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100 Cards in this Set
- Front
- Back
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inflammation
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host response to injury
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4 components of inflammation
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vascular responses
migration of leukocytes activation of leukocytes systemic reactions |
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The most basic ways to get rid of injurious agents
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entrapment and phagocytosis
neutralization of noxious stimuli by hypertrophy of the host cells or one of it's organelles |
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cells of the connective tissue
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mast cells
CT fibroblasts resident macrophages lymphocytes |
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main characteristics of acute inflammation
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exudation of fluid and plasma proteins (edema)
emigration of leukocytes (PMNs- neutrophils) |
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main characteristics of chronic irritation
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lymphocytes (instead of neutrophils)
macrophages proliferation of blood vessels fibrosis tissue necrosis |
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compare acute and chronic inflammation
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acute:
minutes, hours, days neutrophils edema Chronic: days and longer lymphocytes, macrophages blood vessels, fibrosis |
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triggers of inflammation
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necrotic tissue or cells
chemical factors from plasma proteins or cells infection toxins trauma physical and chemical agents tissue necrosis foreign bodies immune reactions |
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vascular changes in acute inflammation
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vasodilation
increased permeability stasis net flow of fluid out of capillaries osmotic pressure is reduced resulting in more extravascular fluid |
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stages of acute inflammation fluid loss
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1. immediate transient response (30 min or less) mediated by histamine and leukotrienes on endothelium
2. delayed response (from hour 2-10) mediated by kinins, complement products and other factors 3. prolonged response: most noticeable after direct endothelial injury |
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cellular events in acute inflammation
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Extravasation of leukocytes
1. lumen: margination, rolling and adhesion to the endothelium 2. transmigration across endothelium 3. migration in interstitial tissues toward a chemotactic stimulus |
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margination
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leukocyte accumulation along the endothelial surface
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rolling
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leukocytes tumbling along the endothelium
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pavementing
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endothelium is lined by white cells
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4 families of adhesion receptors
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selectins: adhesions of leukocytes to endothelial cells
immunoglobulin: serve as ligand integrins on leukocytes integrins: cell-cell or cell-matrix interactions mucin like glycoprotens: ligands on ECM and cell surfaces, ligands for leukocyte adhesion |
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chemotaxis
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leukocytes emigrate in tissues toward the site of injury
locomotion along a chemical gradient |
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endogenous chemoattractants
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1. components of the complement system (C5a)
2. products of the lipoxygenase pathway (leukotriene B4) 3. cytokines (chemokines, Il-8) |
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leukocyte activation results in:
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increased cytosolic CA
activation of enzymes like protein Kinase C and phospholipase A2 |
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functional responses induced by leukocyte activation
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production of arachadonic acid metabolites due to activation of phoshpholipase A2 by increased Ca
degranulation and secretion of lysosomal enzymes activation of oxidative burst secretion of cytokines (amplify and regulate inflammation)(mainly from macrophages, but also from mast cells and leukocytes) modulation of leukocyte adhesion molecules |
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receptors involved in leukocyte activation
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toll like receptors
seven-transmembrane G protein coupled receptors cytokine receptors opsonin receptors: alternative pathway, coating with IgG |
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phagocytosis steps
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1. recognition and attachment of the particle by the leukocyte
2. engulfment and formation of a phagocytic vacuole 3. killing or degradation of the ingested material |
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substances released from leukocytes during phagocytosis
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lysosomal enzymes
reactive oxygen intermediates products of arachidonic acid metabolism including prostaglandins and leukotrienes these are capable of causing endothelial injury and may amplify the affects of the initial injury |
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diseases caused by the inflammatory reaction
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acute
adult resp. distress syndrome transplant rejection asthma glomerulonephritis reperfusion injury septic shock vasculitis Chronic arthritis asthma atherosclerosis chronic lung disease chronic tissue rejection |
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leukocyte function defects
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leukocyte adhesion
phagolysosome function microbicidal activity most frequent cause: bone marrow suppression leading to reduced production |
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passive termination of inflammatory response by
