Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014INFLAMMATION OVERVIEW

1. A protective response2. Get rid of damaged/necrotic tissue and foreign invaders such as microbes

i. Destroy -->infectious agentsii. Dilutes -->infectious agents

iii. Walls off -->infectious agentsInitial cause : microbes / toxinsInjurious consequence : necrotic cell / tissue

3. Complex reaction in tissue -> responses of blood vessels and leukocytes (plasma proteins)4. Inflammatory stimulus generate/activate -> various cells / plasma proteins to produce -> soluble factors ->

trigger vascular and cellular reactions5. Termination of inflammation:

a. When offending agent is eliminatedb. Rxn resolves rapidly, mediators are broken down and dissipatedc. Leukocytes have short lifespan in tissuesd. Anti-inflammatory mechanism activated

i. controls inflammatory responseii. Prevent excessive host tissue damage

6. Intertwined with Repair ProcessRepair Process:a. Heal damaged tissueb. Repair begins at inflammationc. Completed when injurious agent is neutralizedd. Replaces damage tissue through:

i. Regeneration of native parenchymal cellsii. Filling of defective tiss. w/ fibrous tiss. (called Scarring)

iii. Or combination of these 2 processes7. Inflammation can be harmful in most situations

a. Inflamm Mechanism has intrinsic ability to destroy both:i. Foreign invaders

ii. Normal tissuesb. Can cause injury or diseasec. Underlies common chronic disease:

i. Rheumatoid arthritisii. Atherosclerosis

iii. Lung Fibrosisiv. Hypersensitivity rxns (insect bites, drugs, toxins

d. Anti-inflamm drugs:i. Control harmful effects of Inflammation

ii. Not interfere on beneficial effectse. Abnormal host responses – contributes to disease (usually in chronic inflammation)

i. Atherosclerosisii. Type-2 Diabetes

iii. Alzheimer diseaseiv. Cancer

f. Referred to as “silent-killer”

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 20148. Has 2 Types:

a. Acute Inflammationi. Rapid onset (minutes)

ii. Short duration (hours or days)Main features:1. Exudation of fluid and plasma proteins (edema)2. Emigration of leukocytes (neutrophils / polymorphonuclear leukocytes)

Successful -> subsidesFail -> progress to chronic phase

b. Chronic Inflammationi. Onset:

1. Follow acute inflammation2. Insidious

ii. Longer durationiii. Associated w/ Lymphocytes or Macrophagesiv. Characterized by:

1. Proliferation of blood vessels2. Fibrosis3. Tissue destruction

HISTORICAL HIGHLIGHTS1. Described in Egyptian Papyrus (3000 BC)2. Celsus, roman writer:

4 Cardinal Signs of Inflammation (more prominent in acute inflamm)i. Rubor (redness)

ii. Tumor (swelling)iii. Calor (heat)iv. Dolor (pain)

3. Rudolf Virchow (19th cent)5th Sign: loss of function (function laesa)

4. John Hunter“Inflammation is not a disease but a nonspecific response w/ salutary effect on host”

5. Elie Metchnikoff (Russian, 1880s)a. Described Phagocytosisb. Purpose of Inflammation – bring phagocytic cells to site and engulf invading bacteria

6. George Bernard Shawa. “Doctor’s Dilemma” b. To cure-all disease -> stimulate the phagocytes

7. Thomas Lewisa. Chemical substances (eg. Histamine) mediate vascular changes in inflammationb. Lead to important discoveries of:

i. Chemical mediators in inflammationii. Use of anti-inflammatory drugs

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014ACUTE INFLAMMATION

1. Rapid host response2. Deliver leukocytes and plasma proteins (antibodies) to site of infection3. 3 Components:

a. Alteration of vascular calibre – lead to inc. blood flowb. Structural changes in microvasculature – permit plasma proteins and leukocytes to leave circulationc. Emigration of leukocytes from microcirc, leukocyte accumulation in site of injury, and leukocyte

activation

4. Stimuli of Acute Inflamm: a. Infections (bacterial, viral, fungal, parasitic) and microbial toxins

i. most common and medically importantii. Sensing mechanisms (receptors) – engagement triggers signalling pathways -> stimulate

production of mediators1. Toll-like receptors (TLRs) / Drosophila protein Toll - for microbial products2. Several cytoplasmic receptors – detect bacteria, viruses, and fungi

b. Tissue necrosisi. From different causes:

1. Ischemia (myocardial infarct)2. Trauma3. Physical and Chemical Injury

ii. Releases several chemicals that cause Inflamm Response1. Uric Acid – a purine metabolite2. Adenosine Triphosphate – normal energy store3. HMGB-1 - DNA-binding protein of unknown function4. DNA released into the cytoplasm5. HIF-1α (hypoxia-induced factor-1α) – hypoxia

a. produced by cells deprived of oxygenb. activates the transcription of many genes - including vascular endothelial

growth factor (VEGF) -> increases vascular permeability

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014c. Foreign bodies (eg. splinters, dirt, sutures)

i. cause traumatic tissue injuryii. carry microbes

d. Immune/Hypersensitivity Reactionsi. normally protective immune system damages the individual's own tissues

ii. injurious immune responses:1. directed against self-antigens -> autoimmune diseases2. excessive reactions against environmental substances or microbes

iii. associated with chronic inflammation1. autoimmune reactions are persistent and difficult to cure2. stimuli for the inflammatory responses cannot be eliminated

iv. induced by cytokines from T Lymphocytes and other immune system cellsv. common in immune-mediated inflammatory disease

5. Sequence of Events in Acute Inflammationa. Reaction of Blood Vessels - series of changes designed to maximize the movement of plasma proteins

and circulating cells out of the circulationi. Exudation - escape of fluid, proteins, and blood cells from the vascular system into the

interstitial tissue or body cavitiesExudate- Presence implies inc. in permeability of small blood vessels -> Inflammatory Response- Extravascular fluid that has:

a. high protein concentrationb. cellular debrisc. high specific gravity

Transudate- An ultrafiltrate of blood plasma <- osmotic or hydrostatic imbalance + inc . vasc. perm- Fluid:

a. low protein content (mostly albumin)b. little or no cellular materialc. low specific gravity

Edema- excess of fluid in the interstitial tissue or serous cavities- either exudate or transudatePus- purulent exudate- rich in :

o leukocytes (mostly neutrophils)o debris of dead cellso microbes

b. Changes in Vascular Flow and Caliberi. begin early after injury

ii. consist of:1. vasodilation

a. earliest manifestations of acute inflammationb. follows a transient constriction of arteriolesc. involves the arterioles (leads to opening of new capillary beds in the area)d. results in: inc. blood flow (cause heat and redness – ERYTHEMA) e. induced by action of mediators on vasc. smooth muscle

i. Histamineii. NO (nitric oxide)

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 20142. Inc. perm. of microvasculature – w/ outpouring of protein-rich fluid in extravasc. tissues3. Loss of fluid and inc. vessel diameter lead to:

a. slower blood flowb. concentration of red cells in small vesselsc. increased viscosity of the blood

4. Statis (vascular congestion) - dilation of small vessels that are packed with slowly moving red cells; localized redness

5. Accumulation of blood leukocytes (neutrophils)6. Activation of endothelial cells by mediators (produced at sites of infection and tissue

damage) -> inc. levels of adhesion molecules7. Adherence of leukocytes to endothelium8. Migration of leukocytes through vascular wall into interstitial tissue

iii. Increased Vascular Permeability (Vascular Leakage)Mechanisms:

a. Contraction of endothelial cells (immediate transient response)i. increases interendothelial spaces

ii. occurs rapidly after exposure to mediatoriii. short-lived (15–30 minutes)

Delayed prolonged leakage- begins after a delay of 2-12 hrs- lasts for several hours or days- caused by contraction of endothelial cells or mild endothelial

damage- in mild injury eg. late-appearing sunburn

Elicited by:1. Histamine2. Bradykinin3. Leukotrienes4. neuropeptide substance P5. many other chemical mediators

b. Endothelial injury -> results to endothelial cell necrosis and detachment- Usually by direct damage to endothelium- Neutrophil adhesion can injure endothelium

c. Transcytosis -> inc. transport of fluids and proteins through endothelial cell- Involve vesiculovacuolar organelle

channels consisting of interconnected, uncoated vesicles and vacuoles

located close to intercellular junctions factors such as VEGF promote vascular leakage by inc.

number and size of these channels

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014

iv. Responses of Lymphatic Vessels (Reactive or Inflammatory Lymphadenitis)1. lymphatics and lymph nodes

a. filters and polices the extravascular fluidsb. proliferate during inflammatory reactions

i. to handle the increased loadii. increased numbers of lymphocytes and macrophages

c. enlarged -> caused by hyperplasia of lymphoid follicles2. In inflammation -> lymph flow is increased -> helps drain edema fluid that accumulates

due to increased vascular permeability3. presence of red streaks near a skin wound -> sign of infection4. lymphadenitis / lymphangitis

a. indicated by streaking that follows the course of lymphatic channelsb. infection of lymph channelsc. painful enlargement of draining lymph nodes

c. Reaction of leukocytes in Inflammationi. Deliver leukocytes to site of injury

ii. Activate leukocytes to eliminate offending agentsiii. Phagocytic leukocytes are important (neutrophils and macrophages)

1. Ingest and kill bacteria and other microbes2. Eliminate necrotic tissue and foreign substances3. Produce growth factors for repair

iv. When strongly activated:1. induce tissue damage and prolonged inflammation2. leukocyte products that destroy microbes and necrotic tissues -> injure normal host

tissues

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014

v. Mechanism:1. Recruitment of Leukocytes to Sites of Infection and Injury (Extravasation)

a. Margination - leukocyte redistribution; Mechanism: Stasis (slow blood flow) -> change in hemodynamic

conditions (wall shear stress decreases) -> WBC assume peripheral position (RBC in central axial column)

b. Rollingi. adhere to endothelium, detach and bind again

ii. at some point leukocytes adhere firmlyiii. mediated by SELECTINS

- Types: L-selectin (leukocytes) E-selectin (endothelium) P-selectin (platelets and endothelium)

