SFP: Inflammation II Flashcards
Identify the cascades activated by Factor XII.
Complement, kinins, and coagulation by products
what are systemic mediators? give examples
they circulate as inactive precursors that require cleavage for activation. examples are complement, kinins, and coagulation factors
Describe the kinin cascade: final product and its effects
Produces bradykinin
Increases vascular permeability, dilates arterioles, contracts bronchial smooth muscle, and causes pain
Name the steps of the kinin cascade
-XIIa converts prekallikrein to kallikrein
-Kallikrein converts high MW kininogen to active bradykinin
What does the clotting cascade produce?
a clot
describe the steps of the clotting cascade
-XIIa activates a series of inactive to active conversions
-Thrombin is produced, which enhances leukocyte adhesion and cleaves C5
-Thrombin converts soluble fibrinogen to a fibrin clot.
-Making a fibrin clot produces fibrinopeptides that increase vascular permeability
Describe the fibrinolytic cascade
-Plasminogen is cleaved by a plasminogen activator or kallikrein to form active protease plasmin
-Plasmin cleaves the fibrin clot
what can plasmin activate
XIIa and complement cascade
What is the purpose of fibrin degradation products?
increase vascular permeability
what is the purpose of factor Xa in the clotting cascade
increases vascular permeability and leukocyte emigration
what is the purpose of thrombin
enhances leukocyte adhesion to endothelial cells and cleaves C5
What is the membrane attack complex?
It is formed from the complement cascade and punches holes in microbial membranes
What are some functions of components of complement cascade
-Forming MAC
-Opsonize for phagocytosis
-Alter vascular permeability
-Leukocyte activation, adherence, and chemotaxis
What cleaves C3 and C5?
Plasmin cleaves C3, thrombin cleaves C5
What do C3a and C5a do?
They act as anaphylatoxins. They encourage mast cell release of histamine and increase vascular permeability
what is a special function of C5a
arachidonic acid metabolism
What cell-derived local mediators come from preformed granules?
Vasoactive amines like histamine, serotonin, and lysosomal enzymes
What cell derived local mediators are synthesized de novo?
Products of membrane phospholipids (prostaglandins, leukotrienes, lipotoxins, PAF), cytokines, and free radicals (nitric oxide and substance P)
Describe the origin and actions of histamine
Comes from mast cells near vessels and basophils/platelets. It dilates arterioles, constricts large arteries, contracts venular endothelial cells to form gaps, and is the principal mediator if immediate increased permeability
What is the principal mediator of immediate increased permeability
Histamine
Describe the origin and actions of serotonin
Originates from delta granules in platelets, and platelet aggregation stimulates their release. They dilate arterioles, constricts large arteries, contracts venular endothelial cells to form gaps
What are the lysosomal enzymes?
Inactive acid proteases and active neutral proteases
What is the function of alpha 1 antitrypsin
They degrade neutral proteases and keep them from damages normal tissue adjacent to inflammation
Describe the origin of arachidonic acid.
They’re derived from broken membranes at the site of tissue damage.
What activates phospholipases that form arachidonic acid
Injury and/or C5a
What pathways metabolize arachidonic acid and what do they form?
Cyclooxygenase: forms prostaglandins TXA2 and PGI2
Lipoxygenase: creates leukotrienes and lipoxins
Common anti-inflammatory drugs target what parts of the arachidonic acid metabolism
Phospholipases or the cyclooxygenase pathway
What are eicosanoids? What do they do?
Products of arachidonic acid metabolism; they lead to swelling and edema
What are the main products formed by the cyclooxygenase pathway and lipoxygenase pathway?
Cyclooxygenase: thromboxane A2 and prostacyclin
Lipoxygenase: leukotrienes and lipotoxins
Describe the formation of the two main products in the cyclooxygenase pathway and their functions
-Cyclooxygenase forms PGG2 followed by PGH2
-Platelets form thromboxane A2
(TXA2) from PGH2. TXA2 causes vasoconstriction and promotes platelet aggregation
-Endothelium forms prostacyclin (PGI2) from PGH2. PGI2 causes vasodilation and inhibits platelet aggregation
What other molecules can process PGH2? What is their effect?
PGD2, PGE2, and PGF2a. they cause vasodilation and potentiate edema
Describe the formation of the main products in the lipoxygenase pathway and their functions
-5-lipoxygenase metabolizes arachidonic acid and forms 5-HPETE
-5-HPTE converts to various leukotrienes via 5-lipoxygenase
-Neutrophils transfer LTA4 (a leukotriene) to platelets to allow them to make lipoxins
-12-lipoxygenase can form
lipotoxins from 5-HPETE
What do leukotrienes do?
Cause vasoconstriction, bronchospasm, and increased permeability
What do lipoxins do?
Cause vasodilation, inhibit neutrophil chemotaxis, and stimulate monocyte adhesion. Tends to stop certain parts of inflammation!
What is the issue with cox2 inhibitors?
They promote clots and lead to increased coronary artery events because they inhibit prostacyclins more than thromboxane.
Describe platelet activating factor
It leads to platelet aggregation, vasoconstriction and bronchiconstriction
What classes of cytokines are associated with acute inflammation
Inflammatory cytokines: TNF and IL-1
Chemokines: colony stimulating chemokines
What are the functions of TNF and IL-1
-They stimulate endothelial cells, neutrophils, and fibroblasts. Stimulating endothelial cells results in increased expression of adhesion factors, increased cytokine and growth factor secretion, and production of eicosacoids and NO.
-they stimulate neutrophils to aggregate and activate. They stimulate fibroblasts to secrete proteolytic enzymes and produce matrix proteins
TNF and IL-1 lead to the production of which interleukin? what is the impact of this?
IL-6; this leads to systemic effects of inflammation (fever, loss of appetite, etc.)
What are the acute phase reactions of systemic effects of acute inflammation
-Acute phase reactions via TNF, IL-1, and IL-6 that cause fever and increased SED rate
-Leukocytosis and increased WBC count from IL-1 and TNF causing increased release from bone marrow
Describe the role of NO in inflammatory events in various tissues.
NO can kill microbes and cause vasodilation. It will reduce leukocyte recruitment and platelet aggregation, which mediates the effects of acute inflammation. It can, however, lead to complete vasodilation and shock.
Describe the origin and actions of substance P
Secreted by nerve fibers in the lungs and GI tract. They initiate inflammation, transmit pain signals, regulates vessel tone, and modulates vascular permeability.
What terminates acute inflammation
Removal of stimulus, the short lifetime of neutrophils, and production of anti-inflammatory mediators like lipoxins, TGF-beta, and IL-10
C reactive protein is made in the ___ and is indicative of the ____ reaction
Liver; acute phase reaction
Production of C reactive protein is induced by what 3 factors?
TNF, IL-1, and IL-6
