes)

bull Production of regulatory and inflammatory mediators

ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells

ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling

ndash Proteases (eg plasminogen activators MMPs)- migration

degradation of ECM growth factor activation

Mucus secretion

Mucus is a hydrated gel that is a

key component of airway defence

The principal gel-forming

components are MUCINS

produced by goblet and mucous

cells

Mucociliary transport

Submucosal gland

Mucus

Goblet

cell Functions

bull Barrier to pathogens

particulates and allergens

bull Maintenance of hydration

bull Serous cells secrete

antibacterials (eg lysozyme)

bull Glands also secrete water and

salts (eg Na+ and Cl-)

13

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Outline

bull Cellular composition of healthy airways

bull Control of airflow

bull Tolerance of the Environment

bull Diseases affecting airflow

ndash Asthma

ndash Chronic Obstructive Pulmonary Disease (COPD)

ndash Infection

2

Essential function of the airways

Gas exchange system

bull Conducts O2 into the body

bull Remove CO2 from the body

Facilitated by

bull mechanical stability

bull control of calibre

bull filtering and

cleansing

3

Lungs are susceptible to many

diseases that may reduce function

Asthma

Chronic obstructive

pulmonary disease

(COPD)

Mesothelioma

Acute respiratory

distress syndrome

(ARDS)

Idiopathic pulmonary

fibrosis

Sarcoidosis

Pulmonary

hypertension Cystic fibrosis

Infection

Bronchitis

Pneumonia Pleurisy

Trachea

Bronchi

Alveoli

4

Structure of a healthy airway

5 Advantages of a multi-lobed structure

Why are there different cells at different locations

Trachea

Primary bronchus

Secondary bronchus

Tertiary bronchus

Smaller bronchi

Bronchioles

Terminal bronchioles

Respiratory bronchioles

Alveolar sacs (150 million)

Ciliated epithelium Basal cell Goblet cell Club cell Serous cell Brush cell Alveolar type I Alveolar type II

BeacuteruBeacute K et al ATLA 37 89ndash141 2009

C

O

N

D

U

C

T

I

N

G

6

Specialised cellular function of epithelial cells

Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant

7

Proximal region - trachea

C-shaped rings of hyaline cartilage support trachea mucosa and

prevent tube collapse during inspiration

Lumen

Epithelium

Cartilage

8

Basic structure of the conducting airway

Cartilage

9

Airway associated cells ndash different roles

Categoryfunction Cell type ndash over 40 different types

Lining cells Ciliated intermediate brush basal epithelium

Contractile cells Smooth muscle

Secretory cells Goblet (epithelium) mucous serous (glands)

Connective tissue Fibroblast interstitial cell produce

elastin collagen proteoglycans cartilage

Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial

bodies

Vascular cells Endothelial smooth muscle pericyte

Immune cells Mast cell dendritic cell lymphocyte eosinophil

macrophage neutrophil

10

The epithelium is not simply a barrier

11

Functions of the conducting airway epithelium

bull Protection by secretion and movement

of mucus by cilia towards the pharynx ndash

mucociliary clearance

bull Physical barrier to pathogens ndash

junctional components between cells (tight adherens

desmosomes)

bull Production of regulatory and inflammatory mediators

ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells

ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling

ndash Proteases (eg plasminogen activators MMPs)- migration

degradation of ECM growth factor activation

Mucus secretion

Mucus is a hydrated gel that is a

key component of airway defence

The principal gel-forming

components are MUCINS

produced by goblet and mucous

cells

Mucociliary transport

Submucosal gland

Mucus

Goblet

cell Functions

bull Barrier to pathogens

particulates and allergens

bull Maintenance of hydration

bull Serous cells secrete

antibacterials (eg lysozyme)

bull Glands also secrete water and

salts (eg Na+ and Cl-)

13

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Essential function of the airways

Gas exchange system

bull Conducts O2 into the body

bull Remove CO2 from the body

Facilitated by

bull mechanical stability

bull control of calibre

bull filtering and

cleansing

3

Lungs are susceptible to many

diseases that may reduce function

Asthma

Chronic obstructive

pulmonary disease

(COPD)