- Ligands: sialylated oligosaccharides bound to mucin-like glycoprotein backbones

- expression of selectins and their ligands is regulated by cytokines produced in response to infection and injury

c. Adhesioni. mediated by complementary adhesion molecules (CAM)

ii. expression is enhanced by secreted proteins called Cytokinesiii. cytokines secreted by tissues in response to injurious agentsiv. Tissue macrophages, mast cells, and endothelial cells

- encounter microbes and dead tissues- respond by secreting Cytokines:

tumor necrosis factor (TNF) interleukin-1 (IL-1) chemokines (chemoattractant cytokines)

> enter the blood vessel> bind to endothelial cell proteoglycans> displayed at high concentrations on the

endothelial surface> bind to and activate the rolling leukocytes

- Integrins family of heterodimeric leukocyte surface proteins mediates firm adhesion TNF and IL-1 -- induce endothelial expression of ligands

for integrins> vascular cell adhesion molecule 1 (VCAM-1,

the ligand for the VLA-4 integrin) > intercellular adhesion molecule-1 (ICAM-1,

the ligand for the LFA-1 and Mac-1 integrins)v. firm integrin-mediated binding of the leukocytes to the endothelium

- results from: combination of cytokine-induced expression of integrin

ligands on the endothelium activation of integrins on the leukocytes

d. Leukocytes stop rolling -> their cytoskeleton is reorganized -> spread out on endothelial surface

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014e. Leukocyte migration through endothelium (TRANSMIGRATION/DIAPEDESIS)

i. Occurs mainly on post-capillary venulesii. Chemokine stimulation -> migration toward chemical concentration

gradient (site of injury or infection)iii. Adhesion molecules are also involved

- Present in intercellular junctions bet. Endothelial cells- PECAM-1 (platelet endothelial cell adhesion molecule) or CD31

iv. Leukocytes1. traverse the endothelium2. pierce the basement membrane (by secreting collagenases)3. enter the extravascular tissue4. migrate toward the chemotactic gradient created by

chemokines5. accumulate in the extravascular site (retained in the site where

they are needed)Leukocyte Adhesion Molecules Genetic Deficiencies:

1. Leukocyte adhesion deficiency type 1 - defect in the biosynthesis of the β2 chain shared by the LFA-1 and Mac-1 integrins

2. Leukocyte adhesion deficiency type 2 - defect in a fucosyl transferase (enzyme that attaches fucose moieties to protein backbones); caused by absence of sialyl-Lewis X, the fucose-containing ligand for E- and P-selectins

f. Chemotaxis of Leukocytesi. Chemoattractants

- exogenous bacterial products

> peptides that possess an N-formylmethionine terminal amino acid

- endogenous chemical mediators

> cytokines> components of the complement system

(particularly C5a)> arachidonic acid (AA) metabolites -

leukotriene B4 (LTB4)ii. chemotactic agents bind to specific seven-transmembrane G protein–

coupled receptors (surface of leukocytes)iii. receptors activate -> second messengers -> increase cytosolic calcium ->

activate small guanosine triphosphatases of the Rac/Rho/cdc42 family and numerous kinases -> induce polymerization of actin -> increased amounts of polymerized actin at leading edge of the cell -> localization of myosin filaments -> leukocyte moves by extending filopodia -> leukocytes migrate toward the inflammatory stimulus

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014g. Nature of Leukocyte Infiltrate varies with:

i. age of inflamm response- 6-24hrs – neutrophils predominate

more numerous in the blood respond rapidly to chemokines attach more firmly to adhesion molecules but short lived, apoptosis and disappear after after

24hrs- 24-48hrs – monocytes replace

Survive longer May proliferate in tissues

ii. type of stimulus- bacteria – neutrophils- viral – lymphocytes- hypersensitivity – eosinophils

2. Recognition of Microbes and Dead TissuesLeukocyte receptors that recognize external stimuli and deliver activating signals:

i. Toll-like receptors (TLRs) – microbial products- recognize components of different types of microbes

ii. G protein–coupled receptors – found on neutrophils, macrophages, and most other types of leukocytes

- recognize short bacterial peptides containing N-formylmethionyl residues

iii. Receptors for opsonins - Opsonization – coat microbes with opsonin; enhance

phagocytosis Antibodies Complement proteins Lectins

iv. Receptors for cytokines- Leukocytes express receptors for cytokines (produced in

response to microbes) interferon-γ (IFN-γ) - secreted by:

> natural killer cells> antigen-activated T lymphocytes (adaptive

immune responses)3. Phagocytosis

a. Sequential Steps:i. recognition and attachment of the particle to be ingested by the

leukocyte- Mannose receptors- Scavenger receptors- Opsonin receptors

ii. engulfment, with subsequent formation of a phagocytic vacuole- extensions of the cytoplasm (pseudopods) wrap foreign particle- plasma membrane pinches off to form a vesicle (phagosome)

that encloses particle- phagosome then fuses with a lysosomal granule- discharge of the granule's contents into the phagolysosome

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014iii. killing or degradation of the ingested material

- accomplished by: reactive oxygen species (ROS) reactive nitrogen species (RNS) derived from NO

- “respiratory burst”- Phagocyte granules contain:

Elastase Defensin Cathelicidins Lysozyme Lactoferrin Major basic protein Bactericidal/permeability increasing protein

d. Other functional responses of Activated Leukocytesi. Produce growth factors – induce tissue repair after injury

1. stimulate the proliferation of endothelial cells and fibroblasts2. synthesis of collagen, and enzymes that remodel connective tissues

ii. secrete inhibitors of the inflammatory response - amplify and control the reaction6. Termination of Acute Inflammatory Response

a. inflammation declines:i. mediators of inflammation are produced in rapid bursts

ii. mediators are produced only as long as the stimulus persistsiii. mediators have short half-livesiv. mediators are degraded after their release

b. neutrophils i. short half-lives in tissues a

ii. die by apoptosis within a few hours after leaving the bloodc. inflammation process triggers a variety of stop signals that serve to actively terminate the reactiond. arachidonic acid metabolite

i. pro-inflammatory leukotrienesii. anti-inflammatory lipoxins

e. anti-inflammatory cytokinesi. transforming growth factor-β (TGF-β)

ii. IL-10f. anti-inflammatory lipid mediators

i. resolvins ii. protectins

g. neural impulses (cholinergic discharge) - inhibit the production of TNF in macrophages

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014MEDIATORS OF INFLAMMATION

The Actions of the Principal Mediators of InflammationMediator Principal Sources Actions

CELL-DERIVED

Histamine Mast cells, basophils, platelets

Vasodilation, increased vascular permeability, endothelial activation

Serotonin Platelets Vasodilation, increased vascular permeability

Prostaglandins Mast cells, leukocytes Vasodilation, pain, fever

Leukotrienes Mast cells, leukocytes Increased vascular permeability, chemotaxis, leukocyte adhesion and activation

Platelet-activating factor

Leukocytes, mast cells Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst

Reactive oxygen species

Leukocytes Killing of microbes, tissue damage

Nitric oxide Endothelium, macrophages

Vascular smooth muscle relaxation, killing of microbes

Cytokines (TNF, IL-1) Macrophages, endothelial cells, mast cells

Local endothelial activation (expression of adhesion molecules), fever/pain/anorexia/hypotension, decreased vascular resistance (shock)

Chemokines Leukocytes, activated macrophages

Chemotaxis, leukocyte activation

PLASMA PROTEIN–DERIVED

Complement products (C5a, C3a, C4a)

Plasma (produced in liver)

Leukocyte chemotaxis and activation, vasodilation (mast cell stimulation)

Increased vascular permeability, smooth muscle contraction, vasodilation, pain

Endothelial activation, leukocyte recruitment

Kinins Plasma (produced in liver)

Proteases activated during coagulation

Plasma (produced in liver)

IL-1, interleukin-1; MAC, membrane attack complex; TNF, tumor necrosis factor

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014Properties and General Principles of Mediator Production and Action

1. Generated either from cells or from plasma proteinsa. sequestered in intracellular granulesb. rapidly secreted by granule exocytosisc. synthesized de novo in response to a stimulusd. Produced by:

i. Plateletsii. Neutrophils

iii. monocytes/macrophagesiv. mast cells v. endothelium

vi. smooth musclevii. fibroblasts

viii. Liver:1. Plasma-derived mediators2. present in the circulation as inactive precursors (must be activated)

2. Active mediators are produced in response to various stimuliStimuli include:

i. microbial productsii. substances released from necrotic cells

iii. proteins of the complement, kinin, and coagulation systems3. One mediator can stimulate the release of other mediators

a. cytokine TNF acts on endothelial cells -> stimulate the production of another cytokine, IL-1, and many chemokines

b. provide mechanisms for amplifying or counteracting—the initial action of a mediator4. Mediators vary in their range of cellular targets5. Once activated and released from the cell, most of these mediators are short-lived

