PATHOGENESIS OF PATHOGENESIS OF BRONCHIAL OBSTRUCTION -BRONCHIAL OBSTRUCTION -

ASTHMA, CASTHMA, COPDOPD

Zuzana HumlováZuzana Humlová

Department of PathophysiologyDepartment of Pathophysiology1st Medical Faculty of Charles 1st Medical Faculty of Charles

UniversityUniversity

1. 1. ASTHMAASTHMA Definition by GINA (Global Initiative for Asthma):Definition by GINA (Global Initiative for Asthma):

Asthma is a Asthma is a chronic inflammatorychronic inflammatory disorder of disorder of airways. Many airways. Many cells and mediatorscells and mediators are involved are involved in this process – eosinophils, mast cells and T-in this process – eosinophils, mast cells and T-lymphocytes. Chronic inflammation is lymphocytes. Chronic inflammation is connected with connected with bronchial hyperrbronchial hyperresponsivnessesponsivness and leads to episodes of wheezing, coughing, and leads to episodes of wheezing, coughing, tightness in the chest, breathlessness, shortage tightness in the chest, breathlessness, shortage of breath specially at night and in the morning. of breath specially at night and in the morning. This episodes are usually connected with This episodes are usually connected with variable obstructionvariable obstruction which is reversible which is reversible spontaneously or by treatment.spontaneously or by treatment.

Allergic asthmaAllergic asthma = asthma induced by = asthma induced by immunological mechanisms. IgE immunological mechanisms. IgE induced asthma – IgE antibodies induced asthma – IgE antibodies triggers early and late-phase of triggers early and late-phase of response, T-lymphocytes late and response, T-lymphocytes late and delayed delayed responses.responses.

Non-allergic asthmaNon-allergic asthma = asthma = asthma induced by non-immunological induced by non-immunological triggerstriggers

Intermittent x persistentIntermittent x persistent

Inflammation causes obstruction of Inflammation causes obstruction of airways by:airways by:

Acute bronchoconstrictionAcute bronchoconstriction

Swelling of bronchial wallSwelling of bronchial wall

Chronic production of mucousChronic production of mucous

Remodeling of airways wallsRemodeling of airways walls

Risk factors:Risk factors:

individual predispositionindividual predisposition (genetic (genetic variability – 5. a 11. chromosome - atopy, variability – 5. a 11. chromosome - atopy, bronchial hyperreactivity, male or female, bronchial hyperreactivity, male or female, nation)nation)

environmentenvironment – exposition to allergens and – exposition to allergens and professional chemicals which lead to professional chemicals which lead to sensitivity, viral and bacterial infection, sensitivity, viral and bacterial infection, food, smoking, social and economic food, smoking, social and economic society, number of family members, society, number of family members, psychosomatic influencepsychosomatic influence

Cells involved in chronic allergic Cells involved in chronic allergic inflammationinflammation

1. Eosinophils1. Eosinophils 2. Mast cells2. Mast cells 3. T-lymphocytes3. T-lymphocytes 4. Neutrophils4. Neutrophils 5. Basophils5. Basophils

HistologyHistology

HistopathologyHistopathology findings during biopsy findings during biopsy examination have not clear affinity to examination have not clear affinity to course of disorder and changes of course of disorder and changes of pulmonary function. Also bronchial pulmonary function. Also bronchial hyperreactivity does not correlate with hyperreactivity does not correlate with histology findingshistology findings

InflammationInflammation

Acute inflammation

Chronic inflammation

Remodeling of airways

Symptoms of bronchoconstriction

Exacerbationnonspecific hyperreactivity

Ongoing obstruction of airways

Therapy and obstructionTherapy and obstruction

Changes ofChanges of ventilation parametersventilation parameters exist exist in patients with proper anti-inflammatory in patients with proper anti-inflammatory

therapytherapy

x x the obstruction of airwaysthe obstruction of airways is not proven is not proven

in all asthmatic patient.in all asthmatic patient.

