Chemical mediators Flashcards
What is meant by the term inflammatory mediators?
they are substances that initiate and regulate inflammatory reactions
- Can be produced locally (at the site of inflammation, or from circulating inactive precursors “from the liver” which are activated at the site of inflammation)
- Acts by binding to specific receptors
Where are cell-derived mediators of inflammation?
1) Sequestered in cells (intracellular granules), like histamine in mast cells
2) De Novo synthesis in response to stimulus, (like prostaglandins, cytokines, arachidonic acid metabolites, etc)
How are active mediators produced?
- In response to various molecules that stimulate inflammation (like microbial products, & substances released from necrotic cells (host proteins), they are mostly short-lived (preventing chronic inflammation) and can stimulate the release of other mediators)
What are the different biological activities of activated mediators?
1) Binds to specific receptors on target cells
2) Direct enzymatic activity (lysosomal proteases, complement system)
3) Mediates oxidative damage (ROS & nitrogen intermediates)
What is the source and action of Histamines (vasoactive amine)?
1) Mast cells
2) Basophils
3) Platelets
- Released in response to (physical injury, antibody binding to mast cell granules (type 1 hypersensitivity, and also to the products of complement “anaphylatoxins” C3a & C5a)
- Vasodilation, Increases vascular permeability and activates endothelial cells, causing wheal and flare reaction of the skin, mediated by binding to receptor (H1 receptors) on microvascular endothelial cells
What is the source and action of Prostaglandins?
1) Mast cells
2) Leukocytes
- Vasodilation, pain, fever
What is the source and action of Leukotrienes?
1) Mast cells
2) Leukocytes
- Increased vascular permeability, chemotaxis, leukocyte adhesion and activation
What is the source and action of the platelet-activating factor?
1) Mast cells
2) Leukocytes
- Vasodilation, Increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst
What is the source and action of chemokines?
1) Activated mast cells
2) Leukocytes
- Chemotaxis & leukocyte activation
What is the source and action of Cytokines (TNF, IL-1, IL-6)?
1) Mast cells
2) Macrophages
3) Endothelial cells
- Local, endothelial activation (expression of adhesion molecules)
- Systemic, fever, metabolic abnormalities, hypotension (shock)
What is the source and action of COMPLEMENT?
1) Found inactive in plasma (produced in the liver)
How is it activated?
1) Classical: C1 will bind to an antibody (IgM or IgG) along with an antigen, becoming a proteolytic enzyme, activating C2,3,4
2) Alternative: Via LPS and endotoxins
3) Lectin: Or finally plasma mannose-binding lectin which binds to microbial carbohydrates directly activating C1
all of them will activate C3 splitting into C3a (chemotaxis and leukocyte activation “inflammation”, C5a does the same thing) & C3b (opsonization “phagocytosis and MAC formation)
- Leukocyte chemotaxis and activation, direct target killing (MAC), Vasodilation (mast cell stimulation), opsonization
What is the source and action of KININS?
1) Found inactive in plasma (produced in the liver)
- Increases vascular permeability, smooth muscle contraction, vasodilation & pain
Which chemical mediators induce pain
1) Prostaglandins
2) Kinins
which chemical mediators induce fever?
1) Prostaglandins
2) Cytokines
What are the vasoactive amines?
- Histamine and serotonin (imp neurotransmitter and in the GIT)
- Present in preformed stores in cells
- Among the first mediators to be released
- Promotes smooth muscle contraction (can cause bronchospasm “we must use anti-histamine”)
Describe serotonin
- Vasoactive amine
- Found within platelet granules, released during platelet aggregation & within neuroendocrine cells (GIT), in the brain, it is important for a good mood
- It is a neurotransmitter of the GIT and causes vasoconstriction
What are the different plasma-derived mediators (plasma proteins)?
1) Kinin system (highly vasoactive)
2) Complement system (vasoactive & chemotactic)
3) Clotting system (vasoactive & cleaves C3)
Describe the kinin system!
- Consists of blood protein which plays a role in inflammation, BP control, Coagulation & pain
- Examples include bradykinin (vasodilator of many cells)
- Generates vasoactive peptides (bradykinin) from plasma proteins namely kininogens, via protease action (kallikreins) which will:
1) Increase vascular permeability
2) Dialate BV
3) Causes smooth muscle contraction
4) Pain
5) Stimulates histamine release
6) Activates arachidonic acid cascade
Describe the clotting system!
Divided into two pathways (extrinsic & intrinsic) which will activate prothrombin (factor 2) into thrombin (factor 2a), in turn, thrombin will cleave the soluble fibrinogen in the circulation into an insoluble fibrin clot
What are the arachidonic acid metabolites?
