InflammationInflammationDr.ROOPADr.ROOPAPremed 3Premed 3

PathophysiologyPathophysiology

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Introduction: Introduction: ““Inflame” – to set fire.Inflame” – to set fire. ““Inflammation is a reaction of a tissue and Inflammation is a reaction of a tissue and

its microcirculation to a pathogenic insult. its microcirculation to a pathogenic insult. It is characterized by the generation of It is characterized by the generation of inflammatory mediators and movement inflammatory mediators and movement of fluid & leukocytes from the blood into of fluid & leukocytes from the blood into extravascular tissues.”extravascular tissues.”

““dynamic response of vascularised tissue dynamic response of vascularised tissue to injury.”to injury.”

Is a protective response.Is a protective response. Serves to bring defense & healing Serves to bring defense & healing

mechanisms to the site of injury.mechanisms to the site of injury.

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Naming of Naming of inflammatory inflammatory

diseases:diseases:[prefix] + ‘itis’[prefix] + ‘itis’

(exceptions exist)(exceptions exist) crohn’s diseasecrohn’s disease

Types of InflammationTypes of Inflammation

Acute Acute

ChronicChronic

Acute InflammationAcute InflammationAcute inflammationAcute inflammation is a rapid response to an is a rapid response to an

injurious agent thatinjurious agent that serves to deliver serves to deliver mediators of host defense—leukocytes and mediators of host defense—leukocytes and plasma proteins—to the site of injury. Acute plasma proteins—to the site of injury. Acute

inflammation has three majorinflammation has three major components: components: (1) (1) alterations in vascular caliber that alterations in vascular caliber that lead to an increase in blood flowlead to an increase in blood flow; (2) ; (2)

structural changes in the structural changes in the microvasculature that permit plasma microvasculature that permit plasma proteins and leukocytes to leave the proteins and leukocytes to leave the circulationcirculation; and (3) ; and (3) emigration of the emigration of the

leukocytesleukocytes from the microcirculation, from the microcirculation, their their accumulationaccumulation in the focus of injury, in the focus of injury, and their and their

activationactivation to eliminate the offending to eliminate the offending agentagent

Acute inflammatory reactions areAcute inflammatory reactions are triggered by a variety of stimuli: triggered by a variety of stimuli:

• • InfectionsInfections (bacterial, viral, parasitic) (bacterial, viral, parasitic) and microbial toxins and microbial toxins

• • TraumaTrauma (blunt and penetrating) (blunt and penetrating) • • Physical and chemical agentsPhysical and chemical agents

(thermal injury, e.g., burns or frostbite; (thermal injury, e.g., burns or frostbite; irradiation; some environmental irradiation; some environmental

chemicals) chemicals) • • Tissue necrosisTissue necrosis (from any cause) (from any cause)

• • Foreign bodiesForeign bodies (splinters, dirt, (splinters, dirt, sutures) sutures)

• • Immune reactionsImmune reactions (also called (also called hypersensitivity reactions) hypersensitivity reactions)

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Acute Vs ChronicAcute Vs Chronic

Flush, Flare & WhealFlush, Flare & Wheal Acute inflammatory Acute inflammatory

cells - Neutrophilscells - Neutrophils Vascular damageVascular damage More exudationMore exudation Little or no fibrosisLittle or no fibrosis

Little signs - Little signs - Fibrosis, Fibrosis,

Chronic Chronic inflammatory cells inflammatory cells – Lymphocytes– Lymphocytes

Neo-Neo-vascularisationvascularisation

No/less exudationNo/less exudation Prominent fibrosisProminent fibrosis

Table 5–1. Differences between Acute and Chronic Inflammation.

  Acute Chronic

Duration Short (days) Long (weeks to months)

Onset Acute Insidious

Specificity Nonspecific Specific (where immune response is activated)

Inflammatory cells Neutrophils, macrophages Lymphocytes, plasma cells, macrophages, fibroblasts

Vascular changes Active vasodilation, increased permeability New vessel formation (granulation tissue)

Fluid exudation and edema + –

Cardinal clinical signs (redness, heat, swelling, pain)

+ –

Tissue necrosis– (Usually) + (Suppurative and necrotizing inflammation)

+ (ongoing)

Fibrosis (collagen deposition) – +

Operative host responses Plasma factors: complement, immunoglobulins, properdin, etc; neutrophils, nonimmune phagocytosis

Immune response, phagocytosis, repair

Systemic manifestations Fever, often high Low–grade fever, weight loss, anemia

Changes in peripheral blood Neutrophil leukocytosis; lymphocytosis (in viral infections) Frequently none; variable leukocyte changes, increased plasma immunoglobulin

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Cardinal Signs of Cardinal Signs of InflammationInflammation RuborRubor : : Redness – Redness –

Hyperaemia.Hyperaemia. CalorCalor : : Warm – Warm –

Hyperaemia.Hyperaemia. DolorDolor : : Pain – Nerve, Pain – Nerve,

Chemical med.Chemical med. TumorTumor:: Swelling – Swelling –

ExudationExudation LossLoss ofof FunctionFunction:: Eg. Eg.