RemodelingRemodeling

destruction of brush epithelium in airwaysdestruction of brush epithelium in airways swelling of the bronchial wallswelling of the bronchial wall stimulation of proliferation of fibroblastsstimulation of proliferation of fibroblasts deposition of collagen in lamina reticularis deposition of collagen in lamina reticularis

of basal membraneof basal membrane hypertrophy of smooth muscleshypertrophy of smooth muscles hyperplasia of goblet cellshyperplasia of goblet cells

The process of remodeling is The process of remodeling is involved by:involved by:

Th2 lymphocytesTh2 lymphocytes (CD25+, production of IL- (CD25+, production of IL-4,13,5,6,10)4,13,5,6,10)

antigen presenting cellsantigen presenting cells mast cellsmast cells (tryptase-converting  angiotensin (tryptase-converting  angiotensin

I to angiotensin II, hypertrophy of smooth I to angiotensin II, hypertrophy of smooth muscles, histamin – fibrogenetic effect)muscles, histamin – fibrogenetic effect)

eosinophilseosinophils (long-living in epithelium and (long-living in epithelium and submucoses, create lipids –PAF, submucoses, create lipids –PAF, LTC4,LTD4, LTB4, peptidesLTC4,LTD4, LTB4, peptides, , cytokines, TGF-cytokines, TGF-α, TGF-β, IL-1,3, GM-CSF, ECP)α, TGF-β, IL-1,3, GM-CSF, ECP)

alveolar macrophagesalveolar macrophages (production of TNF- (production of TNF-α, IL-6)α, IL-6)

epithelial cellsepithelial cells (desquamation of (desquamation of epithelium, lost of integrity, TGF-β, IGF-1, epithelium, lost of integrity, TGF-β, IGF-1, KGF- β, alteration of differentiation and KGF- β, alteration of differentiation and proliferation of epithelial cells, apoptosis)proliferation of epithelial cells, apoptosis)

endothelial cellsendothelial cells

myocytesmyocytes (proliferation of myocytes - after (proliferation of myocytes - after stimulation with IL-11, which is produced stimulation with IL-11, which is produced by mezenchymal cells after stimulation by mezenchymal cells after stimulation with allergen, PGDF, EGF, the effect of with allergen, PGDF, EGF, the effect of gelatinase A (MMP-2) and B (MMP-9), gelatinase A (MMP-2) and B (MMP-9), production of IL-6,8, eotaxin, PGE2, production of IL-6,8, eotaxin, PGE2, RANTES, MCP-1,2,3, expression of ICAM-1, RANTES, MCP-1,2,3, expression of ICAM-1, VCAM-1, production of NO, GM-CSF, IL-5)VCAM-1, production of NO, GM-CSF, IL-5)

fibroblasts fibroblasts (activation of fibroblasts, (activation of fibroblasts, creation of myofibroblasts, release of GM-creation of myofibroblasts, release of GM-CSF and TGF-β, increasing pro-CSF and TGF-β, increasing pro-inflammatory activity of eosinophils)inflammatory activity of eosinophils)

Subepithelial structures:Subepithelial structures:

thickness of thickness of basal membranebasal membrane increasing deposition of increasing deposition of extracellular matrixextracellular matrix

under epitheliumunder epithelium deposition of deposition of collagencollagen I., III., IV., V. and VII. in I., III., IV., V. and VII. in

reticular membranereticular membrane increasing deposition of increasing deposition of proteoglycansproteoglycans

(lumican, biblycan, decorin, fibromodulin, (lumican, biblycan, decorin, fibromodulin, hyaluron, versica) hyaluron, versica)

tenascintenascin (corresponds with activity of chronic (corresponds with activity of chronic inflammation)inflammation)

fibronectinfibronectin

Increasing number of smooth muscles fibres

Increasing number of mucous glands

Ongoing of inflammatory cells

Release of fibrogenetic factors

Elastolysis

Sever bronchospasms during exacerbation

Increase of mucous secretion during exacerbation

InflammationDeposition of collagen in basal and epithelial membranes

Decrease of elasticity of the wall

Pathogenetic process of inflammation

Pathophysiological and clinic Pathophysiological and clinic consequencesconsequences

in some patients the grade of in some patients the grade of remodelingremodeling not not necessarily correlates with bronchial necessarily correlates with bronchial hyperreactivity hyperreactivity

remodeling correlates with plasma level of remodeling correlates with plasma level of eosinophils,eosinophils, but does not correlate with the but does not correlate with the grade of bronchial hyperreactivity nor with period grade of bronchial hyperreactivity nor with period and severity of asthma and severity of asthma

long period of asthma is connected with long period of asthma is connected with collagen collagen and fibronectin depositionand fibronectin deposition and with lowering of and with lowering of bronchial hyperreactivitybronchial hyperreactivity

decrease of FEV1 although the proper therapydecrease of FEV1 although the proper therapy no correlation between thickening of the reticular no correlation between thickening of the reticular

membrane and the period of asthma and membrane and the period of asthma and decrease of FEV1 in adultsdecrease of FEV1 in adults