Mesothelioma

Acute respiratory

distress syndrome

(ARDS)

Idiopathic pulmonary

fibrosis

Sarcoidosis

Pulmonary

hypertension Cystic fibrosis

Infection

Bronchitis

Pneumonia Pleurisy

Trachea

Bronchi

Alveoli

4

Structure of a healthy airway

5 Advantages of a multi-lobed structure

Why are there different cells at different locations

Trachea

Primary bronchus

Secondary bronchus

Tertiary bronchus

Smaller bronchi

Bronchioles

Terminal bronchioles

Respiratory bronchioles

Alveolar sacs (150 million)

Ciliated epithelium Basal cell Goblet cell Club cell Serous cell Brush cell Alveolar type I Alveolar type II

BeacuteruBeacute K et al ATLA 37 89ndash141 2009

C

O

N

D

U

C

T

I

N

G

6

Specialised cellular function of epithelial cells

Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant

7

Proximal region - trachea

C-shaped rings of hyaline cartilage support trachea mucosa and

prevent tube collapse during inspiration

Lumen

Epithelium

Cartilage

8

Basic structure of the conducting airway

Cartilage

9

Airway associated cells ndash different roles

Categoryfunction Cell type ndash over 40 different types

Lining cells Ciliated intermediate brush basal epithelium

Contractile cells Smooth muscle

Secretory cells Goblet (epithelium) mucous serous (glands)

Connective tissue Fibroblast interstitial cell produce

elastin collagen proteoglycans cartilage

Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial

bodies

Vascular cells Endothelial smooth muscle pericyte

Immune cells Mast cell dendritic cell lymphocyte eosinophil

macrophage neutrophil

10

The epithelium is not simply a barrier

11

Functions of the conducting airway epithelium

bull Protection by secretion and movement

of mucus by cilia towards the pharynx ndash

mucociliary clearance

bull Physical barrier to pathogens ndash

junctional components between cells (tight adherens

desmosomes)

bull Production of regulatory and inflammatory mediators

ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells

ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling

ndash Proteases (eg plasminogen activators MMPs)- migration

degradation of ECM growth factor activation

Mucus secretion

Mucus is a hydrated gel that is a

key component of airway defence

The principal gel-forming

components are MUCINS

produced by goblet and mucous

cells

Mucociliary transport

Submucosal gland

Mucus

Goblet

cell Functions

bull Barrier to pathogens

particulates and allergens

bull Maintenance of hydration

bull Serous cells secrete

antibacterials (eg lysozyme)

bull Glands also secrete water and

salts (eg Na+ and Cl-)

13

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Lungs are susceptible to many

diseases that may reduce function

Asthma

Chronic obstructive

pulmonary disease

(COPD)

Mesothelioma

Acute respiratory

distress syndrome

(ARDS)

Idiopathic pulmonary

fibrosis

Sarcoidosis

Pulmonary

hypertension Cystic fibrosis

Infection

Bronchitis

Pneumonia Pleurisy

Trachea

Bronchi

Alveoli

4

Structure of a healthy airway

5 Advantages of a multi-lobed structure

Why are there different cells at different locations

Trachea

Primary bronchus

Secondary bronchus

Tertiary bronchus

Smaller bronchi

Bronchioles

Terminal bronchioles

Respiratory bronchioles

Alveolar sacs (150 million)

Ciliated epithelium Basal cell Goblet cell Club cell Serous cell Brush cell Alveolar type I Alveolar type II

BeacuteruBeacute K et al ATLA 37 89ndash141 2009

C

O

N

D

U

C

T

I

N

G

6

Specialised cellular function of epithelial cells

Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant

7

Proximal region - trachea

C-shaped rings of hyaline cartilage support trachea mucosa and

prevent tube collapse during inspiration

Lumen

Epithelium

Cartilage

8

Basic structure of the conducting airway

Cartilage

9

Airway associated cells ndash different roles

Categoryfunction Cell type ndash over 40 different types

Lining cells Ciliated intermediate brush basal epithelium

Contractile cells Smooth muscle

Secretory cells Goblet (epithelium) mucous serous (glands)