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Heat Redness Swelling Pain Loss Of Func.

The 5 Cardinal Signs of The 5 Cardinal Signs of

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Inflammation - MechanismInflammation - Mechanism

1. Vaso dilatation

2. Exudation - Edema

3. Emigration of cells

4. Chemotaxis

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Mechanism of Inflammation:Mechanism of Inflammation:

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Leukocyte cellular eventsLeukocyte cellular events

Leukocytes leave the vasculature routinely Leukocytes leave the vasculature routinely through the following sequence of events:through the following sequence of events:– Margination and rollingMargination and rolling– Adhesion and transmigrationAdhesion and transmigration– Chemotaxis and activationChemotaxis and activation

They are then free to participate in:They are then free to participate in:– Phagocytosis and degranulationPhagocytosis and degranulation– Leukocyte-induced tissue injuryLeukocyte-induced tissue injury

PRINCIPAL CELL EFFECTORSPRINCIPAL CELL EFFECTORS

11stst 24 hours: NEUTROPHILS 24 hours: NEUTROPHILS Bacterial infections, infarctionBacterial infections, infarction Come from the bone marrow reserve Come from the bone marrow reserve

poolpool Band neutrophils: less mature cellsBand neutrophils: less mature cells

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NeutrophilsNeutrophils

-- the key cell -- the key cell type of the type of the acute acute inflammatorinflammatory responsey response

22ndnd-3-3rdrd day: neutrophils are replaced day: neutrophils are replaced by monocytes-macrophagesby monocytes-macrophages

Tuberculosis, salmonellosisTuberculosis, salmonellosis

EosinophilsEosinophils

Allergic reactionsAllergic reactions Parasitic infectionsParasitic infections Hodgkin lymphomaHodgkin lymphoma

Mast cells and basophilsMast cells and basophils

Chronic myelogenous leukemiaChronic myelogenous leukemia Myeloproliferative diseasesMyeloproliferative diseases histaminehistamine

Cellular response of Cellular response of leukocytesleukocytes

EmigrationEmigrationMarginationMarginationPavementingPavementingRolling/TumblingRolling/TumblingAdhesionAdhesionTransmigrationTransmigration

ChemotaxisChemotaxis PhagocytosisPhagocytosis

OpsonizationOpsonization Intracellular microbial killingIntracellular microbial killing

Oxygen-dependentOxygen-dependentOxygen-independentOxygen-independent

MARGINATIONMARGINATION

THE ENDOTHELIAL CELLS ARE THE ENDOTHELIAL CELLS ARE ACTIVATED, ATTRACT THE SURFACE ACTIVATED, ATTRACT THE SURFACE GLYCOPROTEINS ON NEUTROPHILS GLYCOPROTEINS ON NEUTROPHILS

DIAPEDESISDIAPEDESIS

INSINUATION OF THE INSINUATION OF THE NEUTROPHILS NEUTROPHILS THRU THE THRU THE ENDOTHELIAL CELLSENDOTHELIAL CELLS

BASEMENT MEMBRANEBASEMENT MEMBRANE

EXTRAVASCULAR TISSUESEXTRAVASCULAR TISSUES

CHEMOTAXISCHEMOTAXIS

NEUTROPHIL DIRECT ITS NEUTROPHIL DIRECT ITS MIGRATION TOWARDS THE MIGRATION TOWARDS THE CHEMOATTRACTANTCHEMOATTRACTANT

PHAGOCYTOSISPHAGOCYTOSIS

FORMATION OF PHAGOSOMEFORMATION OF PHAGOSOME

LYSOSOMELYSOSOME

PHAGOLYSOSOMEPHAGOLYSOSOME

Intracellular microbial killing:Intracellular microbial killing:

Oxygen-dependent killing is the Oxygen-dependent killing is the MOST important microbial processMOST important microbial process

