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116 Cards in this Set
- Front
- Back
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2 major vasoactive amines
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1. Histamine
2. Serotonin |
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Where is histamine found?
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-richest sources in mast cell granules
-found in blood basophils and platelets |
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What stimulates mast cell degranulation?
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-physical injury
-binding of Abs to mast cells (allergic rxns) -anaphylatoxins- C3a & C5a -histamine-releasing proteins derived from leukocytes -neuropeptides (substance P) -cytokines (IL-1, IL-8) |
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Effects of histamine release
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-dilation of arterioles
-increased venule permeability -principle mediator of the immediate transient phase of increased vascular permeability (produces inter-endthelial gaps) |
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Where is serotonin found?
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-platelets
-certain neuroendocrine cells (GI tract) |
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When is serotonin released?
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-stimulated when platelets aggregate
-after contact with collagen, throbmin, ADP, & Agn-Ab complexes -platelet release reaction is a key component of coagulation |
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Substances derived from arachidonic acid (AA)
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1. Prostaglandins
2. Leukotrienes 3. Lipoxins |
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Where does the AA used to synthesize certain mediators come from?
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AA released from membrane phospholipids in response to mechanical, chemical, and physical stimuli
Phospholipase A2 |
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Enzymes that synthesize AA-derived mediators (cicosanoids)
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Cyclooxygenases- generate prostaglandins
Lipoxygenases- produce leukotrienes and lipoxins |
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What cell types produce prostaglandins?
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mast cells
macrophages endothelial cells many others |
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Enzymes that produce prostaglandins
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COX-1: constitutively expressed
COX-2: inducible |
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What mediator is produced by the COX-1 and COX-2 cyclooxygenases?
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Prostaglandins
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Most important prostaglandins of inflammation
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PGE2
PGD2 PGF2a PGI2 (prostacyclin) TxA2 (thromboxane) |
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Potent inhibitor of platelet aggregation
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Prostacyclin (PGI2)
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Prostacyclin (PGI2)
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-vasodilator
-potent INHIBITOR of platelet aggreation -potentiates permeability-increasing and chemotactic effects of other mediators |
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Major prostaglandin made by mast cells
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PGD2
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PGD2
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-major prostaglandin made by mast cells, along with PGE2 (which is more widely distributed)
-causes vasodilation -increases permeability of post-capillary venules, potentiating edema formation |
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Causes uterine & bronchial smooth mm contraction
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PGF2a
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PGF2a
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-stimulates contraction of uterine and bronchial smooth mm and small arterioles
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Chemoattractant for neutrophils
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PGD2
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PGD2
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Chemoattractant for neutrophils
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PGE2
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-hyperalgesic
-makes skin hypersensitive to painful stimuli -involved in cytokine-induced fever during infections |
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Cells that produce leukotrienes
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Leukocytes
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Enzyme class that produces leukotrienes
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Lipoxygenases
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Effects of leukotrienes
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-vascular effects
-chemoattractants for leukocytes |
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Chemoattractants for leukocytes
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Leukotrienes
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Predominant lipoxygenase in neutrophils
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5-lipoxygenase
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3 types of lipoxygenases
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1. 5-lipoxygenase
2. LTB4 3. Cysteinyl-containing leukotrienes C4, D4& E4 (LTC4, LTD4, LTE4) |
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Actions of lipoxygenase TB4
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-potent chemotactic agent and activator of neutrophils
-causes aggregation and adhesion of cells to venular endothelium -generation of ROS -releases lysosomal enzymes |
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Actions of cysteinyl-containing leukotrienes
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Intense vasoconstriction
Bronchospasm Increased vascular permeability |
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Origin of lipoxins
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Generated from AA by lipoxygenase pathway
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Inhibitors of inflammation
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Lipoxins
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What 2 cell populations are required for lipoxin biosynthesis?
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1. Leukocytes (esp. neutrophils) produce intermediates
2. Platelets convert intermediates to lipoxins by interacting with leukocytes |
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Principal actions of lipoxins
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Inhibit leukocyte recruitment and cellular components of inflammation
Inhibit neutrophil chemotaxis and adhesion to endothelium |
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Relationship between production of lipoxin and leukotrienes
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Inverse relationship- suggests that lipoxins may be ENDOGENOUS NEGATIVE REGULATORS of leukotrienes
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Mechanism of anti-inflammatory drugs
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Inhibit synthesis of eicosanoids
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ASA; NSAIDS
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Cycooxygenase inhibitors
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Cyclooxygenase acivity
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Inhibits both COX-1 and COX-2
Inhibits prostaglandin synthesis |
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Which drug does not affect 5-lipoxygenases?
