Pathology 8: Chemical Mediators of Inflammation Flashcards
What are the types of cell derived mediators?
- Vasoactive amines: histamine and serotonin
- Arachondonic acid metabolites
- Nitric oxide (NO)
- Cytokines
What are the types of plasma derived mediators?
Complement system
Where is histamine stores?
In a performed state in
- mast cells
- basophils
- Platelets
How quickly can histamine be released if needed?
Instantly
Where are mast cells normally located?
In connective tissues near BV
- may release histamine
What is histamine released in response to?
- Physical injury (heat, cold, trauma)
- Immune rxn (IgE binding)
- Presence of complement fragments C3a and C5a (anaphylatoxins)
What are the actions of histamine?
- Dilation of arterioles
- Increased vascular permeability of venules
what does Increased vascular permeability of venules lead to?
endothelial contraction in venules
What is 5-hydrooxytryptamine?
Serotonin
Where is serotonin stored preformed? and what is it released in response to?
- Platelets
- Platelet aggregation
What is the action of serotonin?
- Dilation of arterioles
- Increased vascular permeability of venules
** Same as histamine
Where does arachidonic acid come from?
The degradation of phospholipids by phospholipase
What is eicosanoids?
Products of arachidonic acid metabolism
What is special about eicosanoids?
it regulates inflammation and homeostasis
What are the two primary classes of inflammatory metabolites?
- Prostaglandins and leukotrienes
What do corticosteroids inhibit?
The action of phospholipases and therefore any production at all of arachidonic acid
What are prostaglandins produced by?
Cyclooxygenases
- COX-1: always expressed
- COX-2: inducible
What are the prostaglandins?
Prostacyclins:
- PGE2
- PGI2
- PGF2
- PGD2
Thromboxane:
- TXA2
What do asprin and NSAIDS inhibit?
COX-1 and COX-2 therefore inhibiting of prostaglandins
What is unaffected by NSAIDS?
lipoxygenase
What is lipoxygenase?
An enzyme that produces leukotrienes and lipoxins from arachidonic acid
What is leukotrienes actions?
- Chemotaxis for leukocytes
- Vascular effects: vasoconstriction and increased vascular permeability
What do lipoxins inhibit?
- Inflammation
- Inhibit leukocyte recruitment and cellular components of inflammation
What produces Nitric Oxide?
-Endothelial cells
-Macrophages
- Neurons
What is nitric oxide synthesized by?
Nitric oxide synthase
What is nitric oxide function in inflammation?
- Vasodilation
- Inhibits cellular inflammatory response
How does nitric oxide inhibits cellular inflammatory response?
- Reduces platelet aggregation and adhesion (anti-inflammatory)
- Inhibits leukocyte recruitment
In what form does Nitric oxide kill microbes?
As free radicals
What are cytokines?
polypeptides produced primarly by macrophages and lymphocytes
What is the action of cytokines?
Modulation of activities of other cells
What are the main cytokines involved in acute inflammation?
- IL-1
- TNF (tumor necrosis factor)
What are the actions of IL-1 and TNF on vascular endothelium?
- Inc expression of leukocytes adhesion molecules
- Production of IL-1 and chemokines
- Increase in pro-coagulation and decrease in anticoagulation activity
What are the actions of IL-1 and TNF on leukocytes?
- activation
- production of cytokines
What are the actions of IL-1 and TNF on fibroblasts?
- Proliferation
- Increase in collagen synthesis
What are the systemic affects of IL-1 and TNF?
- Fever
- Leukocytosis
- Increased acute-phase proteins
- Decreased appetite
- Increase sleep
What is a complement plasma protein mediator?
- Defense system against microbes
- Formation of MAC- membrane attack complex
What does compliment activation cause?
- increased vascular permeability
- Chemotaxis
- Opsonization
What are complement proteins stored as?
Inactive plasma precursors: C1-9
What are the three pathways of complement activation?
- Classical
- Alternative
- Lectin
What is the classical pathway of complement activation?
- Reaction with IgG and IgM containing antigen-antibody complex
What is the alternative pathway of complement activation?
- Contact with microbial surfaces and polysaccharides
- Ex: cobra venom and endotoxins
What is the lectin pathway of complement activation?
Plasma mannose-binding lectin binds to microbes
What does complement activation lead to?
Formation of enzyme C3 convertase
What does C3 convertase do?
Cleaves C3
what does C3 cleavage lead to?
- Release of C3a (anaphylatoxin)
- Covalent attachment of C3b (initiates formation of C5 convertase)
What does C5 convertase lead to?
Formation of C5-9 (MAC)
What are the complement derived mediators?
- C3a
- C5a
- C3b
What are the anaphylatoxins?
- C3a and C5a
What does C3a and C5a do?
Facilitate histamine release from mast cell
- Vasodilate
- Increase permeability
What does just C5a do?
- Activates lipoxygenase pathway of arachidonic acid metabolism in neutrophils and monocytes
- Chemotactic for neutrophils, monocytes, eosinophils, and basophils
What does c3b do?
Acts as opsonins when fixed to bacteria; facilitating phagocytosis by neutrophils and macrophages (receptor)
