General Pathology > Inflammation: Mediators > Flashcards

Inflammation: Mediators Flashcards

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1
Q

What are the Mediators of inflammation?

A
  • Wide variety of chemical substances are necessary to regulate theinflammatory response
  • Mediators are potent once activated
  • Activity must be closely regulated
    • rapidly decay
    • Enzymatically destroyed
    • Scavenged/bloocked by inhibitors
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2
Q

What are the categories of inflammation mediators?

A
  • Plasma-derived mediators
  • Cell-derived mediators
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3
Q

What are Plasma-derived Mediators?

A
  • Produced mainly in the liver
  • Circulates in blood as inactive precursor
  • Ex:
    • Hageman Factor (Factor XII) pathways
    • Kinins
    • Plasmin
    • Complement
    • Inflammation inhibitors
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4
Q

What are Cell-derived Mediators?

A
  • Produced / stored in granules in specific cells
  • Produced & released upon cell activation
    • Effects tend to be localized
  • Ex:
    • Vasoactive amines
    • Membrane lipid products
      • Arachidonic acid metabolites
      • Platelet activating factor (PAF)
    • Oxygen metabolites
    • Cytokines
    • Lysosomal enzyme products
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5
Q

What is Hageman Factor pathwasy?

A
  • Hageman Factor (Factor XII) best known as the initiator of intrinsic coagulation
    • result in formation of fibrin
  • Activated Factor XII:
    • activates Kinin pathways
      • leads to production of bradykinin
    • Activation of plasminogen
      • leads to production of fibrinolytic agents
    • Activation of complement
      • plasmin cleaves C3 and C5
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6
Q

What are the pathways of Kinin formation?

A
  1. Plasma Kinin Pathway
  2. Tissue Kinin Pathway
  • End product is bradykinin
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7
Q

What is the Plasma Kinin Pathway?

A
  • Associated with Hageman factor activation
    • Initiated by Factor XII interaction with HMWK / Factor XI / Prekallikrein complex
  • Bradykinin is derived from the cleavage of HMWK by kallikrein
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8
Q

What is the Tissue Kinin pathway?

A
  • Initiated by LMWK cleavage by tissue kallikreins
    • LMWK poduced by many different tissues andsecreted in conjunction with a tissue kallikrein
    • Source:
      • Salivary gland
      • Prostate
      • Pancrease
      • Lymph nodes
      • Mast cells / basophils
      • Complement fragments
  • LMWK is cleaved into Kallidin which is converted to bradykinin
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9
Q

What are the activities of Bradykinin?

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 bradykinnin B2 receptor which is expressed in injured tissue
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10
Q

How is Bradykinin inactivated?

A
  • Inactivated by kininases
    • Angiotensin converting enzyme (Kininase II) from endothelium
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11
Q

What is Plasmin?

A
  • Derived from the cleavage of plasminogen
    • Mediated by various enzymed:
      • Tissue plasminogen Activator (tPA)
      • urokinase
      • Killikrein
      • Factor XIIa
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12
Q

What are the major functions of Plasmin/

A
  • Fibrinolysis
  • Activation of Factor XII
  • Complemnt System activation
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13
Q

What is Fibrinolysis?

A
  • Fibrin degradation products are the result
    • These products can increase vascular permeability and are chemotactic for neutrophils
  • Deficiency can result in thrombosis
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14
Q

What is Plasmin’s role in Complement system activation?

A
  • Plasmin directly cleaves C3 to C3a
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15
Q

How is the Complement System Activated?

A
  • Activtion occurs in a cascade by several different pathways
    • Classical pathway
    • Alternate pathway
    • Mannose-binding lctin (MBL) pathway
  • Activation generates a wide variety of biolodically active products
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16
Q

What is the Classical Pathway of the Complement System?

A
  • Initiated by antibody complexes
    • IgG and/or IgM crosslinks and activates C1
  • Classical 3 convertase
    • Formed by binding C4 and C2 (C4b2a)
    • This cleaves C3 to form C3a and C3b
  • Classical 5 convertase
    • Formed by C4b2a binding C3b (C4b2a3b)
    • This cleaves C5 to form C5a and C5b
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17
Q

What is the Alternate Pathway of the Complement System?