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the mediators of inflammation -have short half-livers
-are degraded after their release -are produced in quick bursts |
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active termination of acute inflammation
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a switch in production of pro-inflammatory leukotrienes to anti-inflammatory lipoxins from arachidonic acid
liberation of an anti-inflammatory cytokine TGF-B from macrophages neural impulses (cholinergic) that inhibit production of TNF in macrophages |
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chemical mediators of inflammation
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originate either from
plasma - precursor forms must be activated cells -sequestered in intracellular granules or synthesized de novo major cell sources: platelets neutrophils monocytes/macrophages mast cells |
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serum
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blood without clotting factors
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transudate
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something that has been filtered through a membrane
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plasma
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yellow colored liquid component of blood, cells are suspended in
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exudate
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white cells and fluid
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pus
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debris and white cells and fluid
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Histamine: Which cells release it and why
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mainly from mast cells
also from basophils and platelets released due to 1.physical injury, 2. immune reactions, 3 fragments of complement, 4. histamine-releasing proteins form leukoctes, 5. neuropeptides (substance P) 6. cytokines |
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Effects of histamine
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dilation of arterioles
increased permeability of venules constricts large arteries principle mediator of immediate transient phase of increased vascular permeability |
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serotonin
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5 hydroxytryptamine
present in platelets and enterochromaffin cells released from platelets when platelets aggregate after contact with collagen, thrombin, ADP, and antigen antibody complexes |
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complement system
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part of both innate and adaptive immunity
cause increased vascular permeability, chemotaxis, and opsonization 2 categories of the biologic function of the complement system: 1. cell lysis by MAC 2. proteolytic fragments of complement effects |
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complement fragments
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C3a, C5a and C4a are split products of complement components that stimulate histamine release which increases vascular permeability, aka anaphylatoxins
C5a: activates lipoxygenase pathway of arachadonic acid metabolism of neutrophils and monocytes causing further release of inflammatory mediators C5a: chemotactic agent for neutrophils, monocytes, eosinophils, basophils C3b: favor phagocytosis by neutrophils and macrophages |
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kinin system
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generates kininogens (vasoactive peptides) by proteases called kallikreins
activate bradykinin increase vascular permeability contraction of smooth muscle dilation of blood vessels pain when injected into the skin |
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clotting system
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intrinsic clotting pathway: activated by Hageman factor (12)
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factor 12
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Hageman factor
involved in kinin cascade and clotting cascade 12a: can induce clotting or activate the fibrinolytic system (cleave fibrin and solubilize the clot) coagulation and inflammation are tightly linked acute inflammation can trigger coagulation and induce thrombus formation |
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link between coagulation system and inflammation
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thrombin (factor 2a)
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enzyme that cleaves fibrinogen to generate fibrin
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thrombin
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protease activated receptors
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PARs
seven-transmembrane G protein coupled receptors expressed on platelets, endothelial and smooth muscle cells and other cell types |
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effects of thrombin binding PAR-1
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- mobilization of P-selectin
- production of chemokines and - expression of leukocyte integrins - induction of cyclooxygnase 2 and - production of prostaglandins - production of PAF and Nitric oxide - changes in endothelial shape |
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arachidonic acid
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derived from dietary sources or by conversion from essential fatty acid linoleic acid
it is esterified in membrane phospholipids and released by phospholipases which may be activated by mechanical, chemical or physical stimuli its metabolites are: leukotrienes prostaglandins lipoxins |
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arachadonic acid metabolites
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eicosanoids
synthesized by 2 enzyme classes: cyclooxygenases: prostaglandins, thromboxanes lipoxygenases: leukotrienes, lipoxins |
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cyclooxygenase pathway
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COX 1
COX 2: inducible generate prostaglandins - prostacyclin: vasodilator, inhibitor of platelet aggregation - thromboxane: potent platelet aggregating agent, vasoconstrictor |
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prostaglandins
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-involved in the pathogenesis of pain and fever in inflammation
-hyperalgesis: causes marked increase in pain -cause vasodilation -incresaes permeability -potentiates edema formation |
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COX2
