Inflammation

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CHAPTER 2 : 

CHAPTER 2 Inflammation (5 OBJECTIVES) 1) (Concept) Understand the chain, progression, or sequence of vascular and cellular events in the histologic evolution of acute inflammation

Slide 3: 

2) (Rote?) Learn the roles of various “chemical mediators” of acute inflammation 3) Know the three possible outcomes of acute inflammation 4) Visualize the three morphologic patterns of acute inflammation 5) Understand the causes, morphologic patterns, principle cells, minor cells, of chronic and granulomatous inflammation

SEQUENCE OF EVENTS : 

SEQUENCE OF EVENTS NORMAL HISTOLOGY  VASODILATATION  INCREASED VASCULAR PERMEABILITY  LEAKAGE OF EXUDATE  MARGINATION, ROLLING, ADHESION  TRANSMIGRATION (DIAPEDESIS)  CHEMOTAXIS  PMN ACTIVATION  PHAGOCYTOSIS: Recognition, Attachment, Engulfment, Killing (degradation or digestion)  TERMINATION  100% RESOLUTION, SCAR, or CHRONIC INFLAMMATION are the three possible outcomes

ACUTE INFLAMMATION : 

ACUTE INFLAMMATION “PROTECTIVE” RESPONSE NON-specific

ACUTE INFLAMMATION : 

ACUTE INFLAMMATION VASCULAR EVENTS CELLULAR EVENTS (PMN or PolyMorphonuclear Neutrophil, Leukocyte?, “POLY”, Neutrophil, Granulocyte, Neutrophilic Granulocyte “MEDIATORS”

ACUTE INFLAMMATION : 

ACUTE INFLAMMATION Neutrophil Polymorphonuclear Leukocyte, PMN, PML “Leukocyte” Granulocyte, Neutrophilic granulocyte “Poly-” Polymorph

Slide 8: 

Rubor Calor Tumor Dolor 5th (functio laesa) HISTORICAL HIGHLIGHTS (Egypt, 3000 BC)

STIMULI for acute inflammation : 

STIMULI for acute inflammation INFECTIOUS PHYSICAL CHEMICAL Tissue Necrosis Foreign Bodies (FBs) Immune “responses”, or “complexes”

Vascular Changes : 

Vascular Changes Changes in Vascular Flow and Caliber Increased Vascular Permeability

INCREASED PERMEABILITY : 

INCREASED PERMEABILITY DILATATION Endothelial “gaps” Direct Injury Leukocyte Injury Transocytosis (endo/exo) New Vessels

LEAKAGE OF PROTEINACEOUS FLUID (EXUDATE, NOT TRANSUDATE) : 

LEAKAGE OF PROTEINACEOUS FLUID (EXUDATE, NOT TRANSUDATE)

EXTRAVASATION of PMNs : 

EXTRAVASATION of PMNs MARGINATION (PMN’s go toward wall) ROLLING (tumbling and HEAPING) ADHESION TRANSMIGRATION (DIAPEDESIS)

ADHESION MOLECULES(glycoproteins) affectingADHESION and TRANSMIGRATION : 

ADHESION MOLECULES(glycoproteins) affectingADHESION and TRANSMIGRATION SECRETINS (from endothelial cells) INTEGRINS (from many cells)

CHEMOTAXIS : 

CHEMOTAXIS PMNs going to the site of “injury” AFTER transmigration

LEUKOCYTE“ACTIVATION” : 

LEUKOCYTE“ACTIVATION” “triggered” by the offending stimuli for PMNs to: 1) Produce eicosanoids (arachidonic acid derivatives) Prostaglandin (and thromboxanes) Leukotrienes Lipoxins 2) Undergo DEGRANULATION 3) Secrete CYTOKINES

PHAGOCYTOSIS : 

PHAGOCYTOSIS RECOGNITION ENGULFMENT KILLING (DEGRADATION/DIGESTION)

CHEMICAL MEDIATORS : 

CHEMICAL MEDIATORS From plasma or cells Have “triggering” stimuli Usually have specific targets Can cause a “cascade” Are short lived

CLASSIC MEDIATORS : 

CLASSIC MEDIATORS HISTAMINE SEROTONIN COMPLEMENT KININS CLOTTING FACTORS EICOSANOIDS NITRIC OXIDE PLATELET ACTIVATING FACTOR (PAF) CYTOKINES /CHEMOKINES LYSOSOME CONSTITUENTS FREE RADICALS NEUROPEPTIDES

HISTAMINE : 

HISTAMINE Mast Cells, basophils POWERFUL Vasodilator Vasoactive “amine” IgE on mast cell

SEROTONIN : 

SEROTONIN (5HT, 5-Hydroxy-Tryptamine) Platelets and EnteroChromaffin Cells Also vasodilatation, but more indirect Evokes N.O. synthetase (a ligase)

COMPLEMENT SYSTEM : 

COMPLEMENT SYSTEM >20 components, in circulating plasma Multiple sites of action, but LYSIS is the underlying theme

KININ SYSTEM : 

KININ SYSTEM BRADYKININ is KEY component, 9 aa’s ALSO from circulating plasma ACTIONS Increased permeability Smooth muscle contraction, NON vascular PAIN

CLOTTING FACTORS : 

CLOTTING FACTORS Also from circulating plasma Coagulation, i.e., production of fibrin Fibrinolysis

