Inflammation: Mediators Flashcards
What are the Mediators of inflammation?
- 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
What are the categories of inflammation mediators?
- Plasma-derived mediators
- Cell-derived mediators
What are Plasma-derived Mediators?
- Produced mainly in the liver
- Circulates in blood as inactive precursor
- Ex:
- Hageman Factor (Factor XII) pathways
- Kinins
- Plasmin
- Complement
- Inflammation inhibitors
What are Cell-derived Mediators?
- 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
What is Hageman Factor pathwasy?
- 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
- activates Kinin pathways
What are the pathways of Kinin formation?
- Plasma Kinin Pathway
- Tissue Kinin Pathway
- End product is bradykinin
What is the Plasma Kinin Pathway?
- 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
What is the Tissue Kinin pathway?
- 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
What are the activities of Bradykinin?
- 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
How is Bradykinin inactivated?
- Inactivated by kininases
- Angiotensin converting enzyme (Kininase II) from endothelium
What is Plasmin?
- Derived from the cleavage of plasminogen
- Mediated by various enzymed:
- Tissue plasminogen Activator (tPA)
- urokinase
- Killikrein
- Factor XIIa
- Mediated by various enzymed:
What are the major functions of Plasmin/
- Fibrinolysis
- Activation of Factor XII
- Complemnt System activation
What is Fibrinolysis?
- Fibrin degradation products are the result
- These products can increase vascular permeability and are chemotactic for neutrophils
- Deficiency can result in thrombosis
What is Plasmin’s role in Complement system activation?
- Plasmin directly cleaves C3 to C3a
How is the Complement System Activated?
- 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
What is the Classical Pathway of the Complement System?
- 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
What is the Alternate Pathway of the Complement System?
- 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
What is the MBL pathway of the Complement system?
- 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