Inflammatory cells Ongoing inflammation Activation of fibroblasts and macrophages

SwellingActivation of inflammatory cells

Decrease of apoptosis Remodeling

Mediators of inflammation Cytokines and GF Proliferation of smooth muscles and mucosa cells

Bronchoconstriction Bronchial hyperresponsivness Epithelial cellsdesquamation

EosinophilsEosinophils

terminal cells developing from bone marrow terminal cells developing from bone marrow under stimulatory effects of GM-CSF, IL-3 and under stimulatory effects of GM-CSF, IL-3 and IL-5IL-5, which activates only eosinophils and , which activates only eosinophils and basophils in humansbasophils in humans

eosinophilseosinophils migrate migrate shortly in tissues and get shortly in tissues and get through the mucous of GIT tract. The process through the mucous of GIT tract. The process is regulated by eotaxin and homing is regulated by eotaxin and homing gastrointestinal adhesive receptor α4β7 gastrointestinal adhesive receptor α4β7 which binds to MAdCAM-1 molecule which binds to MAdCAM-1 molecule expressed in gastrointestinal tissue.expressed in gastrointestinal tissue.

live 2 weeks in tissuelive 2 weeks in tissue (GIT parasites) (GIT parasites)

eoeossinophiliainophilia in peripheral blood is not a result in peripheral blood is not a result of migration to the tissues but is under the of migration to the tissues but is under the surveillance of migratory signals from surveillance of migratory signals from vasculature of targeting organvasculature of targeting organ

IL-4, IL-13IL-4, IL-13 induce the expression of VCAM-1 induce the expression of VCAM-1 which binds to very latte antigen–4, the which binds to very latte antigen–4, the receptor of eosinophils, and to P- selectinreceptor of eosinophils, and to P- selectin

CC chemokines like eotaxinCC chemokines like eotaxin bind CC bind CC chemokine receptor 3, target eosinophiles to chemokine receptor 3, target eosinophiles to the tissue where they stay alive long time due the tissue where they stay alive long time due to IL-5 which diminishes apoptosis and due to to IL-5 which diminishes apoptosis and due to the effects of GM-CSFthe effects of GM-CSF

Mediators released by eosinophilsMediators released by eosinophils: major : major basic protein (MBP), eosinophilic cationic basic protein (MBP), eosinophilic cationic protein (ECP), peroxidase, neurotoxin, sulfidic protein (ECP), peroxidase, neurotoxin, sulfidic peptic leukotrienes, PAF, GM-CSF, TGF-α, peptic leukotrienes, PAF, GM-CSF, TGF-α, TGF-βTGF-β

Degranulation of eosinophilsDegranulation of eosinophils – supposing by – supposing by crossing Fcγ, Fcα, together with adhesive crossing Fcγ, Fcα, together with adhesive receptor of macrophage antigen-1 – Mac-1receptor of macrophage antigen-1 – Mac-1

Cytokines involved in Cytokines involved in pathogenesis of asthmapathogenesis of asthma

IL-4IL-4 cross-linking of immunoglobulines in B cross-linking of immunoglobulines in B

lymphocytes – production of IgE and IgG4lymphocytes – production of IgE and IgG4 increases of expression of VCAM-1 and increases of expression of VCAM-1 and

mucous secretionmucous secretion inhibits of activation of Th1 and production inhibits of activation of Th1 and production

of IFNγof IFNγ

IL-13IL-13 induces production of IgE a IgG4induces production of IgE a IgG4 activates mast cellsactivates mast cells increases bronchial hyperreactivity and increases bronchial hyperreactivity and

contractility of smooth muscles, affects the contractility of smooth muscles, affects the differentiation of ciliadifferentiation of cilia

induces the production of eotaxin, VCAM-1induces the production of eotaxin, VCAM-1 supress production of pro-inflammatory supress production of pro-inflammatory