Mediators formed from the phospholipids of our cell membrane, via the activation of phospholipase in our cell membrane like:
1) Prostaglandins
2) Leukotrienes
3) Lipoxins
Describe the cyclooxygenase metabolism of arachidonic acid.
- Produced by mast cells, macrophages, and endothelial cells
- There are two types COX1 & COX2, which mediate the conversion of AA to:
1) Prostacyclin (PGI2): Vasodilation, and inhibits platelets aggregation
2) Throboxane A2 (TXA2): Causes vasoconstriction, promotes platelet aggregation
3) Prostaglandins D2 & E2: Vasodilates and increases vascular permeability
Describe the lipoxygenase metabolism of arachidonic acid.
- Produced in leukocytes and mast cells
- Forms leukotrienes and lipoxin:
Leukotrienes:
1) A4 (converted to B4 which is a strong chemotactic agent)
2) C4 (BRONCHOSPASM, AND INCREASES VASCULAR PERMEABILITY)
3) D4 (BRONCHOSPASM, AND INCREASES VASCULAR PERMEABILITY)
4) E4 (BRONCHOSPASM, AND INCREASES VASCULAR PERMEABILITY)
Lipoxin A4 and B4, inhibit neutrophil adhesion and chemotaxis
What inhibits both cycloxygenase & lipoxygenase?
Steroids inhibit both (like corticosteroids inhibit phospholipase, inhibiting the secretion of AA from the start), Aspirin inhibits cycloxygenase only
What are the different types of cytokines?
Acute inflammation:
1) TNF
2) IL-1
3) IL-6
4) Chemokines
5) IL-17
Chronic inflammation:
1) IL-12
2) IFN-Y
3) IL-17
What is TNF & IL-1(Secreted? function?)?
- Major cytokines that mediate inflammation
- Produced mainly by activated macrophages can be stimulated by endotoxin and other microbial products, immune complexes, physical injury, etc
- Serve a critical role in promoting the adhesion of leukocytes to the endothelium and their migration through it
Which cytokine produces the effects of a septic shock?
TNF: the hemodynamic effects of septic shock -hypotension, decreased vascular resistance, increased heart rate, and decreased blood pH.
What is meant by cachexia?
- a pathologic state characterized by weight loss, muscle atrophy, and anorexia that accompanies some chronic infections and cancers.
- TNF regulates energy balance by promoting lipid and protein catabolism and by suppressing appetite.
What is the acute phase reaction of TNF & il-1?
1) Fever
2) Increase sleep
3) Decreased appetite
4) Increased acute phase proteins
5) Neutrophilia
What are the endothelial effects of TNF & IL-1?
1) Increases leukocyte adherance
2) Increases the synthesis of prostaglandins
3) Increases the activity of procoagulants
4) Decreases anticoagulant
5) Increases IL-1, 6, & 8 & PDGF
What are the fibroblastic effects of TNF & IL-1?
- Increases proliferation, collagen synthesis, protease and PGE synthesis
What are the leukocyte effects of TNF & IL-1?
Increases cytokine secretion (IL-1 & 6)
What is the function of INF-y & IL-12?
- From activated T-lymphocytes as they release IFN-y which will activate macrophages to release cytokine including IL-12
- Their main action is in the activation of neutrophils and monocytes
What are the functions of Nitric oxide and oxygen metabolites?
- Released from activated macrophages and vascular endothelium
- Inhibits platelet aggregation, reduces leukocyte adhesion, and kills microorganisms via the release of ROS
Which chemical mediators vasodilate BV?
1) Prostaglandins
2) Histamine
3) Nitric oxide
Which chemical mediators Increases the vascular permeability?
1) Vasoactive amine (Histamine & seretonin)
2) Bradykinin
3) Leukotrienes (C4, D4, E4)
4) PAF (platelet activating factor)
5) C3a & C5a
6) Substance P
Which chemical mediators that induces chemotaxis, & leukocyte recruitment and activation?
1) C5a
2) Lekotriene B4 (produces by the lipoxygenase arm of Arachidonic Acid metabolism)
3) Chemokines
4) IL-1 & TNF
5) Bacterial products
Which chemical mediators induces fever?
1) IL-1, 6 & TNF (Acute cytokines)
2) Prostaglandins
Which chemical mediator induces pain?
1) Prostaglandin
2) Bradykinin
which chemical mediator induces tissue damage?
1) Neutrophil and macrophages products
2) Lysosomal enzymmes
3) Oxygen metabolites
4) Nitric oxide