Connective tissue Fibroblast interstitial cell produce

elastin collagen proteoglycans cartilage

Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial

bodies

Vascular cells Endothelial smooth muscle pericyte

Immune cells Mast cell dendritic cell lymphocyte eosinophil

macrophage neutrophil

10

The epithelium is not simply a barrier

11

Functions of the conducting airway epithelium

bull Protection by secretion and movement

of mucus by cilia towards the pharynx ndash

mucociliary clearance

bull Physical barrier to pathogens ndash

junctional components between cells (tight adherens

desmosomes)

bull Production of regulatory and inflammatory mediators

ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells

ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling

ndash Proteases (eg plasminogen activators MMPs)- migration

degradation of ECM growth factor activation

Mucus secretion

Mucus is a hydrated gel that is a

key component of airway defence

The principal gel-forming

components are MUCINS

produced by goblet and mucous

cells

Mucociliary transport

Submucosal gland

Mucus

Goblet

cell Functions

bull Barrier to pathogens

particulates and allergens

bull Maintenance of hydration

bull Serous cells secrete

antibacterials (eg lysozyme)

bull Glands also secrete water and

salts (eg Na+ and Cl-)

13

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Structure of a healthy airway

5 Advantages of a multi-lobed structure

Why are there different cells at different locations

Trachea

Primary bronchus

Secondary bronchus

Tertiary bronchus

Smaller bronchi

Bronchioles

Terminal bronchioles

Respiratory bronchioles

Alveolar sacs (150 million)

Ciliated epithelium Basal cell Goblet cell Club cell Serous cell Brush cell Alveolar type I Alveolar type II

BeacuteruBeacute K et al ATLA 37 89ndash141 2009

C

O

N

D

U

C

T

I

N

G

6

Specialised cellular function of epithelial cells

Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant

7

Proximal region - trachea

C-shaped rings of hyaline cartilage support trachea mucosa and

prevent tube collapse during inspiration

Lumen

Epithelium

Cartilage

8

Basic structure of the conducting airway

Cartilage

9

Airway associated cells ndash different roles

Categoryfunction Cell type ndash over 40 different types

Lining cells Ciliated intermediate brush basal epithelium

Contractile cells Smooth muscle

Secretory cells Goblet (epithelium) mucous serous (glands)

Connective tissue Fibroblast interstitial cell produce

elastin collagen proteoglycans cartilage

Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial

bodies

Vascular cells Endothelial smooth muscle pericyte

Immune cells Mast cell dendritic cell lymphocyte eosinophil

macrophage neutrophil

10

The epithelium is not simply a barrier

11

Functions of the conducting airway epithelium

bull Protection by secretion and movement

of mucus by cilia towards the pharynx ndash

mucociliary clearance

bull Physical barrier to pathogens ndash

junctional components between cells (tight adherens

desmosomes)

bull Production of regulatory and inflammatory mediators

ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells

ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling

ndash Proteases (eg plasminogen activators MMPs)- migration

degradation of ECM growth factor activation

Mucus secretion

Mucus is a hydrated gel that is a

key component of airway defence

The principal gel-forming

components are MUCINS

produced by goblet and mucous

cells

Mucociliary transport

Submucosal gland

Mucus

Goblet

cell Functions

bull Barrier to pathogens

particulates and allergens

bull Maintenance of hydration

bull Serous cells secrete

antibacterials (eg lysozyme)

bull Glands also secrete water and

salts (eg Na+ and Cl-)

13

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Why are there different cells at different locations

Trachea

Primary bronchus

Secondary bronchus

Tertiary bronchus

Smaller bronchi

Bronchioles

Terminal bronchioles

Respiratory bronchioles

Alveolar sacs (150 million)

Ciliated epithelium Basal cell Goblet cell Club cell Serous cell Brush cell Alveolar type I Alveolar type II