EICOSANOIDS(ARACHIDONIC ACID DERIVATIVES) : 

EICOSANOIDS(ARACHIDONIC ACID DERIVATIVES) Part of cell membranes 1) Prostaglandins (incl. Thromboxanes) 2) Leukotrienes 3) Lipoxins (new) MULTIPLE ACTIONS AT MANY LEVELS

Prostaglandins(thromboxanes included) : 

Prostaglandins(thromboxanes included) Pain Fever Clotting

Leukotrienes : 

Leukotrienes Chemotaxis Vasoconstriction Increased Permeability

Lipoxins : 

Lipoxins INHIBIT chemotaxis Vasodilatation Counteract actions of leukotrienes

Platelet-Activating Factor(PAF) : 

Platelet-Activating Factor(PAF) Phospholipid From MANY cells, like eicosanoids ACTIVATE PLATELETS, powerfully

CYTOKINES/CHEMOKINES : 

CYTOKINES/CHEMOKINES CYTOKINES are PROTEINS produced by MANY cells, but usually LYMPHOCYTES and MACROPHAGES, numerous roles in acute and chronic inflammation TNFα, IL-1, by macrophages CHEMOKINES are small proteins which are attractants for PMNs (>40)

NITRIC OXIDE : 

NITRIC OXIDE Potent vasodilator Produced from the action of nitric oxide synthetase from arginine

LYSOSOMAL CONSTITUENTS : 

LYSOSOMAL CONSTITUENTS PRIMARY Also called AZUROPHILIC, or NON-specific Myeloperoxidase Lysozyme (Bact.) Acid Hydrolases SECONDARY Also called SPECIFIC Lactoferrin Lysozyme Alkaline Phosphatase Collagenase

FREE RADICALS : 

FREE RADICALS O2 – (SUPEROXIDE) H2O2 (PEROXIDE) OH- (HYDROXYL RADICAL) VERY VERY DESTRUCTIVE

NEUROPEPTIDES : 

NEUROPEPTIDES Produced in CNS (neurons) SUBSTANCE P NEUROKININ A

OUTCOMES OFACUTE INFLAMMATION : 

OUTCOMES OFACUTE INFLAMMATION 1) 100% complete RESOLUTION 2) SCAR 3)CHRONIC inflammation

Morphologic PATTERNSof Acute INFLAMMATION(EXUDATE) : 

Morphologic PATTERNSof Acute INFLAMMATION(EXUDATE) Serous (watery) Fibrinous (hemorrhagic, rich in FIBRIN) Suppurative (PUS) Ulcerative

Slide 39: 

BLISTER, “Watery”, i.e., SEROUS

Slide 40: 

FIBRINOUS

Slide 41: 

PUS = PURULENT ABSCESS = POCKET OF PUS

Slide 42: 

PURULENT, FIBRINOPURULENT

Slide 43: 

ULCERATIVE

SEQUENCE OF EVENTS : 

SEQUENCE OF EVENTS NORMAL HISTOLOGY  VASODILATATION  INCREASED VASCULAR PERMEABILITY  LEAKAGE OF EXUDATE  MARGINATION, ROLLING, ADHESION  TRANSMIGRATION (DIAPEDESIS)  CHEMOTAXIS  PMN ACTIVATION  PHAGOCYTOSIS: Recognition, Attachment, Engulfment, Killing (degradation or digestion)  TERMINATION  100% RESOLUTION, SCAR, or CHRONIC inflammation

CHRONIC INFLAMMATION (MONOS) : 

CHRONIC INFLAMMATION (MONOS) LYMPHOCYTE MONOCYTE MACROPHAGE HISTIOCYTE

CAUSES ofCHRONIC INFLAMMATION : 

CAUSES ofCHRONIC INFLAMMATION 1) PERSISTENCE of Infection 2) PROLONGED EXPOSURE to insult 3) AUTO-IMMUNITY

Cellular Players : 

Cellular Players LYMPHOCYTES MACROPHAGES (aka, HISTIOCYTES) PLASMA CELLS EOSINOPHILS MAST CELLS

MORPHOLOGY : 

MORPHOLOGY INFILTRATION TISSUE DESTRUCTION HEALING

GRANULOMASGRANULOMATOUS INFLAMMATION : 

GRANULOMASGRANULOMATOUS INFLAMMATION 4 COMPONENTS FIBROBLASTS LYMPHS HISTIOS “GIANT” CELLS

GRANULOMASGRANULOMATOUS INFLAMMATION : 

GRANULOMASGRANULOMATOUS INFLAMMATION CASEATING (TB) NON-CASEATING

LYMPHATICDRAINAGE : 

LYMPHATICDRAINAGE SITE REGIONAL LYMPH NODES

SYSTEMIC MANIFESTATIONS(NON-SPECIFIC) : 

SYSTEMIC MANIFESTATIONS(NON-SPECIFIC) FEVER, CHILLS C-Reactive Protein (CRP) “Acute Phase” Reactants Erythrocyte Sedimentation Rate (ESR) increases Leukocytosis Pulse, Blood Pressure Cytokine Effects, e.g., TNF(α), IL-1

Slide 53: 

NORMAL SPE Serum Protein Electrophoresis In ACUTE Inflammation Alpha-1 & alpha-2 are increased, i.e., “acute phase” reactants.