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What are the major chemical mediators of inflammation?
- vasoactive amines
- complement system
- kinin system
- coagulation pathway
- fibrinolytic pathway
- arachodonic acid metabolites
- nitric oxide
What are the major categories of mediators?
plasma-derived and cell-derived
What are the major categories of cell-derived mediators?
- : underline;"">Pre-formed - stored in granules and released upon stimulation (Histamine, Serotonin)
- cause vasodilation
- primary source is mast cells, platelets, basophils
- : underline;"">Synthesized - under appropriate stimulation - Arachidonic acid derivatives (cyclooxygenase, lipoxygenase)
- oxygen radicals
- neutrophil products
- macrophage products
What role does Hageman factor play in inflammation?
- Hageman factor = Factor 12
- activated by kinin, complement, clotting, and fibrinolytic systems
- interact continuously in course of inflammation to localize area of destruction
Describe the kinin system.
- kallikreins (proteases) generate kininogens (vasoactive peptides)
- HMWK (high-molecular weight kininogen) + 12 --> 12a + Prekallikrein --> Kallikrein (activates F12 in loop feedback) + HMWK --> Bradykinin
- most important product: bradykinin
- causes arteriolar dilation
- pain & contraction of smooth muscle
- kallikrein is a potent activator of Hageman factor (F12)
- converts C5--> C5a
Explain the kinin system in relation to pain.
- protective mechanism with survival value (link to consciousness)
- sensory nerves stimulated by
- low pH
- high extracellular [K+]
- Net result: pain!
- painless infectious are more dangerous (go undetected)
- silent chlamydial salpingitis is more important cause of infertility and ectopic pregnancy (bc of tubul damage)
Describe the major components of the complement cascade system.
- Classical & Alt. Pathways
- C3 is critical control point (interacts with both pathways)
- C3a & C5a = anaphylotoxins
- release histamine from mast cells
- C5a = chemotaxis
- C3b & C5a = stimulate neutrophil degranulation
- C3b, C2a, C4b = opsonins
- MAC complex
- C5-C7 = chemotactic for neutrophils
What activates the complement system?
- release of enzymes from dying cells (tissue necrosis)
- Ag-Ab complexes --> classical pathway
- endotoxins of Gram(-) --> alternative pathway
- products of kinin, coagulation, and fibrinolytic pathways
Describe the coagulation pathway and its relationships to fibrinolytic systems. What do these pathways have in common?
- Intrinsic pathway
- Hageman Factor (F12) is activated by surface contact
- Extrinsic pathway
- Tissue Factor released at sites of injury activates F7
- Results in clotting & fibrinolysis balanced by 12a --> kallikrein --> plasmin
- inducted by 12a (Hageman factor)
- complement & counterbalance each other
- important molecules: fibrinogen, fibrin, thrombin, plasminogen, plasmin
How is coagulation related to inflammation?
- Thrombin splits fibrinogen to fibrinopeptides
- induces vascular permeability
- Thrombin increases leukocyte adhesion & fibroblast proliferation
- Factor 10a increases vascular permeability & leukocyte exudation
- Plasmin cleaves C3 & fibrin resulting in vascular permeability
- Plasmin actives Hageman factor
What are ecosanoids? How are they formed? What can they form?
What are the effects of arachidonic metabolites?
- increased vascular permeability
- pyrogenesis (fever)
- neutrophil activation
Describe the COX pathway.
Describe the LOX pathway.
- leads to formation of leukotrienes, which cause
- chemotaxis (eosinophils, PMNs)
- increased vascular permeability
- act late in inflammation
- Inhibitors of leukotriens are used in asthmatics
- Formed by platelets with LTA4 from leukocytes
- Inhibits neutrophil chemotaxis & adhesion
- Stimulates monocyte adhesion
- Stimulates vasodilation
- Inhibits action of LTC4 (vasoconstriction)
- May be negative regulator of leukotrienes
- Collaborative productoin: PMNs / platelets
- Inhibit PMN activities
What are the major vasoactive amines released from mast cells and platelets? What are their functions?
- Histamine - abundant in mast cell granules which are abundant arond blood vessels
- Serotonin - action similar to histamine; found in platelets & released after platelet aggregation or PAF influence
- PAF - numerous effects which are 100-100,000x more effective than histamine including vasodilation & increased vascular permeability
Describe the general characteristics of cytokines.
- Produced by lymphocytes or macrophages after stimulation by toxins, injury, or inflammatory mediators
- Biggest influences: LPS (Gram-) & IFNg (viruses, etc.)
- Include: lymphokines, monokines, chemokines, colony stimulating factors, interleukins, & growth factors
- Categorized by actions
- Paracrine - activation of neighboring cells including neutrophiles & fibroblasts
- Endocrine - acts systemically (acute phase rxns) including: fever, fatigue, lower appetite, increased WBC
What functions do the cytokines provide?
- Regulate lymphocytes - IL2, 4, 10 & TGF-b
- Natural immunity - TNF-a, IL1b, IL6, IFNg, & IFNb
- Activate macrophages - IFNg, TNFa&b, IL5, 10, 12
- Chemokines - IL8 (leukocytes), lymphotaxin, eotaxin
- Stimulate hematopoiesis - IL3, 7, c-kit, CSF, & stem cell factor
Which cytokines are considered most important?
IL-1: endothelial cell activation
IL-2: T-cell growth factor
TNF-a: a.k.a. cachectin
IL-1 & TNFa are the most important
- endothelial cell activation
- acute phase response
- fibroblast stimulation
- stimulate leukocytes to secrete cytokines
Describe the general characteristics of nitric oxide.
- Formed by NO synthase (NOS)
- constitutively expressed
- expression increased with Ca influx
- NOS induced in macrophages by TNF-a or IFN-g
- Potent vasodilator
- Involved in pathogenesis of septic shock
- Actions: short-lived; depend on [NO]
- small amounts in endothelial cells cause smooth muscle relaxation & vasodilation; anti-thrombogenic to platelets
- small amouns in neurons --> neurotransmitter
- large amounts in macrophages --> cytotoxic free radical; kill bacteria / tumors
- inappropriate release --> shock
What are the possible outcomes of acute inflammation?
- Resolution - when process is limited to tissues capable of regeneration
- Scarring - tissue fixed by fibrosis; extensive process or tissues unable to regenerate
- Abcess formation - invading organism cannot be eradicated or drained; accumulation of pus
- Chronic inflammation - irritant persists; evolution to mononuclear infiltrate