Cell-Derived Mediators1. Vasoactive Amines

a. important actions on blood vesselsb. stored as preformed molecules in cellsc. first mediators to be released during inflammationd. Histamine

i. richest sources: mast cells; also in blood basophils and plateletsii. present in mast cell granules

iii. released by mast cell degranulationiv. in response to a variety of stimuli

1. physical injury such as trauma, cold or heat2. binding of antibodies to mast cells (allergic reactions)3. anaphylatoxins (C3a and C5a)4. histamine-releasing proteins derived from leukocytes5. neuropeptides (substance P)6. cytokines (IL-1, IL-8)

v. causes dilation of arterioles and increases the permeability of venules

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014e. Serotonin (5-hydroxytryptamine)

i. preformed vasoactive mediatorii. actions similar to histamine

iii. present in platelets and certain neuroendocrine cells (GIT)iv. Release of serotonin from platelets <- stimulated when platelets aggregate after contact with

collagen, thrombin, adenosine diphosphate, and antigenantibody complexesv. increased vascular permeability

2. Arachidonic Acid (AA) Metabolitesa. 20-carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid)b. derived from:

i. dietary sourcesii. conversion from the essential fatty acid linoleic acid

c. normally esterified in membrane phospholipidsd. Prostaglandins (PGs)

i. produced by: 1. mast cells2. macrophages3. endothelial cells

ii. produced by the actions of two cyclooxygenases (COX-1 and COX-2)iii. important PGs in inflammation:

1. PGE2

2. PGD2

3. PGF2α

4. PGI2 (prostacyclin)5. TxA2 (thromboxane)

e. Leukotrienesi. lipoxygenase enzymes - responsible for production

ii. secreted mainly by leukocytesiii. chemoattractants for leukocytesiv. have vascular effectsv. Types:

1. 5-lipoxygenase a. predominant in neutrophilsb. converts AA to 5-hydroxyeicosatetraenoic acidc. chemotactic for neutrophils d. precursor of the leukotrienes

2. LTB4

a. potent chemotactic agent and activator of neutrophilsb. effects:

i. aggregation and adhesion of the cells to venular endotheliumii. generation of ROS

iii. release of lysosomal enzymes3. cysteinylcontaining leukotrienes C4, D4, and E4 (LTC4, LTD4, LTE4)

a. intense vasoconstriction b. bronchospasm (important in asthma)c. increased vascular permeability

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014f. Lipoxins

i. generated from AA by the lipoxygenase pathwayii. inhibitors of inflammation

iii. neutrophils produce intermediates in lipoxin synthesisiv. inhibit:

1. leukocyte recruitment and cellular components of inflammation2. neutrophil chemotaxis and adhesion to endothelium

Anti-inflammatory drugs:Cyclooxygenase inhibitors - inhibit both COX-1 and COX-2 (inhibit prostaglandin synthesis)

Aspirin Nonsteroidal anti-inflammatory drugs (NSAIDs) – indomethacin

o Lipoxygenase inhibitors inhibit leukotriene production - Zileuton block leukotriene receptors – Montelukast

o Broad-spectrum inhibitors – corticosteroids act by reducing the transcription of genes encoding COX-2, phospholipase A2, pro-

inflammatory cytokines (such as IL-1 and TNF), and iNOS3. Platelet-Activating Factor (PAF)

a. phospholipid-derived mediatorb. causes platelet aggregationc. multiple inflammatory effectsd. produced by: (in both secreted and cell-bound form)

i. platelets ii. basophils

iii. mast cellsiv. neutrophilsv. macrophages

vi. endothelial cellse. causes:

i. vasoconstriction ii. bronchoconstriction

iii. increased leukocyte adhesion to endothelium (by enhancing integrin-mediated leukocyte binding)

iv. chemotaxisv. degranulation

vi. oxidative burstf. extremely low concentrations -> causes vasodilation and increased venular permeabilityg. PAF elicit most of vascular and cellular reactions of inflammationh. boosts the synthesis of other mediators (eicosanoids)

4. Reactive Oxygen Speciesa. production is dependent on the activation of the NADPH oxidase systemb. increase the expression of chemokines, cytokines and endothelial leukocyte adhesion molecules ->

amplifying the inflammatory response

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 20145. Nitric Oxide (NO)

a. released from endothelial cellsb. endothelium -derived relaxing factorc. synthesized from L-arginine by the enzyme nitric oxide synthase (NOS)d. three different types of NOS:

i. endothelial (eNOS)ii. neuronal (nNOS)

iii. inducible (iNOS)e. relaxes vascular smooth muscle and promotes vasodilationf. inhibitor of:

i. cellular component of inflammatory responsesii. platelet aggregation and adhesion

iii. several features of mast cell–induced inflammationiv. leukocyte recruitment

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 20146. Cytokines

Cytokine Principal Sources Principal Actions in Inflammation

IN ACUTE INFLAMMATION

TNF Macrophages, mast cells, T lymphocytes Stimulates expression of endothelial adhesion molecules and secretion of other cytokines; systemic effects

IL-1 Macrophages, endothelial cells, some epithelial cells

Similar to TNF; greater role in fever

IL-6 Macrophages, other cells Systemic effects (acute-phase response)

Chemokines Macrophages, endothelial cells, T lymphocytes, mast cells, other cell types

Recruitment of leukocytes to sites of inflammation; migration of cells to normal tissues

IN CHRONIC INFLAMMATION

IL-12 Dendritic cells, macrophages Increased production of IFN-γ

IFN-γ T lymphocytes, NK cells Activation of macrophages (increased ability to kill microbes and tumor cells)

IL-17 T lymphocytes Recruitment of neutrophils and monocytes

IFN-γ, interferon-γ; IL-1, interleukin-1; NK cells, natural killer cells; TNF, tumor necrosis factor.