cytokinescytokines

IL-5IL-5 produced by mast cells and Th2 produced by mast cells and Th2

lymphocytes, epithelial cells and lymphocytes, epithelial cells and eosinophilseosinophils

affects the proliferation and the affects the proliferation and the differentiation of B lymphocytesdifferentiation of B lymphocytes

induces expression of IL-2Rinduces expression of IL-2R proliferating and differentiating factor for proliferating and differentiating factor for

eosinophilseosinophils

IL-12IL-12 produced by macrophages, dendritic cells produced by macrophages, dendritic cells

and monocytesand monocytes decreases production of Th2 cytokines decreases production of Th2 cytokines

and then production of IgE and IgG1and then production of IgE and IgG1 decreases number of eosinophils in decreases number of eosinophils in

peripheral blood and in sputumperipheral blood and in sputum

IL-10IL-10 large immunosupressive and anti-large immunosupressive and anti-

inflammatory effectinflammatory effect decreases expression of iNOS, COX2decreases expression of iNOS, COX2 decreases release of IL-2, expression of decreases release of IL-2, expression of

MHC class II., CD80, CD86 and CD32 on MHC class II., CD80, CD86 and CD32 on the surface of APC and then presentation the surface of APC and then presentation of allergen, RANTES, IL-5of allergen, RANTES, IL-5

correlation with asthma severitycorrelation with asthma severity

IFNγIFNγ low levels in atopic peoplelow levels in atopic people stimulatory effects on Th1 cells, inhibitory stimulatory effects on Th1 cells, inhibitory

effects on Th2 cellseffects on Th2 cells the nebulissation of IFNγ decreases the the nebulissation of IFNγ decreases the

number of eosinophils in BAL but this number of eosinophils in BAL but this effect is not significanteffect is not significant

TGF-βTGF-β remodelingremodeling induction of expression of Fas receptor on induction of expression of Fas receptor on

the surface of epithelial cells, activation of the surface of epithelial cells, activation of apoptosis, fagocytosis by macrophages, apoptosis, fagocytosis by macrophages, exsudation of plasma, fibrosisexsudation of plasma, fibrosis

Classification of asthmaClassification of asthma::

A. Atopic (allergic) asthmaA. Atopic (allergic) asthma in combination with allergic rhinitis, atopic dermatitis, in combination with allergic rhinitis, atopic dermatitis,

genetic predispositiongenetic predisposition confirmation of spec. IgE antibodies, prick tests, confirmation of spec. IgE antibodies, prick tests,

inhalation challengeinhalation challenge B. Endogenous asthmaB. Endogenous asthma without specific known influence, obviously in women without specific known influence, obviously in women

after exposition to cold weather, refract to the standard after exposition to cold weather, refract to the standard therapytherapy

C. Exercise induced asthmaC. Exercise induced asthma physical exercising, provocation by inhalation of physical exercising, provocation by inhalation of

chemicals, cold or hot weatherchemicals, cold or hot weather

D. D. Aspirin induced asthmaAspirin induced asthma typical triads-nasal polyps, urticaria and asthma typical triads-nasal polyps, urticaria and asthma

induced by application of aspirininduced by application of aspirin other drugsother drugs E. E. Allergic bronchopulmonary aspergillosisAllergic bronchopulmonary aspergillosis aspergillus acts as an allergen challenge in aspergillus acts as an allergen challenge in

atopic people and induces aspergillus asthma atopic people and induces aspergillus asthma or alergic bronchopulmonary aspergillosisor alergic bronchopulmonary aspergillosis

in the chest radiography are intermitent infiltrates in the chest radiography are intermitent infiltrates in lungs, the viscosity of mucous is increased in lungs, the viscosity of mucous is increased and mucous plugs, bronchiectasia and mucous plugs, bronchiectasia

F. F. Gastroesophageal refluxGastroesophageal reflux

bronchospasm induced by reflexbronchospasm induced by reflex G. Sinobronchial syndromeG. Sinobronchial syndrome

combination of sinusitis with nasal polyps and combination of sinusitis with nasal polyps and with asthmawith asthma

H. Professional asthmaH. Professional asthma

induced by inhalation and exposition to industry induced by inhalation and exposition to industry chemicalschemicals

