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General Pathology VDMP832 > Acute Inflammation - Mediators > Flashcards

Acute Inflammation - Mediators Flashcards

1
Q

Mediators of Inflammtion

A
  • Wide variety of chemical substances are necessary to regulate the inflammatory response
  • Potent once activated and their activity must be closely regulated
    • rapidly decay
    • Enymatically destroyed
    • Scavenged or blocked by inhibitors
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2
Q

Mediators of Inflammation:

Plasma-derived mediators

A
  • Produced mainly in the liver and circulate in the blood as inactive precursors
  • Common Mediators Include:
    • Hageman Factor pathways
    • Kinins
    • Plasmin
    • Complement
    • Inflammatory inhibitors
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3
Q

Mediators of Inflammation:

Cell-derived mediators

A
  • Preformed and stored in granules
  • Produced and released upon cell activation
    • release and effects tend to be localized
  • Common mediators include:
    • Vasoactive amines
    • Membrane lipid products
      • arachidonic acid metabolites
      • Platelet activating factor
    • Oxygen metabolites
    • Cytokines
    • Lysosomal enzymes products
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4
Q

Hageman Factor pathway

A
  • Hageman Factor (Factor 12) is best known as the initator of intrinsic coagulation
    • result is the formation of fibrin
  • Activated factro 12, also:
    • Activates kinin pathway
    • Activation of plasminogen
    • Activation of complement
      • cleaves C3 and C5
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5
Q

Kinins

A
  • Two pathways of formation
    • plasma kinin pathway
    • Tissue kinin pathway
  • The end product of both pathways is bradykinin
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6
Q

Plasma Kinin Pathway

A
  • Pathway associatted with hageman Factor Activation
    • Initiated by factor 12 interaction with HMWK/factor 11/perkallikrein complex
  • Bradykinin is derived from the cleavage of HMWK by kallikrein
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7
Q

Tissue Kinin Pathway

A
  • Initiated by LMWK cleavage by tissue kallikreins
    • LMWK is produced by many different tissues and secreted in conjuction with a tissue kallikrein
  • Sources of LMWK/tissue kallikrein include:
    • Salivary gland, prostate, pancreas, lymph node, mast cells/basophils, complement fragment
  • LMWK is cleaved into kallidin which is subsequently convereted into Bradykinin
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8
Q

Bradykinin:

Activities

A
  • Increased vascular permeability:
    • Vascular effects are mediated by binding bradykinin B1 receptor which is expressed by normal tissue
  • Vasodilation
  • Extravascular Smooth Muscle Contraction
  • Pain:
    • mediated by binding bradykinin B2 receptor which is expressed in injured tissue
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9
Q

Bradykinin:

Inactivated by

A

Kinases

Angiotensin converting enzyme from endothelium

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10
Q

Plasmin:

Derived From

A

the cleavage of plasminogen

Mediated by various enzymes including:

Tissue plasminogen Activator

Urokinase

Kallikrein

Factro 12a

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11
Q

Plasmin:

Major Functions:

A
  • Fibrinolysis
    • fibrin degradation products are the result
      • These can increase vascular permeability and are chemotactic for neutrophils
  • Activation of Factor 12
  • Complement system activation
    • directly cleaves C3 to C3a
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12
Q

Complement

A

Activation generates a wide variety of biologically active products:

Activation occurs in a cascade by several different pathways:

Classical

Alternate

Mannose-binding lectin

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13
Q

Complement:

Classical Pathway

A

Initiated by immune complexes

  • Initiaged by antibody complexes
    • IgG and or IgM crosslinking ant activates C1
  • Classical 3 convertase
    • formed by binding C4 and C2
    • Cleaves C3 to C3a and C3b
  • Classical 5 convertase
    • formed by C4b2a binding C3b
    • cleaves C5 to C5a and C5b
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14
Q

Complement:

Alternate Pathway

A

Can be activated by bacterial and fungal cell walls, parasites, some tumor cell membranes, and activatied plasma proteins