7. Chemokinesa. family of small (8 to 10 kD) proteinsb. chemoattractants for specific types of leukocytesc. four major groups (according to the arrangement of the conserved cysteine (C) residues in the mature

proteins):i. C-X-C chemokines (α chemokines)

1. act primarily on neutrophils2. secreted by activated macrophages, endothelial cells, and other cell types3. causes activation and chemotaxis of neutrophils

ii. C-C chemokines (β chemokines)1. Include:

a. monocyte chemoattractant protein (MCP-1)b. eotaxinc. macrophage inflammatory protein-1α (MIP-1α)d. RANTES (regulated and normal T-cell expressed and secreted)e. attract monocytes, eosinophils, basophils, and lymphocytes

iii. C chemokines (γ chemokines) - specific for lymphocytesiv. CX3C chemokines

1. Fractalkine2. exists in two forms:

a. the cell surface-bound proteini. can be induced on endothelial cells by inflammatory cytokines

ii. promotes strong adhesion of monocytes and T cellsb. soluble form

i. derived by proteolysis of the membrane-bound proteinii. has potent chemoattractant activity for monocytes and T cells

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014d. two main function:

i. they stimulate leukocyte recruitment in inflammation ii. control the normal migration of cells through various tissues

8. Neuropeptidesa. secreted by sensory nerves and various leukocytesb. initiation and propagation of an inflammatory response

Plasma-Protein Derived Mediators1. Complement System

a. consists of more than 20 proteinsb. functions in both innate and adaptive immunity for defense against microbial pathogensc. causes:

i. increased vascular permeabilityii. chemotaxis

iii. opsonizationd. Pathways:

i. classical pathway- triggered by fixation of C1 to antibody (IgM or IgG)

ii. alternative pathwayTriggered by: (in the absence of antibody)

o microbial surface molecules (eg. endotoxin, or LPS)o complex polysaccharideso cobra venomo and other substances

iii. lectin pathway - plasma mannose-binding lectin binds to carbohydrates on microbes and

directly activates C1e. Functions:

i. Inflammationii. Phagocytosis

iii. Cell lysisf. tightly controlled by cell-associated and circulating regulatory proteins

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 20142. Coagulation and Kinin Systems

a. Bradykinin, C3a, and C5a - mediators of increased vascular permeabilityb. C5a - mediator of chemotaxisc. Thrombin - has effects on endothelial cells and many other cell typesd. C3a and C5a can be generated by several types of reactions:

i. immunologic reactions - involving antibodies and complement (the classical pathway)ii. activation of alternative and lectin complement pathways by microbes (absence of antibodies)

iii. agents not directly related to immune responses:1. plasmin2. kallikrein3. serine proteases

e. Activated Hageman factor (factor XIIa) initiates four systems involved in the inflammatory response:i. kinin system - produces vasoactive kinins

ii. clotting system 1. induces formation of thrombin2. has inflammatory properties

iii. fibrinolytic system - induce inflammation1. produces plasmin 2. degrades fibrin to produce fibrinopeptides

iv. complement system1. produces anaphylatoxins and other mediators2. kallikrein by feedback -> activate Hageman factor (amplification of the reaction)

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014Role of Mediators in Different Reactions of InflammationRole in Inflammation Mediators

Vasodilation Prostaglandins

Nitric oxide

Histamine

Increased vascular permeability Histamine and serotonin

C3a and C5a (by liberating vasoactive amines from mast cells, other cells)

Bradykinin

Leukotrienes C4, D4, E4

PAF

Substance P

Chemotaxis, leukocyte recruitment and activation

TNF, IL-1

Chemokines

C3a, C5a

Leukotriene B4

(Bacterial products, e.g., N-formyl methyl peptides)

Fever IL-1, TNF

Prostaglandins

Pain Prostaglandins

Bradykinin

Tissue damage Lysosomal enzymes of leukocytes

Reactive oxygen species

Nitric oxide

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014

OUTCOMES OF ACUTE INFLAMMATION

1. Complete resolution - restoration of the site of acute inflammation to normal; injury is limited or short-lived2. Healing by connective tissue replacement (fibrosis) - involves tissues that are incapable of regeneration;

connective tissue grows into the area of damage or exudate, converting it into a mass of fibrous tissue (Organization)

3. Progression to chronic inflammation

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION

1. Serous inflammation a. outpouring of a thin fluid that may be derived from:

i. plasma ii. secretions of mesothelial cells

b. usually in:i. peritoneal cavities

ii. pleural cavitiesiii. pericardial cavities

c. accumulation of fluid in these cavities -> effusiond. skin blister <- from a burn or viral infection : large accumulation of serous fluid