Phagocytosis activates HMP shunt Phagocytosis activates HMP shunt

oxidative burstoxidative burst

suppplies electrons to NADPH oxidasesuppplies electrons to NADPH oxidase

superoxide anionsuperoxide anion

Hydrogen peroxideHydrogen peroxide

Hydrogen peroxideHydrogen peroxide

Oxides microbial proteins and Oxides microbial proteins and disrupts cell wallsdisrupts cell walls

Myeloperoxidase-halide system of Myeloperoxidase-halide system of bacterial killingbacterial killing

After killing and eliminating the After killing and eliminating the microbes, the activated leukocytes microbes, the activated leukocytes play other functionsplay other functions

1.Macrophages produce GF(growth 1.Macrophages produce GF(growth factor) that stimulate endothelial cell factor) that stimulate endothelial cell proliferation and fibroblasts.proliferation and fibroblasts.

2.Synthesis of collagen2.Synthesis of collagen 3,Aids in the process of repair.3,Aids in the process of repair.

DEGRANULATIONDEGRANULATION THE TOXIC SUBSTANCES MAY CAUSE THE TOXIC SUBSTANCES MAY CAUSE

LOSS OF FUNCTION (FUNCTIO LAESA)LOSS OF FUNCTION (FUNCTIO LAESA)

INCREASED BLOOD FLOW DUE TO INCREASED BLOOD FLOW DUE TO RELAXATION OF THE TERMINAL RELAXATION OF THE TERMINAL ARTERIOLES ARTERIOLES

RUBOR AND CALORRUBOR AND CALOR

CONTRACTION OF CAPILLARY CONTRACTION OF CAPILLARY ENDOTHELIAL CELLSENDOTHELIAL CELLS

INCREASED VASCULAR INCREASED VASCULAR PERMEABILITYPERMEABILITY

SWELLINGSWELLING

TUMORTUMOR

MILDEST: EXTRAVASATION OF MILDEST: EXTRAVASATION OF WATER, LOW MOLECULAR WEIGHT WATER, LOW MOLECULAR WEIGHT PROTEINSPROTEINS

MODERATE: + HMW(high molecular MODERATE: + HMW(high molecular weight) PROTEINSweight) PROTEINS

SEVERE: + BLOOD CELLSSEVERE: + BLOOD CELLS

MEDIATORS OF ACUTE MEDIATORS OF ACUTE INFLAMMATIONINFLAMMATION

Exogenous:Exogenous:microbial productsmicrobial products

Endogenous:Endogenous:1. vasoactive amines1. vasoactive amines

histaminehistamineserotoninserotonin

2. Arachidonic acid metabolites2. Arachidonic acid metabolitescyclooxygenase pathwaycyclooxygenase pathwaylipooxygenase pathwaylipooxygenase pathway

3. Cytokines3. Cytokines4. Kinin system4. Kinin system5. Complement system5. Complement system

HistamineHistamine

increase capillary permeabilityincrease capillary permeability

contracts postcapillary venulescontracts postcapillary venules Source: basophils, mast cells,plateletsSource: basophils, mast cells,platelets Stimuli:Stimuli:

binding of IgEbinding of IgE

binding of C3a and binding of C3a and C5a:”anaphylotoxins”C5a:”anaphylotoxins”

heat, coldheat, cold

Interleukin-1Interleukin-1

SerotoninSerotonin

5-hydroxytryptamine5-hydroxytryptamine Action: similar to histamineAction: similar to histamine Source: plateletsSource: platelets

Arachidonic acid Arachidonic acid metabolitesmetabolites

Cyclooxygenase Cyclooxygenase pathwaypathway

Enzymes:COX-1,COX-2Enzymes:COX-1,COX-2 Products:Products:

1.1. Platelet TxA2Platelet TxA2

--vasoconstrictor,platelevasoconstrictor,platelet aggregatort aggregator

2. Endothelial prostacyclin2. Endothelial prostacyclin

-vasodilator,inhibits -vasodilator,inhibits platelet aggregationplatelet aggregation

Lipooxygenase Lipooxygenase pathwaypathway

Products: Products: hydroperoxyeicosatetrhydroperoxyeicosatetraenoic acid (HPETE)aenoic acid (HPETE)

5-HPETE5-HPETE

-leukotrienes-leukotrienes

Important leukotrienesImportant leukotrienes

LTB4: chemotactic for neutrophilsLTB4: chemotactic for neutrophils

LTC4,LTD4,LTE4LTC4,LTD4,LTE4““slow reacting substance of slow reacting substance of anaphylaxis”anaphylaxis”vasocontrictionvasocontrictionbronchospasm (bronchcontriction)bronchospasm (bronchcontriction)increase capillary permeabilityincrease capillary permeability