  • Initiated by C3 cleavage by mycrobial products
    • also activated by kinin, factor 12a, plasmin, and kallikrein cleavage of C3
  • Alternate C3 convertase
    • formed by binding C3b and factor B
    • Cleaves C3 to form C3a and C3b
  • Alternate C5 Convertase
    • Formed by C3bBb binding additional C3b
    • cleaves C5 to C5a and C5b
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15
Q

Complement:

Mannose-Binding Lectin (MBL) Pathway

A

Activaed by binding MBL to mannose on bacterial surfaces

  • Initiated by microbial products that bind MBL
    • forms MBL-associated serine proteases that cleave C4 and C2
  • Classical C3 convertase is formed
    • C4b2a
  • All bu the initiation is the same as the classical pathway
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16
Q

Complement:

Terminal Pathway

A
  • Initiated by cleaving C5 to C5a and C5b
    • Mediated by classical or alternate C5 convertase
  • C5b anchors formation of hte MAC that inserts into lipid membranes
  • MAC forms an hole in the membrane resulting in osmotic lysis of hte cell or bacteria
17
Q

Complement:

Why is it Imporant?

A
  • Activated with or without prior exposure to the agent
    • There are multiple pathways for activation
  • Functions of complement fragments
    • C3a and C5a increase vascular permeability
    • C3b and C5a stimulate neutrophil degranulation
    • C3b is an opsonin and enhances platelet aggregation
    • C5a and C5b67 are chemotactic for various leukocytes
    • C5b6789 destroys bacterial and cell membranes
18
Q

Inflammatory Inhibitors

A

It is critical to inactivate inflammatory mediators before their activity becomes excessive or detrimental

  • Alpha-2 macroglobulin
    • A large family of protease inhibitors
      • inhibit plasmin, kallikrein, thrombin
  • Kininases
    • enzymes that phosphorylate proteins to alter their function
  • Alpha-1 antitrypsin
    • protease inhibitor of the serpin family
      • Inhibits many serine proteases
19
Q

Cell-derived mediators or Inflammation

A
  • Vasoactive amines
  • Membrane Lipid Products
    • Arachidonic Acid metabolites
    • Platelet Activating factor
  • Oxygen metabolites
  • Cytokines
  • Lysosomal enzyme products
20
Q

Vasoactive Amines

A
  • Histamine and Serotonin:
    • Serotonin is most important in rodents
      • located in rodent mast cells and mammalian platelets
  • These are formed and stored in the granules of mast cells, basophils, and platelets
  • The are released by stimuli:
    • Allergic IgE reactions
    • Cold Temperature
    • C3a and C5a
    • Cytokines
    • Substance P
21
Q

Vasoactive Amines:

Biological Effects

A

Vasodilation

Increased Vascular permeability

Smooth muscle constriction (Airway)

Eosinophil chemotaxis

Pain

Itching

22
Q

Arachidonic Acid Metabolites

A
  • Arachidonic Acid (AA) is a polyunsaturated fatty acid component fo cell membrane phospholipids
    • Mainly present in endothelium, leukocytes, and platelet membranes
  • Degradation of AA by phospholipase A2 results in numerous products with potent biological effects
    • degradation can be initiated by:
      • inflammatory stimuli
      • Substances involved in hemostasis
      • Endocrine stimulation
      • Mechanical and Physical Factors
23
Q

Arachidonic Acid Metabolites:

Cyclooxygenase (COX) Pathway

A
  • Present in many different cells
  • Three isoenzymes control the pathway
    • COX-1
      • constitutively expressed in nearly all tissues
    • COX-2
      • expressed following inflammatory stimuli
    • COX-3
      • A variant of COX-1 present mainly in the cerebrum
  • These produces an intermediate prostaglandin, PGH2
24
Q

Arachidonic Acid Metabolites:

COX pathway:

Intermediate PGH2

A
  • Intermediate converted to at least 5 end products by specific synthases
    • PGD2:
      • Allergy/ Vasodilation
      • Mast cells
    • PGF2:
      • Vasoconstriction, muscle contraction
      • Endothelium, epithelium
    • PGE2
      • Fecer, Vasodilation / increased permeability
      • Endothelium, Epithelium, Fibroblasts, Leukocytes
    • PGI2:
      • Vasodilation and Anti-platelet
      • Endothelium
    • TXA2:
      • Vasoconstriction and pro-platelet
      • Platelets
25
Q