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NSAIDs
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Lipoxygenase activity inhibitors
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Inhibit leukotriene production (Zileuton)
Block leukotriene receptors (Montelukast)- useful in asthma tx |
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Broad-spectrum inhibitor
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Corticosteriods
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Corticosteriod activity
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Powerful anti-inflammatory agents
Reduces transcription of genes in coding COX-2, phospholipase A2, pro-inflammatory cytokines (such as IL-1 and TNF) |
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Polyunsaturated fatty acids in fish oil
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-serve as poor substrates for conversion to active metabolites
-excellent substrates for production of anti-inflammatory lipid products EX: resolvins & protectins |
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Causes platelet aggregation
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Platelet-activating factor (PAF)
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Platelet-activating factor (PAF)
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-phospholipid-derived mediator
-causes platelet aggregation -known to have multiple inflammatory effects |
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Which cell types can elaborate PAF?
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Platelets
Basophils Mast cells Neutrophils Macrophages Endothelial cells |
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What do PAFs cause?
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Causes vasoconstiriction and bronchoconstriction
At extremely low concentrations: -induces vasodilation -increased venular permeability Increased leukocyte adhesion, chemotaxis, degranulation, and the oxidative burst Boosts synthesis of other mediators (eicosanoids) |
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What is the production of ROS dependent on?
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Activation of the NADPH oxidase system
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Major ROS species produced within cells
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Superoxide anion
Hydrogen peroxide Hydroxyl radical combine with NO to form reactive nitrogen species |
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Examples of antioxidants
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Supeoxide dismutase
Catalase Gutathione peroxidase Ceruloplasmin Serum transferrin |
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Called 'endothelium-derived relaxing factor'
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Nitric oxide
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Cells that produce NO
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-endothelial cells
-macrophages -some neurons |
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Effect of NO on cells
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Acts in paracrine manner on target cells
Dual actions in inflammation: -relaxation of smooth mm cells -promotes vasodilation -inhiboits cellular components of inflammatory response Reduces platelet aggregation and adhesion Inhibits mast-cell activity Inhibits leukocyte recruitment |
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Microbicidal agent
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NO and its derivitives
*mediator of host defense against infection |
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Cells that produce cytokines
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-principally activated lymphocutes and macrophages
-also endothelial, epithelial, and connective tissue cells |
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Major cytokines that mediate inflammation
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TNF & IL-1
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Cells that produce TNF & IL-1
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Activated macrophages
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What stimulates TNF & IL-1 secretion?
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-endotoxin and other microbial products
-immune complexes -physical injury -variety of inflammatory stimuli |
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Main effects of TNF & IL-1
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Induce systemic acute-phase responses associated with infection/injury
Regulate E balance by: -promoting lipid and protein -suppressing appetite |
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Sustained production of these substances lleads to cachexia
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TNF & IL-1
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Cachexia
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-pathologic state characterized by weight loss and anorexia
-accompanies some chronic infections and neoplastic diseases |
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2 main functions of chemikines
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1. Stimulate leukocyte recruitment in inflammation
2. Control the normal migration of cells through various tissues |
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How are chemokines classified?
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4 major groups according to the arrangement of the conserved cysteine (C) residues in the mature proteins:
1. C-X-C chemokines (alpha) 2. C-C chemokines (beta) 3. C chemokines (gamma) 4. CX3C chemokines |
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Chemokine that acts primarily on neutrophils
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C-X-C (alpha) chemokines
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IL-8 belongs to this group of chemokines
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C-X-C (alpha) chemokines
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Which cell types secrete C-X-C (alpha) chemokines?
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macrophages
endothelial cells other cell types |
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What do C-X-C (alpha) chemokines cause?
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Activation and chemtaxis of neutrophils
Limited activity on monocytes & eosinophils |
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Most important inducers of C-X-C (alpha) chemokines?
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-microbial products
-other cytokines, mainly IL-1 & TNF |
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Which cells do C-C (beta) chemokines act on
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attract monocytes, eosinophils, basophils, & lymphocutes
NOT neutrophils |
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Which chemokine attracts monocytes, eosinophils, basophils, and lymphocytes but NOT neutrophils?
