Lecture 5微生物学美国IndianaUniversityPurdueUniversity授课05 Still waters run deep.流静水深流静水深,人静心深人静心深 Where there is life, there is hope。有生命必有希望。有生命必有希望Lecture 5Constitutive DefensesBarriers to entrySee Schaechter text, Table 6.1Mucous membranescovered by protective layer of mucusMechanical and chemical barrier that allows proper functioningCross-linked gel structure composed of glycoprotein subunitsBIOL 5332Lecture 5Mucus MembranesEntraps particles and prevents them from getting to mucus membraneHydrophilic: allows passage of a number of bodily substancesAntimicrobial substances (lysozyme and peroxidase)Can withstand substantial weight, but still be propelled by ciliaBIOL 5333Lecture 5Defenses of Deep TissuesRole of constitutive defensesList of humoral mediators of constitutive defenses (See Schaechter text, Table 6.2)BIOL 5334Lecture 5Defenses of Deep TissuesRole of constitutive defenses, contd.Inflammatory response does not require previous contact with microorganismElicited by complex effectors, many of which are complement systemNormally at basal level and must be further increased by presence of microorganisms in tissuesMost important consequence of activity is phagocyte attractionBIOL 5335Lecture 5Defenses of Deep TissuesInteraction of constitutive (inflammatory response) and inducible defenses (immune response)Inducible response cannot occur without constitutive mediatorsMediators lead to induction of immune response and also defend against microbial invaderBIOL 5336Lecture 5InflammationGeneral aspectsReaction to tissue injurymanifested by pain, swelling, heat, and throbbing of locationLocation appears red and shiny, hot and painful to touch as a result of changes in local blood vessels and lymphaticsTissues may return to normal or scarring may resultBIOL 5337Lecture 5InflammationTissues may return to normal or scarring may result; depends on extent of damage done:By injuryBy infecting microbesBy inflammatory responseBIOL 5338Lecture 5InflammationDescription of changesBlood supply increases to affected part due to vasodilationCapillaries become more permeable, allowing fluid and large molecules to move into tissuesConsequence of inflammationpH of inflamed tissues loweredProduction of lactic acidantimicrobialBIOL 5339Lecture 5InflammationMolecular basis of inflammatory response and acute phase responseInflammatory response starts with activation of complement or of blood-clotting cascadeComplement and clotting are interactiveEither can set off the otherNormally, clotting is seen when acute inflammatory response is severeBIOL 53310Lecture 5Molecular BasisInflammatory response leads to production and release of a number of chemical effectors of inflammation responsible for vascular permeability, vasodilation, and painHistamineKininLeukotrienes and prostaglandinsBIOL 53311Lecture 5Molecular BasisHistamine is one of best-knownDilates blood vessels and increases permeabilityMechanism of productionThree peptides (C3a, C4a, and C5a; anaphylotoxins) produced by activation of complement systemStimulate release of histamine from mast cellsBIOL 53312Lecture 5Molecular BasisKininsmall basic peptidesAlter vascular toneIncrease permeabilityMay initiate or potentiate release of other chemical mediators from leukocytesBradykinin is best-knownBIOL 53313Lecture 5Molecular BasisProduction of kininsHageman factor activated during inflammation (one of substances that can activate is LPS)Induces production of kininsAlso plays important role in blood coagulationCleavage of precursor kininogens activated by enzymes (kallikreins) produced during clotting cascade or release from granulocytesBIOL 53314Lecture 5Molecular BasisLeukotrienes and prostaglandinsAct on motility and metabolism of wbcTwo plus certain phospholipids cause aggregation of blood platelets (important to stop bleeding)Prostaglandins synthesized in hypothalamus act on temperature regulatory centers of brain and cause feverBIOL 53315Lecture 5Molecular BasisAspirin prevents both synthesis and effects of prostaglandinsFever provides:Important warning sign of infectionInterference with antimicrobial mechanismBIOL 53316Lecture 5Mechanism of InflammationInjured tissue cells release inflammatory mediators that activate inner lining (endothelium) of capillariesBIOL 53317Lecture 5Mechanism of InflammationWithin capillaries, selectins (cell adhesion molecules) Psel then EselRandomly attract and attach neutrophilsSlow them down; cause to move through capillariesBIOL 53318Lecture 5Mechanism of InflammationEncounter inflammatory activatorsIntegrins on neutrophils (adhesion receptors)Attach to endothelial receptorsICAM1intracellular cell adhesion moleculeVCAMvascular adhesion moleculeBIOL 53319Lecture 5Mechanism of InflammationNeutrophils stick to endothelium and stop movingUndergo dramatic shape changes; migrate through wall into tissue spaceBIOL 53320Lecture 5Mechanism of InflammationInflammatory mediators released by injured tissue also raise acidity in extracellular fluidDecrease in pH activates extracellular enzyme kallikrein; splits bradykin from precursorBIOL 53321Lecture 5Mechanism of InflammationBradykin binds to receptors on capillary wall, opening junctions between cells; allows leukocytes and