BeacuteruBeacute K et al ATLA 37 89ndash141 2009

C

O

N

D

U

C

T

I

N

G

6

Specialised cellular function of epithelial cells

Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant

7

Proximal region - trachea

C-shaped rings of hyaline cartilage support trachea mucosa and

prevent tube collapse during inspiration

Lumen

Epithelium

Cartilage

8

Basic structure of the conducting airway

Cartilage

9

Airway associated cells ndash different roles

Categoryfunction Cell type ndash over 40 different types

Lining cells Ciliated intermediate brush basal epithelium

Contractile cells Smooth muscle

Secretory cells Goblet (epithelium) mucous serous (glands)

Connective tissue Fibroblast interstitial cell produce

elastin collagen proteoglycans cartilage

Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial

bodies

Vascular cells Endothelial smooth muscle pericyte

Immune cells Mast cell dendritic cell lymphocyte eosinophil

macrophage neutrophil

10

The epithelium is not simply a barrier

11

Functions of the conducting airway epithelium

bull Protection by secretion and movement

of mucus by cilia towards the pharynx ndash

mucociliary clearance

bull Physical barrier to pathogens ndash

junctional components between cells (tight adherens

desmosomes)

bull Production of regulatory and inflammatory mediators

ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells

ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling

ndash Proteases (eg plasminogen activators MMPs)- migration

degradation of ECM growth factor activation

Mucus secretion

Mucus is a hydrated gel that is a

key component of airway defence

The principal gel-forming

components are MUCINS

produced by goblet and mucous

cells

Mucociliary transport

Submucosal gland

Mucus

Goblet

cell Functions

bull Barrier to pathogens

particulates and allergens

bull Maintenance of hydration

bull Serous cells secrete

antibacterials (eg lysozyme)

bull Glands also secrete water and

salts (eg Na+ and Cl-)

13

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Specialised cellular function of epithelial cells

Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant

7

Proximal region - trachea

C-shaped rings of hyaline cartilage support trachea mucosa and

prevent tube collapse during inspiration

Lumen

Epithelium

Cartilage

8

Basic structure of the conducting airway

Cartilage

9

Airway associated cells ndash different roles

Categoryfunction Cell type ndash over 40 different types

Lining cells Ciliated intermediate brush basal epithelium

Contractile cells Smooth muscle

Secretory cells Goblet (epithelium) mucous serous (glands)

Connective tissue Fibroblast interstitial cell produce

elastin collagen proteoglycans cartilage

Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial

bodies

Vascular cells Endothelial smooth muscle pericyte

Immune cells Mast cell dendritic cell lymphocyte eosinophil

macrophage neutrophil

10

The epithelium is not simply a barrier

11

Functions of the conducting airway epithelium

bull Protection by secretion and movement

of mucus by cilia towards the pharynx ndash

mucociliary clearance

bull Physical barrier to pathogens ndash

junctional components between cells (tight adherens

desmosomes)

bull Production of regulatory and inflammatory mediators

ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells

ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling

ndash Proteases (eg plasminogen activators MMPs)- migration

degradation of ECM growth factor activation

Mucus secretion

Mucus is a hydrated gel that is a

key component of airway defence

The principal gel-forming

components are MUCINS

produced by goblet and mucous

cells

Mucociliary transport

Submucosal gland

Mucus

Goblet

cell Functions

bull Barrier to pathogens

particulates and allergens

bull Maintenance of hydration

bull Serous cells secrete

antibacterials (eg lysozyme)

bull Glands also secrete water and

salts (eg Na+ and Cl-)

13

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Proximal region - trachea

C-shaped rings of hyaline cartilage support trachea mucosa and

prevent tube collapse during inspiration

Lumen

Epithelium

Cartilage

8

Basic structure of the conducting airway

Cartilage

9

Airway associated cells ndash different roles

Categoryfunction Cell type ndash over 40 different types

Lining cells Ciliated intermediate brush basal epithelium

Contractile cells Smooth muscle

Secretory cells Goblet (epithelium) mucous serous (glands)