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C-C (beta) chemokines
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Lymphotactin (chemokine specific for lymphocytes)
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C (gamma) chemokines
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Cell type that C (gamma) chemokines mainly act on
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Lymphocytes
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Fractalkine
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CX3C chemokines
2 forms: 1. cell surface-bound proteins 2. soluble form |
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2 types of neutrophil granules
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1. Smaller specific (secondary) granules
2. Larger azurophil (primary) granules |
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Contents of specific (secondary) granules of neutrophils
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lysozyme
collagenase gelatinase lactoferrin plasminogen activator histaminase alkakine phosphatase |
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Contents of azurophil (primary) granules
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myeloperoxidase
bactericidal factors (lysozyme, defensins) acid hydrolases variety of neutral proteases |
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What is the function of neutrophil granules?
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-both tupes can fuse with phagoytic vacuoles containing engulfed material
-granule contents can be released into the extracellular space |
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Mediator secreted my sensory nerves and various leukocytes
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Neuropeptides
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Role of neuropeptides
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Aid in initiation and propagation of inflammation
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Substance P and neurikinin A
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Neuropeptides Family of tachykinin neuropepdides produced in CNS and PNS
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Biologic functions of neuropeptides
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-transmission of pain signals
-regulation of blood pressure -stimulation of secretion by endocrine cells -increasing vascular permeability |
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3 interrelated systems of plasma protein-derived mediators
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1. C' system
2. Kinin system 3. Clotting system |
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Critical step of the C' activation
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Proteolysis of the third (and most abundant) component, C3
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3 functionally divided categories of C' system
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1. Inflammation
2. Phagocytosis 3. Cell lysis |
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C' components involved in inflammation (anaphylatoxins)
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C3a
C5a C4a (lesser extent) |
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Action of anaphylatoxins
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-stimulate histamine release from mast cells
-increase vascular permeability -cause vasodilation |
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Powerful chemotactic agent for neutrophils, monocytes, eosiophils, & basophils
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C5a
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Activates lipoxygenase pathway of AA metabolism in neutrophils and monocytes
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C5a
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Effects of C5a
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Powerful chemotactic for neutrophils, monocutes,eosinophils, & basophils
Activates lipoxygenase pathway of AA metabolism in neutrophils & monocytes Causes further release of inflammatory mediators |
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C' components involved in phagocytosis
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C3B and cleavage product iC3b (inactive C3b)
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Function of C3b & iC3b
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Act as OPSONINS when fixed to microbial cell wall
Promote PHAGOCYTOSIS by neutrophils & macrophages |
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Act as opsonins
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C3b & iC3b
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C' component of cell lysis
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Deposition of MAC on cells
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Effect of MAC deposition on cells
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-cells permeable to water and ions
-results in death (lysis) of cells |
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End result of coagulation and kinin systems
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1. Activation of thrombin
2. Formation of fibrin |
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Activator of intrinsic clotting pathway
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Hageman factor (factor XII)
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Where is Hageman factor (factor XII) synthesized?
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Synthesized in liver; circulates in an inactive form
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How is Hageman factor (factor XII) activated?
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Activated upon contact with negatively charged surfaces
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Active form of factor XII effect on kinin
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XIIa converts plasma prekallikrein into active protolytic form (kallikrein)
Cleaves plasma glycoprotein precursor high-MW kininogen, to produce bradykinin |
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Kinins
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-vasoactive peptides
-derived from plasma proteins (kininigens) -action of specific proteases (kallikreins |
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Actions of bradykinin
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-increases vascular permeability
-contraction of smooth mm -dilation of blood vessels -pain when injected into skin |
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Kininase
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Enzyme that inactivates bradykinin (bradykinin is short-lived)
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What system is activated by factor XIIa as it is inducing fibrin clot formation?
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Fibrinolytic system
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Action of fibrinolytic system
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Cascade counterbalances clotting by cleaving fibrin
SOLUBILIZING the clot |
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What cleaves plasminogen to plasmin?
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Kallikrein
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Kallikrein
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Cleaves plasminigen
Plasma protein that binds to the evolving fibrin clot to generate PLASMIN |
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Primary function of plasmin
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-lyse fibrin clots
-cleaves C3 to produce C3 fragments -degrades fibrin to form fibrin split products -activates Hageman factor (triggers multiple cascades) |
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Mediators of increased vascular permeability
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Bradykinin, C3a, C5a
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Mediator of chemotaxis
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C5a
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Affects endothelial cells and many other cell types
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Thrombin
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4 systems initiated by activated Hageman factor (factor XIIa)
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1. Kinin system
2. Clotting system 3. Fibrinolytic system 4. C' system |
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System that produces vasoactive kinins
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Kinin system
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System that induces thrombin formation
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Clotting system
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System that produces plasmin
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Fibrinolytic system
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System that degrades fibrin to produce fibrinopeptides
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Fibrinolytic system
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System that produces anaphylatoxins and other mediators
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C' system
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