2. Fibrinous inflammationa. fibrinogen pass the vascular barrierb. fibrinous exudate development

i. characteristic of inflammation in the lining of body cavities1. meninges2. pericardium 3. pleura

ii. removed by: 1. fibrinolysis 2. clearing of debris by macrophages

c. fibrin appearance: (histologically)i. eosinophilic meshwork of threads

ii. amorphous coagulum3. Suppurative or Purulent Inflammation: Abscess

a. production of large amounts of pus or purulent exudatei. Consisting of:

1. Neutrophils2. liquefactive necrosis3. edema fluid

b. pyogenic (pus-producing) bacteria – staphylococcic. eg. acute appendicitisd. Abscesses

i. localized collections of purulent inflammatory tissueii. caused by suppuration buried in a tissue, an organ, or a confined space

iii. produced by deep seeding of pyogenic bacteria into a tissueiv. central region

1. mass of necrotic leukocytes and tissue cells2. zone of preserved neutrophils around

v. vascular dilation occurvi. parenchymal and fibroblastic proliferation occur

vii. indicates chronic inflammation and repair

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014

4. Ulcera. local defect, or excavation, of surface of an organ or tissueb. produced by the sloughing (shedding) of inflamed necrotic tissuec. tissue necrosis and resultant inflammation exist on or near a surfaced. most commonly encountered in:

i. mucosa of the mouth, stomach, intestines, or genitourinary tractii. skin and subcutaneous tissue of lower extremities (older persons who have circulatory

disturbances that predispose to extensive ischemic necrosis)

CHRONIC INFLAMMATION

1. Causes of Chronic Inflammationa. Persistent infections

i. microorganisms that are difficult to eradicate1. mycobacteria2. viruses3. fungi4. parasites

ii. delayed-type hypersensitivityiii. granulomatous reaction - specific pattern of inflammatory response

b. Immune-mediated inflammatory diseasesi. caused by excessive and inappropriate activation of immune system

ii. autoimmune diseases - immune reactions develop against own tissues1. rheumatoid arthritis2. multiple sclerosis

iii. unregulated immune responses against microbes - inflammatory bowel diseaseiv. Immune responses against common environmental substances - allergic diseases(bronchial

asthma)c. Prolonged exposure to potentially toxic agents either:

i. exogenous - inflammatory lung disease; Silicosis- silica inhaled for prolonged periods ii. endogenous – Atherosclerosis - chronic inflammatory process in arterial wall by endogenous

toxic plasma lipid components2. Morphologic features

a. Infiltration with mononuclear cellsi. Macrophages

ii. Lymphocytesiii. Plasma cells

b. Tissue destruction - induced by the persistent offending agent or by the inflammatory cellsc. Attempts at healing by connective tissue replacement of damaged tissue

i. Angiogenesis - proliferation of small blood vesselsii. Fibrosis

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 20143. Role of Macrophages in Chronic Inflammation

a. Macrophagesi. one component of mononuclear phagocyte system/reticuloendothelial system

ii. cells of bone marrow origin1. blood monocytes 2. tissue macrophages

a. liver (Kupffer cells)b. spleen and lymph nodes (sinus histiocytes)c. lungs (alveolar macrophages)d. central nervous system (microglia)

b. Extravasation of monocytes i. governed by the same factors that are involved in neutrophil emigration

1. adhesion molecules 2. chemical mediators with chemotactic and activating properties

ii. monocyte -> macrophage (upon reaching extravascular tissue)iii. activated by a variety of stimuli

1. microbial products that engage TLRs2. cellular receptors3. cytokines (eg. IFN-γ) secreted by:

a. sensitized T lymphocytesb. natural killer cells

4. chemical mediators

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014

iv. products of activated macrophages1. eliminate injurious agents such as microbes2. nitiate the process of repair3. responsible for tissue injury in chronic inflammation

v. Activation of macrophages increase levels of:1. lysosomal enzymes 2. reactive oxygen and nitrogen species3. production of cytokines4. growth factors5. mediators of inflammation

4. Other cell types involved in Chronic Inflammationa. Lymphocytes

i. mobilized in both antibody-mediated and cell-mediated immune reactionsii. Antigen-stimulated (effector and memory) lymphocytes of different types (T and B cells)

b. Plasma cellsi. develop from activated B lymphocytes

ii. produce antibodies directed against persistent foreign or self antigensiii. tertiary lymphoid organs

- lymphoid organogenesis (patients with long-standing rheumatoid arthritis)

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014c. Eosinophils

i. abundant in immune reactions mediated by IgE and in parasitic infectionsii. eotaxin - chemokine important for eosinophil recruitment

d. Mast cells i. widely distributed in connective tissues

ii. participate in both acute and chronic inflammatory reactionsiii. occurs during:

1. allergic reactions to foods2. insect venom3. drugs4. anaphylactic shock

iv. ability to both promote and limit inflammatory reactions in different situations

5. Granulomatous Inflammationa. distinctive pattern of chronic inflammationb. Immune reactions are usually involved in the development of granulomasc. granuloma -> cellular attempt to contain an offending agent that is difficult to eradicate

i. strong activation of T lymphocytes leading to macrophage activationii. can cause injury to normal tissues

d. microscopic aggregation of macrophages -> transformed into epithelium-like cellsi. surrounded by a collar of mononuclear leukocytes

ii. principally lymphocytesiii. occasionally plasma cells

e. Older granulomas develop an enclosing rim of fibroblasts and connective tissuef. epithelioid cells fuse -> form giant cells

i. periphery ii. center of granulomas

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014Giant Cells:

1. Langhans-type giant cell – peripheral 2. Foreign body–type giant cell – haphazard

g. 2 types:i. Foreign body granulomas

ii. Immune granulomas

Examples of Diseases with Granulomatous InflammationDisease Cause Tissue Reaction

Tuberculosis Mycobacterium tuberculosis

Caseating granuloma (tubercle): focus of activated macrophages (epithelioid cells), rimmed by fibroblasts, lymphocytes, histiocytes, occasional Langhans giant cells; central necrosis with amorphous granular debris; acid-fast bacilli

Leprosy Mycobacterium leprae Acid-fast bacilli in macrophages; noncaseating granulomas

Syphilis Treponema pallidum Gumma: microscopic to grossly visible lesion, enclosing wall of histiocytes; plasma cell infiltrate; central cells necrotic without loss of cellular outline

Cat-scratch disease Gram-negative bacillus Rounded or stellate granuloma containing central granular debris and recognizable neutrophils; giant cells uncommon

Sarcoidosis Unknown etiology Noncaseating granulomas with abundant activated macrophages

Crohn disease (inflammatory bowel disease)

Immune reaction against intestinal bacteria, self-antigens

Occasional noncaseating granulomas in the wall of the intestine, with dense chronic inflammatory infiltrate

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 2014SYSTEMIC EFFECTS OF INFLAMMATION

1. Fevera. elevation of body temperature ( 1° - 4°C)b. manifestations of acute-phase responsec. in response to pyrogens

i. act by stimulating prostaglandin synthesis in the vascular and perivascular cells of the hypothalamus

ii. exogenous pyrogens - bacterial productsiii. endogenous pyrogens - cytokines such as IL-1 and TNFiv. increase the enzymes (cyclooxygenases) that convert AA into prostaglandinsv. prostaglandins (PGE2)in hypothalamus -> stimulate production of neurotransmitters (cyclic

adenosine monophosphate) - function to reset the temperature set point at a higher levelvi. NSAIDs (aspirin) reduce fever by inhibiting prostaglandin synthesis

2. Acute-phase proteinsa. C-reactive protein (CRP)

i. opsonins and fix complementii. Elevated serum levels of CRP - marker for increased risk of myocardial infarction in patients with

coronary artery diseaseb. Fibrinogen

i. binds to red cells and causes them to form stacksii. basis for measuring the erythrocyte sedimentation rate - simple test for the systemic

inflammatory responsec. Serum amyloid A (SAA) protein

i. opsonins and fix complementii. replaces apolipoprotein A

iii. alter the targeting of high-density lipoproteins from liver cells to macrophagesiv. source of energy-producing lipidsv. causes secondary amyloidosis

3. Leukocytosisa. leukocyte count climbs to 15,000 or 20,000 cells/μL b. high levels of 40,000 to 100,000 cells/μL - extreme elevations (leukemoid reaction)c. neutrophilia - increase in the blood neutrophil countd. lymphocytosis - viral infections; increase in the number of lymphocytese. eosinophilia - bronchial asthma, allergy, and parasitic infestations; inc. eosinophilsf. leukopenia - decreased number of circulating white cells (typhoid fever and infections caused by some

viruses, rickettsiae, and certain protozoa)

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Pathology - Inflammation Chapter 2 Summary – Robbins and Cotran 8th ed. CPU MD 20144. Manifestations:

a. increased pulse and blood pressureb. decreased sweating (redirection of blood flow from cutaneous to deep vascular beds)c. rigors (shivering)d. chills (search for warmth)e. anorexiaf. somnolenceg. malaise

5. In severe bacterial infections (sepsis) - septic shock; high levels of cytokinesa. disseminated intravascular coagulationb. cardiovascular failurec. metabolic disturbance

CONSEQUENCES OF DEFECTIVE OR EXCESSIVE INFLAMMATION

1. Defective inflammationa. results in increased susceptibility to infectionsb. associated with delayed wound healing

2. Excessive inflammationa. unregulated immune responses against common environmental antigens – Allergyb. immune responses develop against normally tolerated self-antigens – Autoimmune Diseases

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