Connective tissue Fibroblast interstitial cell produce

elastin collagen proteoglycans cartilage

Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial

bodies

Vascular cells Endothelial smooth muscle pericyte

Immune cells Mast cell dendritic cell lymphocyte eosinophil

macrophage neutrophil

10

The epithelium is not simply a barrier

11

Functions of the conducting airway epithelium

bull Protection by secretion and movement

of mucus by cilia towards the pharynx ndash

mucociliary clearance

bull Physical barrier to pathogens ndash

junctional components between cells (tight adherens

desmosomes)

bull Production of regulatory and inflammatory mediators

ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells

ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling

ndash Proteases (eg plasminogen activators MMPs)- migration

degradation of ECM growth factor activation

Mucus secretion

Mucus is a hydrated gel that is a

key component of airway defence

The principal gel-forming

components are MUCINS

produced by goblet and mucous

cells

Mucociliary transport

Submucosal gland

Mucus

Goblet

cell Functions

bull Barrier to pathogens

particulates and allergens

bull Maintenance of hydration

bull Serous cells secrete

antibacterials (eg lysozyme)

bull Glands also secrete water and

salts (eg Na+ and Cl-)

13

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Basic structure of the conducting airway

Cartilage

9

Airway associated cells ndash different roles

Categoryfunction Cell type ndash over 40 different types

Lining cells Ciliated intermediate brush basal epithelium

Contractile cells Smooth muscle

Secretory cells Goblet (epithelium) mucous serous (glands)

Connective tissue Fibroblast interstitial cell produce

elastin collagen proteoglycans cartilage

Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial

bodies

Vascular cells Endothelial smooth muscle pericyte

Immune cells Mast cell dendritic cell lymphocyte eosinophil

macrophage neutrophil

10

The epithelium is not simply a barrier

11

Functions of the conducting airway epithelium

bull Protection by secretion and movement

of mucus by cilia towards the pharynx ndash

mucociliary clearance

bull Physical barrier to pathogens ndash

junctional components between cells (tight adherens

desmosomes)

bull Production of regulatory and inflammatory mediators

ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells

ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling

ndash Proteases (eg plasminogen activators MMPs)- migration

degradation of ECM growth factor activation

Mucus secretion

Mucus is a hydrated gel that is a

key component of airway defence

The principal gel-forming

components are MUCINS

produced by goblet and mucous

cells

Mucociliary transport

Submucosal gland

Mucus

Goblet

cell Functions

bull Barrier to pathogens

particulates and allergens

bull Maintenance of hydration

bull Serous cells secrete

antibacterials (eg lysozyme)

bull Glands also secrete water and

salts (eg Na+ and Cl-)

13

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Airway associated cells ndash different roles

Categoryfunction Cell type ndash over 40 different types

Lining cells Ciliated intermediate brush basal epithelium

Contractile cells Smooth muscle

Secretory cells Goblet (epithelium) mucous serous (glands)

Connective tissue Fibroblast interstitial cell produce

elastin collagen proteoglycans cartilage

Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial

bodies

Vascular cells Endothelial smooth muscle pericyte

Immune cells Mast cell dendritic cell lymphocyte eosinophil

macrophage neutrophil

10

The epithelium is not simply a barrier

11

Functions of the conducting airway epithelium

bull Protection by secretion and movement

of mucus by cilia towards the pharynx ndash

mucociliary clearance

bull Physical barrier to pathogens ndash

junctional components between cells (tight adherens

desmosomes)

bull Production of regulatory and inflammatory mediators

ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells

ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling

ndash Proteases (eg plasminogen activators MMPs)- migration

degradation of ECM growth factor activation

Mucus secretion

Mucus is a hydrated gel that is a

key component of airway defence

The principal gel-forming

components are MUCINS

produced by goblet and mucous

cells

Mucociliary transport

Submucosal gland

Mucus

Goblet

cell Functions

bull Barrier to pathogens

particulates and allergens

bull Maintenance of hydration

bull Serous cells secrete

antibacterials (eg lysozyme)

bull Glands also secrete water and

salts (eg Na+ and Cl-)