fluid into tissuesAlso, simultaneously binds to mast cells in connective tissue Activates mast cells (by influx Ca+2) degranulation; release of preformed mediators histamineBIOL 53322Lecture 5Mechanism of InflammationIf nerves damaged, they release substance P; also bind to mast cells, increasing preformed mediator releaseHistamine makes intercellular junctions in capillary wall wider, so more fluid, leukocytes, kallikrein, and bradykinin precursors move out, causing edemaBIOL 53323Lecture 5Mechanism of InflammationBradykinin then binds to nearby capillary cells and stimulates production of prostaglandins PGE2 and PGE2, causing tissue swellingProstaglandins also bind to nerve endings, causing painBIOL 53324Lecture 5Mechanism of InflammationChange in mast cell plasma membrane permeability allows phospholipase A2 to be converted to arachidonic acidArachidonic acid proceeds through cyclo- oxygenase pathway -OR- lipoxygenase pathway (depends on mast cell type)BIOL 53325Lecture 5Mechanism of InflammationPathways yield synthesized mediatorsProstaglandin E2 F2Thromboxane A2Slow-reacting substanceLeukotrienesSee Prescott, Fig. 29.13 Biochemical Effects of InflammationBIOL 53326Lecture 5InflammationAcute phase responseduring inflammation, certain proteins are released (chiefly from the liver) and their concentration rises in seraBIOL 53327Lecture 5Acute Phase ResponseRise in sera is disproportionateC-reactive protein (reacts with C polysaccharide of pneumococci and other bacterial Ag) and serum amyloid A protein increase 1000 times or more1-antitrypsin and complement factor B increase by 2 or 3 foldBIOL 53328Lecture 5Acute Phase ResponseDifferent functionsC-reactive proteinenhances inflammatory response by activating complement1-antitrypsininhibits proteases that function in inflammationBIOL 53329Lecture 5Acute Phase ResponseOther important proteins releasedThose that avidly bind iron and other metalsReduces availability of required ions for microorganismsHelps inhibit microbe growthInduction of responseproteins (cytokines) formed by “activated monocytes”BIOL 53330Lecture 5Induction of ResponseInterleukin-1 (IL-1); endogenous pyrogenCauses fever by stimulating prostaglandinsStimulates proliferation of cells involved in immune responseEnhances stickiness of inside surface of endothelial cells in capillaries to neutrophilsFacilitate movement to particular areaBIOL 53331Lecture 5Induction of ResponseTumor necrosis factor (TNF; cachectin)Has antitumor activityCauses weight loss (severe problem in certain chronic infections, such as tuberculosis and some cancers)BIOL 53332Lecture 5Induction of ResponseCharacteristics of both IL-1 and TNFPlay major role in “shock response” elicited during some serious bacterial infectionsBoth made in response to presence of microorganismsBIOL 53333Lecture 5Induction of ResponseOther important cytokinesInterleukin-2Involved in proliferation of immunologically important cellsUsed therapeutically to treat certain tumorsInterleukin-6 (hepatocyte-stimulating factor)Involved in synthesis of acute phase response proteins by the liverBIOL 53334Lecture 5ComplementGeneral characteristicsComprises as many as 26 proteins found in sera and some as a part of cell membranesMediates large number of biological effectsInteracts with other complex systems, includingBlood-clotting Specific immune responseBIOL 53335Lecture 5ComplementNormally present at basal levelWhen activated, enhances antimicrobial defensesMaking intruding bacteria susceptible to phagocytosisCausing lysis of bacteriaProducing chemotactic substancesPromoting inflammatory responseBIOL 53336Lecture 5ComplementActivation (proteolytic cleavage of precursor) in one of two ways that produce same end productsClassical pathway:activated by presence of Ag-Ab complexesAlternative pathway: independent of Ab elicited by bacterial surface components, such as LPSBIOL 53337Lecture 5Role of ComplementIn patient studies, patients genetically lacking some of complement components are very susceptible to bacterial diseases (some life-threatening)Enhancing phagocytosisRecruitment of wbc by chemotactic proteinFacilitation by proteins called opsoninsBIOL 53338Lecture 5Role of ComplementResponsible for lysis of:BacteriaSome virusesForeign cellsCan even lyse foreign cells with membranes containing viral proteinBIOL 53339Lecture 5Role of ComplementMechanism of lysiscarried out by membrane attack complexInserts itself into membranes and alters their permeabilityParticularly important with bacteria that have resistance mechanisms against phagocytosisNeisseria (gonorrhea) & streptococci (meningitis)Patients with genetic deficiencies for mak components very susceptible to these diseasesBIOL 53340Lecture 5Role of ComplementInduces inflammatory response via formation of interleukin-1, TNF, and anaphylatoxinsBeneficial: inflammatory response helps fight invading microbesBIOL 53341Lecture 5Role of ComplementNegative: in patients with hypersensitivity disorders, inflammatory response damages sensitive tissueCause leukocytes to secrete lysosomal enzymesDiseases include rheumatoid arthritis, serum sickness, and infective endocarditisBIOL 53342Lecture 5Lecture 5Questions?Comments?Assignments.BIOL 53343