Acute Inflammation - Mediators

Question 1

Mediators of Inflammtion

Answer 1

• 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

Question 2

Mediators of Inflammation:

Plasma-derived mediators

Answer 2

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

Question 3

Mediators of Inflammation:

Cell-derived mediators

Answer 3

• 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

Question 4

Hageman Factor pathway

Answer 4

• 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

Question 5

Kinins

Answer 5

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

Question 6

Plasma Kinin Pathway

Answer 6

• 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

Question 7

Tissue Kinin Pathway

Answer 7

• 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

Question 8

Bradykinin:

Activities

Answer 8

• 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

Question 9

Bradykinin:

Inactivated by

Answer 9

Kinases

Angiotensin converting enzyme from endothelium

Question 10

Plasmin:

Derived From

Answer 10

the cleavage of plasminogen

Mediated by various enzymes including:

Tissue plasminogen Activator

Urokinase

Kallikrein

Factro 12a

Question 11

Plasmin:

Major Functions:

Answer 11

• 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

Question 12

Complement

Answer 12

Activation generates a wide variety of biologically active products:

Activation occurs in a cascade by several different pathways:

Classical

Alternate

Mannose-binding lectin

Question 13

Complement:

Classical Pathway

Answer 13

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

Question 14

Complement:

Alternate Pathway

Answer 14

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

Question 15

Complement:

Mannose-Binding Lectin (MBL) Pathway

Answer 15

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

Question 16

Complement:

Terminal Pathway

Answer 16

• 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

Question 17

Complement:

Why is it Imporant?

Answer 17

• 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

Question 18

Inflammatory Inhibitors

Answer 18

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

Question 19

Cell-derived mediators or Inflammation

Answer 19

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

Question 20

Vasoactive Amines

Answer 20

• 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

Question 21

Vasoactive Amines:

Biological Effects

Answer 21

Vasodilation

Increased Vascular permeability

Smooth muscle constriction (Airway)

Eosinophil chemotaxis

Pain

Itching

Question 22

Arachidonic Acid Metabolites

Answer 22

• 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

Question 23

Arachidonic Acid Metabolites:

Cyclooxygenase (COX) Pathway

Answer 23

• 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

Question 24

Arachidonic Acid Metabolites:

COX pathway:

Intermediate PGH2

Answer 24

• 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

Question 25

Arachodonic Acid Metabolites:

Lipoxygenase (LOX) Pathway

Answer 25

• 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

Question 26

Arachidonic Acid Metabolites:

LOX pathway

LTA4 intermediate

Answer 26

• 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

Question 27

Arachodonic Acid Metabolites:

LOX pathway:

Lipoxins

Answer 27

• 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

Question 28

Platelet Activating Factor

Answer 28

• 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

Question 29

Reactive Oxygen Metabolites

Answer 29

• 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

Question 30

Reacitve Oxygen Metabolites:

Effects on Inflammation

Answer 30

• 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

Question 31

Nitric Oxide Metabolites

Answer 31

• 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

Question 32

Nitric Oxide Metabolites:

Effects on Inflammation

Answer 32

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

Question 33

Cytokines

Answer 33

• 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

Question 34

Neuropeptides

Answer 34

• 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

Question 35

Substance P

Answer 35

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