13

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

The epithelium is not simply a barrier

11

Functions of the conducting airway epithelium

bull Protection by secretion and movement

of mucus by cilia towards the pharynx ndash

mucociliary clearance

bull Physical barrier to pathogens ndash

junctional components between cells (tight adherens

desmosomes)

bull Production of regulatory and inflammatory mediators

ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells

ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling

ndash Proteases (eg plasminogen activators MMPs)- migration

degradation of ECM growth factor activation

Mucus secretion

Mucus is a hydrated gel that is a

key component of airway defence

The principal gel-forming

components are MUCINS

produced by goblet and mucous

cells

Mucociliary transport

Submucosal gland

Mucus

Goblet

cell Functions

bull Barrier to pathogens

particulates and allergens

bull Maintenance of hydration

bull Serous cells secrete

antibacterials (eg lysozyme)

bull Glands also secrete water and

salts (eg Na+ and Cl-)

13

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Functions of the conducting airway epithelium

bull Protection by secretion and movement

of mucus by cilia towards the pharynx ndash

mucociliary clearance

bull Physical barrier to pathogens ndash

junctional components between cells (tight adherens

desmosomes)

bull Production of regulatory and inflammatory mediators

ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells

ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling

ndash Proteases (eg plasminogen activators MMPs)- migration

degradation of ECM growth factor activation

Mucus secretion

Mucus is a hydrated gel that is a

key component of airway defence

The principal gel-forming

components are MUCINS

produced by goblet and mucous

cells

Mucociliary transport

Submucosal gland

Mucus

Goblet

cell Functions

bull Barrier to pathogens

particulates and allergens

bull Maintenance of hydration

bull Serous cells secrete

antibacterials (eg lysozyme)

bull Glands also secrete water and

salts (eg Na+ and Cl-)

13

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Mucus secretion

Mucus is a hydrated gel that is a

key component of airway defence

The principal gel-forming

components are MUCINS

produced by goblet and mucous

cells

Mucociliary transport

Submucosal gland

Mucus

Goblet

cell Functions

bull Barrier to pathogens

particulates and allergens

bull Maintenance of hydration

bull Serous cells secrete

antibacterials (eg lysozyme)

bull Glands also secrete water and

salts (eg Na+ and Cl-)

13

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Function of airway smooth muscle

TONE

(airway calibre)

Contraction

Relaxation

STRUCTURE

Spiral

organisation

SECRETION

Mediators

Cytokines

Chemokines

14

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Tertiary bronchus

bull Reduced cartilage

more smooth muscle

bull Fewer goblet cells and

submucosal glands

bull Increase in club cells

producing surfactant

15

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Bronchiole

16

bull Single layer of ciliated epithelium

bull No cartilage

bull Reduced smooth muscle

bull No goblet cells or submucosal

glands

bull More club cells producing surfactant

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Distal region ndash site of gas exchange

bull Alveoli - passive gas exchange

with capillary network ndash 150

million

bull Collagen elastic fibres and

fibroblasts and macrophages

present in septal junctions

bull Several alveoli grouped into

lobules surrounded by

connective tissue

17

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Lung parenchyma

bull Type I alveolar cells - simple squamous

epithelium non-ciliated and main site of gas

exchange ndash covers 90 of alveolus

bull Type II alveolar cells (septal cells) ndash produce

surfactant to reduce surface tension preventing

alveoli collapse and renew type I cells

Type II alveolar cells

Type I alveolar cells

18

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Control of airflow

bull Relaxation of smooth muscle = bronchodilation = increased airflow

bull Constriction of smooth muscle = bronchoconstriction = reduced airflow

Inflammation ndash driven constriction

of airway smooth muscle

Smooth muscle tone controlled by

autonomic nervous system

adrenal medullary hormones and

local factors

Autonomic nervous system

Parasympathetic Sympathetic

Muscarinic

beta2 alpha

- Constricts smooth muscle

- Causes mucus gland secretion

- Constricts

blood vessels

- Relaxes smooth muscle

19

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Regulators of airflow

bull Nerves

- parasympathetic (cholinergic - constriction)