CH. Asthmatic equivalentCH. Asthmatic equivalent

dry cough, irritating, without breathlessnessdry cough, irritating, without breathlessness

Classification of asthma Classification of asthma severityseverity::

StepStep 1. Intermitent asthma 1. Intermitent asthma rare symptoms < than 1x per week, short rare symptoms < than 1x per week, short

episodes of worsening episodes of worsening night symptoms 2x monthlynight symptoms 2x monthly no symptoms between attacksno symptoms between attacks PEF or FEV1 > 80%, variability < 20%PEF or FEV1 > 80%, variability < 20%

Step Step 2. Mild persistent asthma2. Mild persistent asthma symptoms <1x per day >1x per weeksymptoms <1x per day >1x per week night symptoms > 2x per monthnight symptoms > 2x per month exacerbation can affect daily activity or exacerbation can affect daily activity or

sleepingsleeping PEF or FEV1 > 80%, variability 20-30%PEF or FEV1 > 80%, variability 20-30%

StepStep 3. Moderate persistent asthma 3. Moderate persistent asthma Everyday symptomsEveryday symptoms Exacerbation affects daily activity and Exacerbation affects daily activity and

sleeping sleeping Night symptoms > 1x per weekNight symptoms > 1x per week Everyday use of releasing drugsEveryday use of releasing drugs PEF or FEV1 between 60- 80%, variability PEF or FEV1 between 60- 80%, variability

> 30%> 30%

StepStep 4. Severe persistent asthma 4. Severe persistent asthma Continuous symptomsContinuous symptoms Frequent exacerbationFrequent exacerbation Physical activity is decreasedPhysical activity is decreased Frequent night symptoms Frequent night symptoms PEF or FEV1 < 60%, variability > 30%PEF or FEV1 < 60%, variability > 30%

Examination methods:Examination methods:

History History variable – seasonal, diurnal, exercisevariable – seasonal, diurnal, exercise breathlessness, cough, wheezing, rhinitisbreathlessness, cough, wheezing, rhinitis physical examination – normal, physical examination – normal,

hyperinflation with sounding se hyperinflation with sounding se percussion, prolonged breath-out, dry percussion, prolonged breath-out, dry phenomenon, pulsus paradoxus, running phenomenon, pulsus paradoxus, running of supraclavicular area, silent lungsof supraclavicular area, silent lungs

SpirometrySpirometry diagnosis, to monitor treatment, estimation and diagnosis, to monitor treatment, estimation and

prevention, examination before an operation prevention, examination before an operation basicbasic– – searchingsearching – PEF (Peak Exspiratory Flow) – PEF (Peak Exspiratory Flow) index of variability index of variability

PEF = PEF = the highest-the lowest x 100the highest-the lowest x 100

0,5 x (the highest + the lowest)0,5 x (the highest + the lowest) - FVC, FEV1, FEV1%FVC- FVC, FEV1, FEV1%FVC enlargedenlarged – spiromet– spirometrry, curve of flow-volume, y, curve of flow-volume,

bronchial challenge tests bronchial challenge tests puls oxymetpuls oxymetrry, rhinomanometryy, rhinomanometry

PletysmographyPletysmography referential method for measuring of referential method for measuring of

resistance, breathing work, compliance and resistance, breathing work, compliance and DLCODLCO

isoterm conditions , two phases- measuring of isoterm conditions , two phases- measuring of intrathoracal volume of gas and measuring of intrathoracal volume of gas and measuring of airways resistanceairways resistance

Bronchomotoric challengeBronchomotoric challenge bronchodilatation test – test of reversibility of bronchodilatation test – test of reversibility of

bronchial obstructionbronchial obstruction salbutamol 200-400 ug, ipratropium 80 ugsalbutamol 200-400 ug, ipratropium 80 ug bronchoconstriction test – bronchial bronchoconstriction test – bronchial

hyperreactivityhyperreactivity histamin 1g na 100 ml of 0,9% NaCl, histamin 1g na 100 ml of 0,9% NaCl,

methacholin, acetylcholin, adenosin-5- methacholin, acetylcholin, adenosin-5- monofosfát, hypertonic NaClmonofosfát, hypertonic NaCl