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INDUCED by inflammatory stimuli
produce prostaglandins involved in inflammatory reactions |
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COX1
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produce prostaglandins involved in inflammation and hemostatic function
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lipoxygenase pathway
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5-lipoxygenase:main enzyme in neutrophils
5HETE (chemotactic for neutrophils) converted to leukotrienes LTB4: chemotactic agent and activator of neutrophil functional responses |
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lipoxins
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inhibit leukocyte recruitment and the cellular components of inflammation
may be involved in regulating leukotrienes and in the resolution of inflammation |
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resolvins
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inhibit leukocyte recruitment and activation by inhibiting cytokine production
aspirin like effect |
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NSAIDS
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inhibit COX pathway
but not lipoxygenase |
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use of lipoxygenase inhibitors
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treatment of asthma
include glucocorticoids |
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dietary way to modulate inflammatory response
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modify the intake and content of dietary lipids by decreasing the consumption of fish oil
fish oil fatty acids serve as poor substrates for conversion to active metabolites by both the cyclooxygenase and lipoxygenase pathways |
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chemokines
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serve as chemoattractants for leukocytes
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Nitric Oxide
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factor released from endothelial cells that caused vasodilation by relaxing vascular smooth muscle
aka endothelium derived growth factor produced by endothelium, macrophages, neurons in brain induces cGMP made from arginine by nitric oxide synthetase |
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factors that induce production of NO
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cytoplasmic calcium ions induce nitric oxide synthetase
inhibited when macrophages and other cells are activated by cytokines |
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effects of NO
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vasodilator
reduces platelet aggregation and adhesion |
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neutrophil granules
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2 main types:
smaller/specific/secondary: lysozyme collagenase gelatinase lactoferrin plasminogen activator histaminase alkaline phosphatase large azurophilic/secondary: myeloperoxidase bactericidal facotrs acid hydrolases neutral proteases THE LARGER AZUROPHIL OR PRIMARY GRANULES ARE RELEASED IN RESPONSE TO HIGHER LEVELS OF AGONISTS AND ARE RELEASED PRIMARILY INTO PHAGOSOME |
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oxygen derived free radicals
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released from leukocytes after exposure to microbes, chemokines, immune complexes, or following an immune challenge
production is dependent on NADPH oxidation system superoxide anion hydrogen peroxide hydroxyl radical are the main species can combine with NO to form reactive nitrogen intermediates |
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neutralization of oxygen derived free radicals
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copper containing serum protein ceruloplasmin
iron free fraction of serum- transferrin superoxide dismuatse catalase: detoxifies H2O2 glutathione peroxidase: H202 detoxifier |
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examples of neuropeptides
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substance P: transmission of pain signals, regulation of BP, stimulation of secretion of endocrine cells
neurokinin |
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hypoxia
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induces inflammatory response by a protein called induced factor 1a which activates VEGF which increases vascular permeability
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stimulators of inflammation
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hypoxia
necrotic cells uric acid |
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3 possible results of acute inflammation
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1. complete resolution
2. healing by CT replacement (fibrosis) 3. progression to chronic inflammation |
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morphological patterns of acute inflammation
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serous: outpouring of a thin fluid, blister
fibrous: more severe injuries, characteristic of inflammation of the lining of body cavities like the meninges, pericardium, pleura suppurative or purulent: neutrophils, necrotic cells, edema fluid released ulcers: sloughing of inflammatory necrotic tissue: most common in the mouth, stomach, intestines, GI tract, LE |
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chronic inflammation
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prolonged inflammation in which inflammation, destruction, and repair occur simultaneously
RA, atherosclerosis, tuberculosis, chronic lung diseeases |
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causes of chronic inflammation
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persistent infections: can evoke delayed type hypersensitivity, sometimes cause a granulomatous reaction
prolonged exposure to potentially toxic agents autoimmunity; RA, lupus |
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morphophologic features of chronic inflammation
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infiltration of mononuclear cells (MACROPHAGES, lymphocytes, plasma cells)
tissue destruction angiogenesis fibrosis |
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mononuclear phagocyte system:
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contains monocytes and tissue macrophages (kupffner cells-liver, spleen, lymph nodes -sinus hisiocytes, lungs- alveolar macrophages)
half life of blood monocytes: 1 day tissue macrophages last several months or years |
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When do monocytes appear at inflamed site?
