physiological processes

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Physiological Processes: Basic Concepts

Physiological Processes:Basic ConceptsSystemic Inflammatory Response Syndrome (SIRS)Multiple Organ Dysfunction Syndrome (MODS)1The Immune System Strives to:Eliminate infection and damaged tissueMaintain an appropriate response levelAvoid or minimise disruption to homeostasisPromote healing2Types of Immunity:Non-specific (innate):Natural barriersInflammation

Specific (acquired):- T and B lymphocytes

3The Inflammatory ResponseThe inflammatory response:A series of localised cellular responsesHelps to eliminate invading antigens and damaged tissue, and prevent them spreading to other areas of the body.Complete the following multimedia tutorial on the basic concepts of inflammation.

http://www.nottingham.ac.uk/nmp/sonet/rlos/bioproc/inflam/index.html

Antigen - any substance that can trigger an immune response.4The Innate Immune System and HomeostasisInvasiveness of microbe.Risk to HomeostasisAction of innate immune systemskin surfacesuperficial tissue layerscirculation & body systemsnatural barrierslocalised inflammationsystemic inflammatory response (SIRS)BENEFICIALDETRIMENTAL5Immunity is mediated by:Soluble molecules:cytokines e.g. interleukin (IL)others: prostaglandin (PG), reactive oxygen species (ROS)

Cytokines:small proteins alter behaviour of other cellsact via cell-surface receptorsshort-livedimportant examples in inflammation:IL-1, IL-6, IL-8, tumour necrosis factoralpha (TNF-).6Trigger: e.g. invading bacteria endotheliumPotent molecules releasede.g. ROSKey effector cells: neutrophilTNF-a, IL-1IL-8Physiological changes associated with immunity i.e. inflammationmacrophageKey effector cell: Chemical mediators of the inflammatory response7Invading bacteriaendotoxin (lipopolysaccharide - LPS)endotheliumplasmamacrophageIL-8chemotaxisneutrophilskin surfacetissue and interstitial fluidChemical mediators of the inflammatory responseIL-1TNFactivates endothelia8vasodilationpermeabilityadhesionrolling adhesionChemical mediators of the inflammatory responseInvading bacteriamacrophageskin surfacetissue and interstitial fluidendotheliumplasmaIL-1TNFaIL-8Check NO and PGendotoxin (lipopolysaccharide - LPS)Nitric oxide (NO)Prostaglandin (PG)9SelectinendotheliumplasmadiapedesisChemical mediators of the inflammatory responseInvading bacteriamacrophageskin surfacetissue and interstitial fluidIL-1TNFaIL-8complement fibrinogen antibodiesendotoxin (lipopolysaccharide - LPS)Nitric oxide (NO)Prostaglandin (PG)10skin surfacetissue and interstitial fluidendotheliumplasmamigration and phagocytosismore neutrophils and monocytes.Chemical mediators of the inflammatory responsemacrophageskin surfaceIL-1TNFaIL-8Nitric oxide (NO)Prostaglandin (PG)complement fibrinogen antibodiesInvading bacteriaendotoxin (lipopolysaccharide - LPS)11reactive oxygen species (ROS)antimicrobial moleculeshydrolytic enzymesCopied to editChemical mediators of the inflammatory responseNeutrophils release powerful chemicals that destroy the pathogen.Some ROS may leak onto nearby tissues12TNF-alpha (TNF) is a powerful pro-inflammatory mediatorActivates endothelium: adhesion molecules are displayed - active substances releasedIncreases vascular permeabilityReleases C-reactive proteinInduces fever via hypothalamusMobilises neutrophils from bone marrow

TNFwith IL-1 and IL-6Chemical mediators of the inflammatory response13pro-inflammatory mediatorsTNF IL-1 IL-6 anti-inflammatory mediators IL-10 IL-4 glucocorticoidsMaintains inflammation at an appropriate magnitude to promote healthRegulation of the inflammatory response by chemical mediators.14What happens if local inflammatory responses fail?Natural barriers and local inflammatory responseSpecific immune responseChronic inflammation: infiltration of lymphocytes and plasma cellsBut cannot prevent microbial invasion into the blood.Acute inflammation: infiltration of neutrophils and macrophagesImmediate2-4 daysPotential outcomebacteraemia / septicaemiasystemic inflammatory response (SIRS)multiple organ dysfunction syndrome (MODS)15What could happen if local inflammatory responses fail

LHLH1. Macrophages activated in the liver and spleen secrete TNF into the blood.2. Systemic shift of fluid from plasma to tissue spaces causes a drop in blood volume and collapse of dilated blood vessels.LH3. Disseminated intravascular coagulation leads to wasting and multiple organ dysfuction.LH16Systemic Inflammation:A systemic inflammatory response causes:

1. systemic vasodilation2. increased capillary leak due to:(b) altered endothelial integrity(c) endothelial injury3. microvascular occlusion17bacterial LPSmacrophages in liver, spleenTNF, IL-1, IL-6vascular endotheliumnitric oxideprostaglandinSystemic Inflammation: 1. systemic vasodilation and vasopermeabilityhypotension, circulation problemsfluid resuscitationremedyremedyvasopressor medication18pro-inflammatory mediatorsTNF IL-1 IL-6 anti-inflammatory mediators IL-10 IL-4 glucocorticoidsMaintains inflammation at an appropriate magnitude to promote healthSystemic Inflammation: 1. systemic vasodilation and vasopermeability (regulation)19* Compensatory anti-inflammatory response syndrome (CARS)magnitude of responseexcessive PRO -inflammatory response*excessive ANTI-inflammatory responseadequate inflammatory responseShock: early mortalityImmunodepression: later mortalityTimeSystemic Inflammation: 1. systemic vasodilation and vasopermeability (regulation)20Due to monocyte deactiviationplasmaendotheliuminterstitial fluidTNF, IL-1capillary leakSystemic Inflammation: 2. Increased capillary leak (b) Altered endothelial integrity21ROSproteinasesdestroyscapillary leakSystemic Inflammation: 2. Increased capillary leak (b) Endothelial injuryplasmaendotheliuminterstitial fluidneutralisesanti-proteinases22TNF, IL-1ROSintrinsic coagulation pathway activatedblood clottingformationbreakdownfactor VIIaextrinsic coagulation pathway activateddisseminated Intravascular Coagulationmicrovascular occlusioncollagen matrix exposedSystemic Inflammation: 3. microvascular occlusion23OrganBlood vesselcapillary leak and build-up of IF increases diffusion distancesticky neutrophils form a plugthrombusischaemiaFunctionalinadequate supply / movement of gases & metabolitesorgan dysfunctionDevelopment of Multiple Organ Dysfunction Syndrome (MODS)Interstitial Fluid (IF)Oxygen and nutrientsCarbon dioxide and wastes24

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