RTGRTG normal, hyperinflationnormal, hyperinflation

BronchoscopyBronchoscopy Endobronchial biopsy – submucosisEndobronchial biopsy – submucosis Bronchoalveolar lavage – phenotypic Bronchoalveolar lavage – phenotypic

differentiation from peripheral blood, express differentiation from peripheral blood, express CD69CD69

Induced sputumInduced sputum Hypertonic NaClHypertonic NaCl Number of eosinophils in sputum corresponds Number of eosinophils in sputum corresponds

to bronchial biopsy and BALto bronchial biopsy and BAL ECPECP

ECP levels in induced sputum corresponded ECP levels in induced sputum corresponded to symptoms score and inversely proportional to symptoms score and inversely proportional to PEF.to PEF.

Significant inflammation –15 ug/l, Significant inflammation –15 ug/l, compensation of asthma - 23 ug/lcompensation of asthma - 23 ug/l

Measuring of breath-out condensated Measuring of breath-out condensated gasgas LTB4, cysteinyl leukotrienes, NO –increased LTB4, cysteinyl leukotrienes, NO –increased

in untreated patients, dependent on flow, in untreated patients, dependent on flow, lower flow-higher NO, constantly 50 ml/slower flow-higher NO, constantly 50 ml/s

Low production of NO in cilia dyskinesis, Low production of NO in cilia dyskinesis, cystic fibrosis, correlation with findings in cystic fibrosis, correlation with findings in biopsy and eosinophils in sputumbiopsy and eosinophils in sputum

Blood gasesBlood gases

2. 2. COCOPPDD

Definition by GOLD (Global Initiative for Definition by GOLD (Global Initiative for Chronic Obstructive Lung Disease):Chronic Obstructive Lung Disease):

COCOPPD is characterized by decreasing D is characterized by decreasing flow in airways (bronchial obstruction) flow in airways (bronchial obstruction) which is not completely reversible. which is not completely reversible. Bronchial obstruction is in the Bronchial obstruction is in the progress and is connected with progress and is connected with abnormal inflammatory response of abnormal inflammatory response of lungs caused by toxic pollutants.lungs caused by toxic pollutants.

Chronic bronchial obstructionChronic bronchial obstruction

Combination of disorder of small airways Combination of disorder of small airways ((obstructive bronchiolitisobstructive bronchiolitis) and ) and destruction of lung tissue (destruction of lung tissue (emphysememphysemaa))

Chronic inflammation – remodeling and Chronic inflammation – remodeling and narrowing of small airwaysnarrowing of small airways

Destruction of lungs and inflammation lead Destruction of lungs and inflammation lead to lose of connection of alveoli with small to lose of connection of alveoli with small airwaysairways

Decrease of elasticityDecrease of elasticity

Risk factorsRisk factors

Genetic factorsGenetic factors (e.g. deficiency of α1- (e.g. deficiency of α1- antitrypsin, ABO secretion status, antitrypsin, ABO secretion status, microsomal epoxid hydroxylase, glutathion microsomal epoxid hydroxylase, glutathion S-transferase, α1- antichymotrypsin, S-transferase, α1- antichymotrypsin, complementary part GcG, TNF- α, complementary part GcG, TNF- α, microsatelit instability), hyperreactivity of microsatelit instability), hyperreactivity of airways, growth of lungsairways, growth of lungs

Exposition to tobacco smokeExposition to tobacco smoke, professional , professional dust and chemicals, air pollution in dust and chemicals, air pollution in environment and in buildings, infection, environment and in buildings, infection, social and economic statussocial and economic status

Small airways (< 2 mm)

Bronchial obstruction

Destruction of tissue

Inflammation

Pathogenetic mechanisms of COPD

Cells involved in inflammation:Cells involved in inflammation:

NeutrophilsNeutrophils BAL and sputum contain activated neutrophils BAL and sputum contain activated neutrophils

but their number is not increased in sections but their number is not increased in sections from bronchi or lung tissue from bronchi or lung tissue

Induced sputum contains increased level of Induced sputum contains increased level of myeloperoxidase and human neutrophil lipocalinmyeloperoxidase and human neutrophil lipocalin

Secretion of proteases- neutrophil elastase, Secretion of proteases- neutrophil elastase, cathepsin G neutrophil protease-3cathepsin G neutrophil protease-3

