Acute Inflammation - Mediators Flashcards
(35 cards)
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
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
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
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
5
Q
Kinins
A
- Two pathways of formation
- plasma kinin pathway
- Tissue kinin pathway
- The end product of both pathways is bradykinin
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
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
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
9
Q
Bradykinin:
Inactivated by
A
Kinases
Angiotensin converting enzyme from endothelium
10
Q
Plasmin:
Derived From
A
the cleavage of plasminogen
Mediated by various enzymes including:
Tissue plasminogen Activator
Urokinase
Kallikrein
Factro 12a
11
Q
Plasmin:
Major Functions:
A
- Fibrinolysis
- fibrin degradation products are the result
- These can increase vascular permeability and are chemotactic for neutrophils
- fibrin degradation products are the result
- Activation of Factor 12
- Complement system activation
- directly cleaves C3 to C3a
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
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
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
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
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
- A large family of protease inhibitors
- Kininases
- 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
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
- Serotonin is most important in rodents
- 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
- degradation can be initiated by:
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
- COX-1
- 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
- PGD2:
25
Arachodonic Acid Metabolites:
Lipoxygenase (LOX) Pathway
* 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
Arachidonic Acid Metabolites:
LOX pathway
LTA4 intermediate
* 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
Arachodonic Acid Metabolites:
LOX pathway:
Lipoxins
* 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
Platelet Activating Factor
* 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
Reactive Oxygen Metabolites
* 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
Reacitve Oxygen Metabolites:
Effects on Inflammation
* 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
Nitric Oxide Metabolites
* 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
Nitric Oxide Metabolites:
Effects on Inflammation
* Enhanced vascular effects
* Inhibition of leukocytes adhesion and chemotaxis
* Antimicrobial Killing
* Cell Injury
33
Cytokines
* 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
Neuropeptides
* 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
Substance P
* Effects on Inflammaiton
* Vasodilation
* Increased vascular permeability
* Leukocyte activation
* including degranulaion of mast cells and eosinophils
* Chemotaxis