CytokinesCytokines Soluble proteinsSoluble proteins Secreted by numerous cells(monocytes-Secreted by numerous cells(monocytes-

macrphages)macrphages) Act as “effector molecules”Act as “effector molecules” IL-1 and TNFIL-1 and TNF ““acute phase response”acute phase response” Fever, increase WBC: systemicFever, increase WBC: systemic Synthesis of C-reactive proteins, complement Synthesis of C-reactive proteins, complement

components, fibrinogen, prothrombincomponents, fibrinogen, prothrombin Synthesis of adhesion moleculesSynthesis of adhesion molecules Neutrophil degranulationNeutrophil degranulation

Kinin systemKinin system

Formed during active secretion in Formed during active secretion in sweat glands, salivary glands, sweat glands, salivary glands, pancreas, kidneyspancreas, kidneys

End product: bradykininEnd product: bradykinin Actions: vascular permeabilityActions: vascular permeability

arteriolar dilationarteriolar dilation

painpain

Complement systemComplement system

20 Plasma proteins20 Plasma proteins HEPATOCYTES,MACROPHAGES,HEPATOCYTES,MACROPHAGES,GIT GIT

CELLSCELLS

Action: cell lysisAction: cell lysis

COMPLEMENT CASCADECOMPLEMENT CASCADE

classical pathwayclassical pathway

alternative pathwayalternative pathway

OPSONIZE BACTERIAOPSONIZE BACTERIA ACTIVATE PMN, MACROPHAGESACTIVATE PMN, MACROPHAGES REGULATES AB RESPONSEREGULATES AB RESPONSE CLEARS AWAY IMMUNE COMPLEXESCLEARS AWAY IMMUNE COMPLEXES INFLAMMATION, TISSUE DAMAGEINFLAMMATION, TISSUE DAMAGE ANAPHYLAXISANAPHYLAXIS

MAC

Classical pathway vs Classical pathway vs alternative pathwayalternative pathway

Starts with C1 + antigen-antibodyStarts with C1 + antigen-antibody Ends with the membrane attack complexEnds with the membrane attack complex

Bacterial surface Bacterial surface activates the activates the pathwaypathway

Works in the Works in the absence of absence of antibodiesantibodies

Less efficient Less efficient

C3b: opsoninC3b: opsonin C3a and C5a: anaphylotoxinsC3a and C5a: anaphylotoxins C5b-C9: “MAC”C5b-C9: “MAC”

membrane attack complexmembrane attack complex

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Inflammation OutcomeInflammation Outcome

Acute Inflammation

Resolution

Chronic Inflammation

Abscess

SinusFistula

Fibrosis/Scar

Ulcer

Injury

ABSCESSABSCESS

Cavity filled with Cavity filled with puspus

Pus: neutrophils, Pus: neutrophils, monocytes and monocytes and cellular debriscellular debris

Fibrous wallFibrous wall Inaccessible to Inaccessible to

circulationcirculation Bacterial infections, Bacterial infections,

especially especially staphylococcistaphylococci

UlcerUlcer

Involves epithelial surfacesInvolves epithelial surfaces Loss of surface epitheliumLoss of surface epithelium

FistulaFistula

Abnormal communication between 2 Abnormal communication between 2 organs organs

or or

between an organ and a surfacebetween an organ and a surface

ScarScar

Final result of tissue destructionFinal result of tissue destruction Distortion of structureDistortion of structure Altered functionAltered function

Patterns of chronic Patterns of chronic inflammationinflammation

Chronic nonspecific inflammationChronic nonspecific inflammation

Granulomatous inflammationGranulomatous inflammation

Chronic nonspecific Chronic nonspecific inflammationinflammation

Proliferation of fibroblasts and new Proliferation of fibroblasts and new vesselsvessels

Increased macrophages, lymphocytes, Increased macrophages, lymphocytes, plasma cellsplasma cells

Macrophage+antigen B lymphocyte Macrophage+antigen B lymphocyte activation antibody-producing activation antibody-producing plasma cellsplasma cells

Scarring and distortion of tissue Scarring and distortion of tissue architecturearchitecture

Most characteristic: CASEOUS NECROSISMost characteristic: CASEOUS NECROSIS Multinucleated giant cellsMultinucleated giant cells

TB, fungal infections, Syphyllis, cat-scratch TB, fungal infections, Syphyllis, cat-scratch fever, foreign bodiesfever, foreign bodies