MacrophagesMacrophages Production of IL-8, LTB4, TNF- αProduction of IL-8, LTB4, TNF- α T lymphocytes CD8+T lymphocytes CD8+ Release of perforin, granzym B, TNF- αRelease of perforin, granzym B, TNF- α EosinophilsEosinophils The role is unknown, usually increase The role is unknown, usually increase

during acute exacerbationduring acute exacerbation Increase of ECP, EPO in induced sputumIncrease of ECP, EPO in induced sputum

Epithelial cellsEpithelial cells Production of inflammatory mediators Production of inflammatory mediators

(eikosanoids, cytokines, adhesive (eikosanoids, cytokines, adhesive molecules)molecules)

E-selektin-attraction and adhesion of E-selektin-attraction and adhesion of neutrophilsneutrophils

TNF- TNF- αα, IL-8, IL-8

Mediators involved in CMediators involved in COPOPD D pathogenesis:pathogenesis:

Leukotriene B4 Leukotriene B4 Strong attraction of neutrophilsStrong attraction of neutrophils Secreted by macrophagesSecreted by macrophages

IL-8IL-8 Selective attraction of neutrophilsSelective attraction of neutrophils Secreted by macrophages, neutrophils Secreted by macrophages, neutrophils

and epithelial cells in bronchiand epithelial cells in bronchi

TNF- αTNF- α activates NF-κB which activates gene for pro IL-activates NF-κB which activates gene for pro IL-

88 in sputum, bronchial biopsyin sputum, bronchial biopsy

Macrophages Chemotactic protein-1 ( MCP-1)Macrophages Chemotactic protein-1 ( MCP-1) attraction of macrophages to the lungsattraction of macrophages to the lungs

Macrophage inflammatory protein-1 (MIP-1)Macrophage inflammatory protein-1 (MIP-1)

Macrophage inflammatory protein -1 α (MIP-1 Macrophage inflammatory protein -1 α (MIP-1 α)α)

GM-CSFGM-CSF – – increased during exacerbationincreased during exacerbation

TGF-β, EGFTGF-β, EGF – – remodeling of bronchiremodeling of bronchi

Endotelin-1Endotelin-1 – – vasoconstriction, chronic vasoconstriction, chronic hypoxemiahypoxemia

Neuropeptides – substance P, VIPNeuropeptides – substance P, VIP – influence – influence on vessels function and secretion of mucouson vessels function and secretion of mucous

Complement –Complement – C5a- C5a- concentration of neutrophils concentration of neutrophils

CellsMacrophagesNeutrophils

CD8+ lymphocytesEosinophils

Epithelial cellsFibroblasts

MediatorsLTB4, IL-8, GRO-1α, MCP-1, MIP-

1α, GM-CSF,Endothelin

Substance PEffects

Increase of mucous secretionFibrosis

Destruction of the alveolus wall

ProteasesNeutrophils

elastaseCathepsinsProtease-3

Collection of MMP

Pathogenesis of COPathogenesis of COPPDD

pollutants in environment ---inflammationpollutants in environment ---inflammation smoking of cigarettessmoking of cigarettes – stimulation of – stimulation of

macrophages and epithelial cells to produce macrophages and epithelial cells to produce TNF- α, IL-8 and LTB4TNF- α, IL-8 and LTB4

exhalations from cars, dust from grainexhalations from cars, dust from grain instability between proteases and anti-instability between proteases and anti-

proteases in lungs proteases in lungs Laurell and Eriksson –1963 – deficiency of α1-Laurell and Eriksson –1963 – deficiency of α1-

antitrypsinu and emphysemaantitrypsinu and emphysema

oxidative stressoxidative stress hydrogen peroxide, NO – directly hydrogen peroxide, NO – directly

measured oxidants produced during measured oxidants produced during smoking of cigarettessmoking of cigarettes

isoprostan F2 α-III, marker of oxidative isoprostan F2 α-III, marker of oxidative stress in lungs, bronchoconstrictionstress in lungs, bronchoconstriction

changes in central and peripheral bronchichanges in central and peripheral bronchi, , lung tissue and vesselslung tissue and vessels

peripheral bronchi are the major place of peripheral bronchi are the major place of the the obstructionobstruction

centrilobular type of emphysemacentrilobular type of emphysema changes includechanges include: increased secretion of : increased secretion of

mucus, the function of cilia is disturbed, mucus, the function of cilia is disturbed, obstruction, hyperinflation of lungs, obstruction, hyperinflation of lungs, disturbed gas exchange – firstly disturbed gas exchange – firstly hypoxahypoxaeemia ( due to irregularity of mia ( due to irregularity of ventilation and perfusion), then ventilation and perfusion), then hypercapnia, pulmonary hypertension and hypercapnia, pulmonary hypertension and cor pulmonalecor pulmonale