A
  • Can be activated by bacterial and fungal cell waslls, parasites, some tumor cell membranes, and activated plasma proteins
  • Initiated by C3 cleavage by microbial products (eg: LPS, fungal polysaccharide)
    • Also activated by kinin, factor XIIa, plasmin and kallikrein cleavage of C3
  • Alternate C3 convertase
    • Formed by binding C3b and factor B (C3bBb)
    • This cleaves C3 to form C3a and C3b
  • Alternate C5 convertase
    • Formed by C3bBb binding additional C3b (C3bBb3b)
    • This cleaves C5 to form C5a and C5b
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18
Q

What is the MBL pathway of the Complement system?

A
  • Activated by binding MBL to mannose on bacterial surfaces
    • Forms MBL-associated serine proteases (MASPs) that cleave C4 and 2
  • Classical C3 convertase is formed
    • C2b2a
  • All but the initiation is the ssame as the classical pathway
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19
Q

How do the Complement Pathways end?

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A
  • All converge with the activation of C5 to initiate the terminal pathway
    • ​endpoint of complement activation
    • results in formation of the membrane attack complex (MAC) that destroys biological membranes
      • MAC = C5b6789
20
Q

What is the Terminal Pathway of the Complement System?

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A
  • Initiated by cleaving C5 to C5a and C5b
    • Mediated by classical / alternate C5 convertase
  • C5b anchors formation of the MAC that inserts into lipid membranes
    • C5b6798999…
      • Up to 18 C9 molecules may participate
  • MAC forms a hole in the membrane
    • Osmotic lysis of the cell / bacteria
21
Q

What are the functions of Complement fragments?

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A
  • C3a / C5a increase vascular permeability
  • C3b / C5a stimulate neutrophil degranulation
  • C3b is an opsonin and ehances platelet aggregation
  • C5a / C5b67 are chemotactic for various leukocytes
  • C5b6789 destroys bacterial and cell membranes
22
Q

Is prior exposure needed to activate the Complement System?

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A
  • No, activated with or without prior exposure to the agent
23
Q

What are Inflammatory inhibitors

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A
  • Critical to inactivate inflammatory mediators before their activity becomes excessive or detrimental
  • Ex:
    • Alpha-2 macroglobulin
      • Family of protease inhibitors
        • Inhibit plasmin, kallikrein, thrombin, others
    • Kininases
      • Enzymes that phosphorylate proteins to alter their function
        • Kininases I and II degrade bradykinin
    • Alpha-1 antitrypsin
      • Protease inhibitor of the serpin family
        • inhibits many serine proteases
24
Q

What are the Cell-derived Inflammation Mediatos?

