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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