Arachodonic Acid Metabolites:

Lipoxygenase (LOX) Pathway

A
  • Present in leukocytes
  • 5-lipoxygenase and 5-lipoxygenase-activating protein control the pathway
    • form the complex 5-HPETE
      • HPETE and HETE are chemotactic for leukocytes
  • This produces an intermediate leukotriene, LTA4
26
Q

Arachidonic Acid Metabolites:

LOX pathway

LTA4 intermediate

A
  • Products of LTA4:
    • LTB4:
      • chemotaxis, vascular permeability degranulation of neutrophils
      • Neutrophils and macrophages
    • LTC4:
      • Vascular permeability, Vasoconstriction
      • Eosinophils/mast cell, macrophages
    • LTC4, LTD4, LTE4:
      • vasodilation and vascular permeability
      • Macrophages
27
Q

Arachodonic Acid Metabolites:

LOX pathway:

Lipoxins

A
  • Lipoxins are derived from LOX
  • Derived from platelets with contributions of AA from other cells
    • Platelet 12-lipoxygenase + LTA4 form neutrophiles yields Lipoxins A4 and B4
  • Functions:
    • Lipoxins are both pro- and anti- inflammatory and tend to conteract leukotrienes
      • effects seem to be concentration dependent: in some cases stimulating chemotaxis, vascular permeability, and oxygen radical formation, and in other cases having the opposite effects
28
Q

Platelet Activating Factor

A
  • Derived form the activity of phospholipase A2 and acetyltransferase on membrane phospholipids
  • Produced by leukocytes, platelets, and endothelial cells
  • Biological activities include:
    • Vasocondtriction and Vasodilaiton
    • Increased vascular permeability
    • Leukocytes chemotaxis, aggregation and adhesion
    • Platelet Activation
29
Q

Reactive Oxygen Metabolites

A
  • These are normal products or aerobic metabolism
    • concentrations are closely controlled by antioxidants
      • superoxide dismutase and catalase, among many others
  • Produced in high concentration by activated leukocytes, endothelium and platelets
    • Important Mechanism in leukocytes for killing microorganisms
30
Q

Reacitve Oxygen Metabolites:

Effects on Inflammation

A
  • Endothelial Injury and increased permeability
  • Generation of chemotactic substances
  • Activate cytokine secretion
  • Feneration of AA metabolites
  • Inactivation of Anti-inflammatory substances
  • Cell and Tissue Damage
31
Q

Nitric Oxide Metabolites

A
  • Produced by endothelium, Macrophages, and neurons
    • Endothelial NO synthetase is constituitively produced, and contributes to vascular smooth muscle relaxation, vasodilation, and inhibition of platelet adhesion and aggregation
    • Inducible NO synthetase is produced by activated macrophages
  • These have many similarities to oxygen metabolites
    • can oxidize proteins and lipid membranes
32
Q

Nitric Oxide Metabolites:

Effects on Inflammation

A
  • Enhanced vascular effects
  • Inhibition of leukocytes adhesion and chemotaxis
  • Antimicrobial Killing
  • Cell Injury
33
Q

Cytokines

A
  • Soluble proteins produced and secreted by cells
    • include growth factors, chemotactic factors, inflammatory mediators, immunoregulatory factors
    • Produced by endothelium, leukocytes, lymohocytes among others
  • Cytokines produce many ofhte local and systemic effects of inflammations
    • Lymphokines
      • immunoregulatory substances
    • Monokines
      • monocyte/marcophage products
        • interleukin-1
        • Tumor necrosis factor
34
Q

Neuropeptides

A
  • Large group of Proteins released by nerve endings that mediate communication between neurons
  • SOme of these produce inflammatory effects
    • neurogenic inflammation
  • Substance P is one example
    • Produced by nerves, macrophages, and lymphocytes
    • A member of the tachykinin family of neuropeptides
35
Q

Substance P

A
  • Effects on Inflammaiton
    • Vasodilation
    • Increased vascular permeability
    • Leukocyte activation
      • including degranulaion of mast cells and eosinophils
    • Chemotaxis

General Pathology VDMP832 (26 decks)

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