Which cells are known to be in acute inflammatory reactions? |
48 hours
neutrophils |
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lymphocytes
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part of chronic inflammation
produce IFN-gamma, a major activator of macrophages |
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eosinophils
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part of chronic inflammation
abundant in immune reactions mediated by IgE and parasitic infections eotaxin: recruits eosinophils |
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Mast cells
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bind the Fc portion of IgE antibody
they degranulate and release histamine participate in anaphylactic reactions |
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granulomatous inflammation
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focal accumulations of activated macrophages
TB Sarcoidosis cat-scratch disease lymhogranuloma inguinale leprosy brucellosis syphilis some mycotic infections berylliosis reactions of irritant lipids ID by biopsy |
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lymphatics
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delicate channels that readily collapse
lined by continuous thin endothelium with loose, overlapping cell junctions, scant basement membrane, and no muscular support |
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systemic effects of inflammation or systemic inflammatory response syndrome
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fever:
produced in response to pyrogens that act by stimulating prostaglandin synthesis lipopolysaccharides are exogenous pyrogens |
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acute phase proteins
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C-reactive protein: marker for increase risk of MI, caused by inflammation involving atherosclerotic plaques
fibrinogen: causes erythrocytes to form rouleaux (stacks) and sediment more rapidly- measure erythrocyte sedimentation rate serum amyloid A protein: causes secondary amyloidosis in chronic inflammation |
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leukocytosis
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elevated WBC count due to increased release of cells from bone marrow and post-mitotic reserve pool
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neutrophilia
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increase in neutrophil count
a common reaction to bacterial infections |
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cause of lymphocytosis
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viral infections
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cause of eosinophilia
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allergies
parastic infections |
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causes of leukopenia
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decreased numbers of WBCs
typhoid fever rickettsiae protozoa |
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systemic effects of inflammation
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increased pulse and BP
decreased sweating rigors: shivering chills anorexia somnolence malaise |
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cytokine that causes disseminated intravascular coagulation
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TNF
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tissue factor
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stimulated by LPS and TNF
initiates coagulation |
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systemic effects of inflammation: sepsis
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cytokines cause liver injury: failure to maintain normal blood glucose due to lack of gluconeogenesis
overproduction of NO-> heart failure and loss of perfusion pressure-> hemodynamic shock |
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septic shock (clinical triad of symptoms)
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1. disseminated intravascular coagulation
2. hypoglycemia 3. cardiovascular failure can result in organ failure |
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neutrophil damage in sepsis
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if neutrophils are activated before they exit the vasculature they can cause damage to endothelial cells and reduce blood flow
the lungs and liver are particularly sensitive to this |
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problems caused by defective inflammation
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increased susceptibility to infections
delayed healing of wounds and tissue damage |
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consequences of defective or excessive inflammation
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fibrosis
examples: cancer allergies autoimmune diseases alzheimer atherosclerosis |
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edema
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excess fluid in interstitial tissue/body cavities
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pus
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exudate with abundant neutrophils/debris
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exudate
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protein rich fluid
high specific gravity sign of infection |
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cardinal signs of inflammation
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rubor: redness
tumor: swelling calor: heat dolor: pain functio laesa: loss of function |
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hallmark of acute inflammation
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increased vascular permeability- edema
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causes of edema
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loss of protein (reduced intravascular osmotic pressure, increased extravascular osmotic pressure)
increased hydrostatic pressure from vasodilation increased extravascular fluid |
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complement
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C3a, C5a, C4a: anaphylatoxins, increased vascular permeabilit/vasodilation by histamine
C5a: chemotactic for PMN, monocytes, basophils, increased adhesion to endothelium C3b/bi: opsonins |
