Inflammation: Mediators Flashcards
(46 cards)
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
2
Q
What are the categories of inflammation mediators?
A
- Plasma-derived mediators
- Cell-derived mediators
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
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
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
- activates Kinin pathways
6
Q
What are the pathways of Kinin formation?
A
- Plasma Kinin Pathway
- Tissue Kinin Pathway
- End product is bradykinin
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
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
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
10
Q
How is Bradykinin inactivated?
A
- Inactivated by kininases
- Angiotensin converting enzyme (Kininase II) from endothelium
11
Q
What is Plasmin?
A
- Derived from the cleavage of plasminogen
- Mediated by various enzymed:
- Tissue plasminogen Activator (tPA)
- urokinase
- Killikrein
- Factor XIIa
- Mediated by various enzymed:
12
Q
What are the major functions of Plasmin/
A
- Fibrinolysis
- Activation of Factor XII
- Complemnt System activation
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
14
Q
What is Plasmin’s role in Complement system activation?
A
- Plasmin directly cleaves C3 to C3a
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
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
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
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
19
Q
How do the Complement Pathways end?
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?
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
- C5b6798999…
- MAC forms a hole in the membrane
- Osmotic lysis of the cell / bacteria
21
Q
What are the functions of Complement fragments?
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?
A
- No, activated with or without prior exposure to the agent
23
Q
What are Inflammatory inhibitors
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
- Family of protease inhibitors
- Kininases
- Enzymes that phosphorylate proteins to alter their function
- Kininases I and II degrade bradykinin
- Enzymes that phosphorylate proteins to alter their function
- Alpha-1 antitrypsin
- Protease inhibitor of the serpin family
- inhibits many serine proteases
- Protease inhibitor of the serpin family
- Alpha-2 macroglobulin
24
Q
What are the Cell-derived Inflammation Mediatos?
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