- sympathetic (adrenergic - dilation)

bull Regulatory and inflammatory mediators

- mast cell histamine - constriction

- arachidonic acid metabolites ndashconstrict and dilate

(eg prostaglandins leukotrienes)

- cytokines ndash constrict and dilate increase mucus

- hormones (eg adrenaline)

bull Proteinases (eg neutrophil elastase)

bull Reactive gas species (eg O2- NO)

Airway disease = Loss of normal control

20

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)

Airway macrophages a collision of functions

bull Induction of

inflammation

pathogens

bull Inhibition of

inflammation

clearance of self

cells and

extracellular

matrix turnover

products

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Epithelial regulation of immunity

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Tolerance

level set to

high =

bacterial

escape

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Tolerance levels set too low

26

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Respiratory diseases with loss of airway function

bull Common conditions

Asthma ndash ~5 of population in industrialised countries

COPD ndash 4th leading cause of death in UK and USA

Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)

bull Airway remodelling

- goblet cell hyperplasia

- submucosal gland hypertrophy

- fibrosis

- smooth muscle hypertrophy (asthma)

- alveolar destruction (COPD)

27

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Asthma

bull Symptoms cough wheeze

shortness of breath and tightness of

the chest

bull Increased airway hyper-reactivity to

a variety of stimuli (smooth muscle

sensitive to constriction)

bull Airway narrowing and airflow

obstruction - usually reversible

(spontaneously or with drugs)

bull Wide spectrum of symptoms and

different severities of disease-

different phenotypes

Normal

Asthma

28

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Asthma pathophysiology

CHRONIC

INFLAMMATION

AIRWAY

REMODELLING

29

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Pathological changes in the asthmatic

airway- remodelling

bull Mucus hypersecretion

bull Denuded epithelium

bull Goblet cell hyperplasia

bull Reticular thickening

bull Appearance of myofibroblasts

bull Smooth muscle cell hypertrophy

bull Angiogenesis

bull Plasma extravasation

30

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Improved therapies

Current

bull Relievers ndash inhalers are usually blue or green

ndash Bronchodilators cause smooth muscle to relax

ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur

bull Preventers ndash inhalers are usually brown orange or red

ndash Inhaled corticosteroids reduce inflammation in the airways

ndash Used daily even when there are no symptoms

bull Combination ndash A bronchodilatoranti-inflammatory drug

5-10 steroid resistant - severe

31

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Chronic Obstructive Pulmonary Disease ndash COPD

bull Globally 64 million people have

COPD

bull Smoking main cause

bull Consists of a number of conditions

including emphysema and chronic

bronchitis

bull Symptoms of cough shortness of

breath tight chest wheeze

bull Can lead to irreversible airway

obstruction ndash no cure

32

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Effect of smoking on FEV1

(Forced expiratory volume in 1 second)

Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Global Initiative on Obstructive Lung

Disease (GOLD)

GOLD has classified COPD as ldquoa disease

state characterised by airflow limitation that

is not fully reversible The airflow limitation

is usually both progressive and associated

with an abnormal inflammatory response of

the lungs to noxious particles or gasesrdquo

World Health Organization The GOLD global strategy for the

management and prevention of COPD 2001wwwgoldcopdorg 34

GOLD 1-4 classification with 4 most severe

Summary

bull Airways conduct air in and out of the lung mechanical stability

bull Airways comprised of many cell types with specific functions

- control of contractionrelaxation

- mucociliary clearance of foreign particles

- reduction of surface tension

bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells

bull Immunity must display appropriate inflammatory tone

bull Respiratory disease leads to loss of lsquocontrolrsquo

- inflammation

- remodelling

- tissue breakdown

Additional information on websites Asthma UK

British Lung Foundation

35