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A
  • Vasoactive amines
  • Membrane lipid products
    • Arachidonic acid metabolites
    • Platelet activating factor (PAF)
  • Oxygen metabolites
  • Cytokines
  • Lysosomal enzyme products
25
What are Vasoactive amines?
* Histamine and serotonin * Formed and stored in the granules of mast cells, basophils, and platelets * Releasd by stimuli: * allergic (IgE) reactions * Cold temps * C3a / C5a * Cytokines (IL-1 and IL-8) * Substance P
26
What species iis serotonin important to?
* Most importat in rodents * Located in rodent mast cells and mamalian platelets
27
What are the Biological effects of Vasoactive amines?
* Vasodilation (artriole) * Increased vascular permeability (venule) * Smooth muscle constriction (airway) * Eosinophil chemotaxis * Pain * Itching
28
WHat are Arachidonic Acid Metabolites?
* A polyunsaturated fatty acid component of cell membrane phospholipids * Mainly present present in edothelium, leukocyte, and platelet membranes
29
* Degradation of AA 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
30
What are the pathways of Arachidonic Acid Metabolism?
* 2 Major pathways * Cyclooxygenase * Lipoxygenase * Cytochrome P450 Pathway * independent pathway wich results in formation of an intermediate compound (HPETE) that is a reactant in the lipoxygenase pathway
31
What is the Cyclooxygenase (COX) pathway?
* Present in many different cells * 3 isoenzymes control the pathway * Produce an intermediate protaglandin, PGH2 * The intermediat form PGH2 is converted to at leat 5 end products by specific synthases
32
What are the 3 isoenzymes that control the COX pathway?
* COX-1 * Constitutively expressed in nearly all tissues * COX-2 * Expressed following inflammatory stimuli * COX-3 * A variant o COX-1 present mainly in the cerebrum
33
What are the end products of PGH2?
* PGD2 : Allergy / vasodilation * Mast cells * PGF2 : Vasoconstriction, muscle contraction * Endothelium and epithelium * PGE2 : Fever, Vasodilation / increased permeability * Endothelium, epithelium, fibroblasts, leukocyts * PGI2 : Vasodilation and anti-platelet * Endothlium * TXA2 : Vasoconstriction and pro-platelet * Platelets
34
What is the lipoxygenase (LOX) pathway?
* Present in leukocytes * 5-lipoxygenase and 5-lipoxygenase-activating protein control the pathway * Form the complex 5-HPETE (hydroxyperoxyeicosatetraenoic acid) * HPETE and HETE are chemotactic for leukocytes * This produces an intermediate leikotriene, LTA4
35
What are the products of LTA4?
* LTB4 : chemotaxis, vascular permeability, degranulation of neutrophils * Neutrophils and macrophages * LTC4 : vascular permeability, vasoconstriction * Eosinophil / mast cell, macrophage * LTC4, LTD4, LTE4 : Vasodilation and vascular permeability * macrophage
36
What is Lipoxins?
* Also derived from LOX * Derived from platelets with contributions of AA from other cells * Platelet 12-lipoxygenase + LTA4 from neutrophils yields lipoxins A4 and B4 * Function: * Lipoxins are both pro- and anti-inflammatory and tend to counteract leukotrienes * Effects seem to be concentration dependent: * some cases stimultinghemotaxis, vascular permeability, and oxygen radical formatin * other cases have oposite effects
37
What is platelet activating factor?
* Derived from the activity of phospholipase A2 and acetyltransferase on mmbrane phospholipids * Produced by leukocytes, platelets and endothelial cells
38
What are the biological activities of Platelet activating factor?
* Vasoconstriction and vasodilation * Increased vascular permeability * Leukocyte chemotaxis, aggregation and adhesion * Platelet activation
39
What are Reactive Oxygen Metabolites?
* These are normal products of aerobic metabolism * Concentrations are closely controlled by antioxidants * Superoxide dismutase and catalase, among many other * Produced in high concentration by activated leukocytes, endothelium and platelets * Importat mechanism in leukocytes for killing microorganisms
40
What are the effects of Reactive Oxygen metabolites on inflammation?
* Endothelial injury and increased permeability * Generation of chemotactic substances * Activate cytokine secretion * Generation of AA metabolites * Inactivation of anti-inflammatory substances * Cell and tissue diamage
41
What are Nitric Oxide metabolites?
* Produced by endothelium, macrophages and neurons * Endothelial NO synthetas (eNOS) is constituitively produced and contributes to vascular smooth muscle relaxation, vasodilation, and inhibition of platelet adhesion and aggregation * Inducible NO synthetase (iNOS) is produced by activated macrophages * Have many similarities to oxygen metabolites * They can oxidize proteins and lipid membranes
42
What are the effects of Nitric Oxide Metabolites on inflammation?
* Enhanced vascular effects (vasodilation) * Inhibition of leukocyte adhesion and chemotaxis * Antimicrobial killing * Cell injury
43
What are Cytokines?
* Soluble proteins produced and screted by cells * These include growth factors, chemotactic factors, inflammatory mediators, immunoregulatory factors * Produced by enothelium, leukocytes, lymphocytes among others * Produce many of the local and systemic effects of inflammation * Lymphokines * immunoregulatoy substances * Monokines * Monocyte / macrophage products * Interleukin - 1 * Tumor necrosis factor
44
What are Neuropeptides?
* A large group of Proteins are relased by nerve endings that mediate communication between neurons * Some of these **produce** inflammatory effects * Neurogenic inflammation * (Ex) Substance P * Produced by nerves, macrophages, and lymphocytes * Member of the tachykinin family of neuropeptides
45
What are the effects of Substance P on inflammation?
* Vasodilation * Increased vascular permeability * Leukocyte activation * including degranulation of mast cells and eosinophils * Chemotaxis
46
What is the importance of inflammatory mediators?
* Drive the inflammatory process * Can create adverse effects due to excessive inflammation * Some of these can be controlled for the benefit of the animal * Anti-histamines * Corticosteroids * Non-steroidal anti-inflammatory drugs
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