Inflammation

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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

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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
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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

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ACUTE INFLAMMATION

• PROTECTIVE RESPONSE
• NON-specific

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ACUTE INFLAMMATION

• VASCULAR EVENTS
• CELLULAR EVENTS (PMN or PolyMorphonuclear
  Neutrophil, Leukocyte?, POLY, Neutrophil,
  Granulocyte, Neutrophilic Granulocyte
• MEDIATORS

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ACUTE INFLAMMATION
Neutrophil Polymorphonuclear Leukocyte, PMN,
PML Leukocyte Granulocyte, Neutrophilic
granulocyte Poly- Polymorph
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HISTORICAL HIGHLIGHTS (Egypt, 3000 BC)
Rubor Calor Tumor Dolor 5th (functio laesa)
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STIMULI for acute inflammation

• INFECTIOUS
• PHYSICAL
• CHEMICAL
• Tissue Necrosis
• Foreign Bodies (FBs)
• Immune responses, or complexes

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Vascular Changes

• Changes in Vascular Flow and Caliber
• Increased Vascular Permeability

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INCREASED PERMEABILITY

• DILATATION
• Endothelial gaps
• Direct Injury
• Leukocyte Injury
• Transocytosis (endo/exo)
• New Vessels

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LEAKAGE OF PROTEINACEOUS FLUID (EXUDATE, NOT
TRANSUDATE)
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EXTRAVASATION of PMNs

• MARGINATION (PMNs go toward wall)
• ROLLING (tumbling and HEAPING)
• ADHESION
• TRANSMIGRATION (DIAPEDESIS)

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ADHESION MOLECULES(glycoproteins)
affectingADHESION and TRANSMIGRATION

• SECRETINS (from endothelial cells)
• INTEGRINS (from many cells)

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CHEMOTAXIS

• PMNs going to the site of injury
• AFTER transmigration

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LEUKOCYTEACTIVATION

• 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

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PHAGOCYTOSIS

• RECOGNITION
• ENGULFMENT
• KILLING (DEGRADATION/DIGESTION)

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CHEMICAL MEDIATORS

• From plasma or cells
• Have triggering stimuli
• Usually have specific targets
• Can cause a cascade
• Are short lived

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CLASSIC MEDIATORS

• PLATELET ACTIVATING FACTOR (PAF)
• CYTOKINES
• /CHEMOKINES
• LYSOSOME CONSTITUENTS
• FREE RADICALS
• NEUROPEPTIDES

• HISTAMINE
• SEROTONIN
• COMPLEMENT
• KININS
• CLOTTING FACTORS
• EICOSANOIDS
• NITRIC OXIDE

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HISTAMINE

• Mast Cells, basophils
• POWERFUL Vasodilator
• Vasoactive amine
• IgE on mast cell

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SEROTONIN

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

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COMPLEMENT SYSTEM

• gt20 components, in circulating plasma
• Multiple sites of action, but LYSIS is the
  underlying theme

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KININ SYSTEM

• BRADYKININ is KEY component, 9 aas
• ALSO from circulating plasma
• ACTIONS
• Increased permeability
• Smooth muscle contraction, NON vascular
• PAIN

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CLOTTING FACTORS

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

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EICOSANOIDS(ARACHIDONIC ACID DERIVATIVES)

• Part of cell membranes
• 1) Prostaglandins (incl. Thromboxanes)
• 2) Leukotrienes
• 3) Lipoxins (new)

MULTIPLE ACTIONS AT MANY LEVELS
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Prostaglandins(thromboxanes included)

• Pain
• Fever
• Clotting

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Leukotrienes

• Chemotaxis
• Vasoconstriction
• Increased Permeability

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Lipoxins

• INHIBIT chemotaxis
• Vasodilatation
• Counteract actions of leukotrienes

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Platelet-Activating Factor(PAF)

• Phospholipid
• From MANY cells, like eicosanoids
• ACTIVATE PLATELETS, powerfully

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CYTOKINES/CHEMOKINES

• CYTOKINES are PROTEINS produced by MANY cells,
  but usually LYMPHOCYTES and MACROPHAGES, numerous
  roles in acute and chronic inflammation
• TNFa, IL-1, by macrophages
• CHEMOKINES are small proteins which are
  attractants for PMNs (gt40)

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NITRIC OXIDE

• Potent vasodilator
• Produced from the action of nitric oxide
  synthetase from arginine

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LYSOSOMAL CONSTITUENTS

• PRIMARY
• Also called AZUROPHILIC, or NON-specific
• Myeloperoxidase
• Lysozyme (Bact.)
• Acid Hydrolases

• SECONDARY
• Also called SPECIFIC
• Lactoferrin
• Lysozyme
• Alkaline Phosphatase
• Collagenase

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FREE RADICALS

• O2 (SUPEROXIDE)
• H2O2 (PEROXIDE)
• OH- (HYDROXYL RADICAL)
• VERY VERY DESTRUCTIVE

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NEUROPEPTIDES

• Produced in CNS (neurons)
• SUBSTANCE P
• NEUROKININ A

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OUTCOMES OFACUTE INFLAMMATION

• 1) 100 complete RESOLUTION
• 2) SCAR
• 3)CHRONIC inflammation

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Morphologic PATTERNSof Acute INFLAMMATION(EXUDAT
E)

• Serous (watery)
• Fibrinous (hemorrhagic, rich in FIBRIN)
• Suppurative (PUS)
• Ulcerative

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BLISTER, Watery, i.e., SEROUS
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FIBRINOUS
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PUS PURULENT
ABSCESS POCKET OF PUS
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PURULENT, FIBRINOPURULENT
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ULCERATIVE
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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

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CHRONIC INFLAMMATION (MONOS)
MONOCYTE MACROPHAGE HISTIOCYTE
LYMPHOCYTE
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CAUSES ofCHRONIC INFLAMMATION

• 1) PERSISTENCE of Infection
• 2) PROLONGED EXPOSURE to insult
• 3) AUTO-IMMUNITY

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Cellular Players

• LYMPHOCYTES
• MACROPHAGES (aka, HISTIOCYTES)
• PLASMA CELLS
• EOSINOPHILS
• MAST CELLS

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MORPHOLOGY

• INFILTRATION
• TISSUE DESTRUCTION
• HEALING

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GRANULOMASGRANULOMATOUS INFLAMMATION
4 COMPONENTS FIBROBLASTS LYMPHS HISTIOS GIANT
CELLS
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GRANULOMASGRANULOMATOUS INFLAMMATION
CASEATING (TB) NON-CASEATING
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LYMPHATICDRAINAGE

• SITE? REGIONAL LYMPH NODES

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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(a), IL-1

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