Classification of COClassification of COPPD grading:D grading:

Grade 0 – high riskGrade 0 – high risk normal spirometrynormal spirometry chronic symptomschronic symptomsGrade I – mildGrade I – mild FEV1/FVC < 70% FEV1/FVC < 70% FEV1>80% FEV1>80% Chronic symptoms are or are not present Chronic symptoms are or are not present

(cough, sputum)(cough, sputum)

Grade II – moderateGrade II – moderate FEV1/FVC < 70%FEV1/FVC < 70% 50% < FEV1< 80%50% < FEV1< 80% Chronic symptoms are or are not present Chronic symptoms are or are not present

(cough, sputum, breathlessness)(cough, sputum, breathlessness)Grade III – severeGrade III – severe FEV1/FVC < 70% FEV1/FVC < 70% 30% < FEV1< 50%30% < FEV1< 50% Chronic symptoms are or are not present Chronic symptoms are or are not present

(cough, sputum, breathlessness)(cough, sputum, breathlessness)

Grade IV – the most severeGrade IV – the most severe FEV1/FVC < 70%FEV1/FVC < 70% FEV1 < 30% or FEV1< 50% and FEV1 < 30% or FEV1< 50% and

respiratory failure or clinical symptoms of respiratory failure or clinical symptoms of cor pulmonalecor pulmonale

Examination methods:Examination methods:

ClinicsClinics History, physical examination, inspection, palpation, History, physical examination, inspection, palpation,

percussion, auscultationpercussion, auscultation Spirometry, bronchodilatation challenge and test Spirometry, bronchodilatation challenge and test

of reversibility by corticosteroidesof reversibility by corticosteroides if FEV1 after application of bronchodilatators is < if FEV1 after application of bronchodilatators is <

80% and FEV1/FVC <70%, the bronchial obstruction 80% and FEV1/FVC <70%, the bronchial obstruction is not fully reversibleis not fully reversible

patient is treated for 6-12 month with inhalation patient is treated for 6-12 month with inhalation corticosteroides and FEV1 is increased about 200 ml corticosteroides and FEV1 is increased about 200 ml and about 15% before treatment, the test is positiveand about 15% before treatment, the test is positive

RTG, CT, HRCTRTG, CT, HRCT hyperinflation – flat diaphragm, hyperinflation – flat diaphragm,

enlargement of retrosternal space, enlargement of retrosternal space, increased transparency of lungs, quick increased transparency of lungs, quick loosing of pulmonary vessels bedloosing of pulmonary vessels bed

Blood gasesBlood gases in patients with FEV1< 40% in patients with FEV1< 40% in patients with clinical symptoms of in patients with clinical symptoms of

respiratory failure, right heart failurerespiratory failure, right heart failure

Pulmonary hemodynamicsPulmonary hemodynamics

pulmonary hypertension, cor pulmonalepulmonary hypertension, cor pulmonale HematocritHematocrit Screening Screening for for deficiency ofdeficiency of

α1-antitrypsinα1-antitrypsin

COLD started before 45 yearsCOLD started before 45 years

Differences between asthma and CODifferences between asthma and COPPDD

COPD ASTHMA

Cells NeutrophilsGreat increase of macrophage

numberIncrease of CD8+ T cells

EosinophilsSmall increase of

macrophage numberIncrease CD4+ Th2

lymphocytesActivation of mast cells

Mediators LTB4IL-8TNF-α

LTD4IL-4, IL-5And others

Results Squamose metaplasia of epithel

Destruction of tissueMucous metaplasiaEnlargement of glands

Fragile epithelThickening of basal

membraneMucous metaplasia Enlargement of glands

Treatment efficacy Corticosteroides have little or no effect in the treatment

Corticosteroides can cure inflammation