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1、Section 1.Introduction 1.Definition:1)Inflammation:a defensive reaction in living tissue with vascular system to injurious stimuli.2)Reaction of BVs is the central link limiting and killing injured factor eliminating and absorbing necrotic tissue3)The inflammatory responses is closely intertwined wi
2、th the process of repair 第1页/共78页4)Significance(1)Beneficial:without inflammation Infections would go unchecked injured organs might remain permanent festering sores wound would never heal(2)Harmful:hypersensitive reactions to drugs,toxins underlie common chronic diseases rheumatoid arthritis,athero
3、sclerosis,and lung fibrosis fibrous repair disfiguring scars or fibrous bands that cause intestinal obstruction or limit the mobility of joints.第2页/共78页2.Causes of inflammation1.Biologic factors:bacteria,Virus,fungi,parasites the most common2.Chemical factors Exogenous:drugs,acid Endogenous3.Physica
4、l agents:trauma,burn 4.Allergic reaction:GN,TB lupus第3页/共78页3.Basic pathologic changes1.Alteration Degeneration,necrosis of local tissue and cellsParenchymal C cellular swelling fatty change coagulative,liquefactive necrosisMesenchymal C mucoid change amyloid change fibrinoid necrosis hyaline change
5、第4页/共78页 2.Exudation:In inflammatory foci,the escape of fluid,proteins(fibrin),blood cells from vascular wall into interstitial tissue,body cavities or surface of the body and mucosa3.Proliferation Parenchymal:epithelium,hepatocyte Mesenchymal:fibroblast,EC,histocyte 第5页/共78页4.Clinical types1)Acute
6、inflammation(1)Relatively short duration,lasting for a few days or a few weeks(2)Lesions exudation of fluid,neutrophils degeneration,necrosis2)Chronic inflammation(1)longer duration for a few months or years(2)Lesions Proliferation:BV,fibrosis LC,PC,Macrophage infiltration第6页/共78页病病 例例 六六病史：病史：男性，男性
7、，4040岁，颈部患岁，颈部患“疖疖”，红、肿、，红、肿、热、痛，热、痛，1010天后局部红肿发展天后局部红肿发展至手掌大，体温至手掌大，体温3838，局部手术切开引流。当晚即恶寒、高热、头痛，次日，局部手术切开引流。当晚即恶寒、高热、头痛，次日体检发现病人轻度黄疸，肝脾肿大，体温体检发现病人轻度黄疸，肝脾肿大，体温3939，WBCWBC计数计数21.0G/L21.0G/L。思考题：思考题：用所学的炎症知识，作出病理诊用所学的炎症知识，作出病理诊 断并解释上述临床表现。断并解释上述临床表现。第7页/共78页Section 2.Acute inflammationTwo major mechan
8、isms of host defense:Antibody Leukocytesmajor components:1)Changes of hemodynamics 2)Fluid exudationFluid exudation 3)Leukocyte extravasation and Leukocyte extravasation and phagocytosisphagocytosisagainst microbes第8页/共78页第9页/共78页I.Changes of hemodynamics1.Alteration in vascular flow and caliber 1)T
9、ransient vasoconstriction of arterioles:lasting for a few seconds.2)Vasodilation and increased blood flow(1)Arteriolar dilation opening of new cap beds increased blood flow inflammatory hyperemia第10页/共78页 (2)Related to the factors of:Body fluid:chemical mediator Nervous:axon reflection 3)Slowing of
10、blood flow:increased permeability of the microvasculature outpouring of fluid into extracellular tissues concentration of RBC and increased viscosity of blood stasis of blood flow第11页/共78页Normal blood flow Vasodilationincreased blood flowSlowing of blood flowStasis of blood flow Extravasation(fluid
11、and leukocyte)第12页/共78页2.Increased vascular permeability Increased permeability the most important cause resulting in exudation of fluid and protein Mechanism of Increased permeability 1)EC retraction Formation of endothelial gaps in venulesImmediate transient response:occurs rapidly after exposure
12、to the mediator and is usually reversible and short-lived(15 to 30 minutes)most common mechanism of vascular leakage and is elicited by:histamine,bradykinin,substance P,leukotriene第13页/共78页2)Cytoskeletal reorganizationDelayed prolonged response induced by cytokines(IL-1,TNF,IFN-),increased permeabil
13、ity after a delay of 4 to 6 hours lasting for more than 24 hours involves venules as well as cap.the endothelial cells retract from one another3)Increased transcytosis across the endothelial cytoplasm By transcytoplasmic channel VEGF,histamine,bradykinin,Increasing the number and the size of channel
14、s第14页/共78页4)Direct endothelial injury Immediate sustained response:severe burn,purulent Bacteria result in EC necrosis and detachment leakage starts immediately after injury sustained at a high level for several hours until damaged BV thrombosed and repaired第15页/共78页5)Leukocyte-mediated endothelial
15、injuryMild-to-moderate thermal injury,toxin,x-radiaton increased leucocyte infiltration involves venules as well as cap.Leukocyte adhere to EC activatedReleasing toxic species and proteolytic enzymes第16页/共78页6)High permeability of new capsduring repair,endothelial cells proliferate and form new bloo
16、d vessels New vessels sprouts remain leaky until ECs differentiate and form intercellular junctions.Certain factors that cause angiogenesis (VEGF)increase permeability Increased density of receptor for vasoactive mediators in the surface of EC第17页/共78页Diagrammatic representation of five mechanisms o
17、f increased vascular permeability in inflammation 第18页/共78页II.Fluid exudation 1)Major causes:Increased vascular permeability escape of a protein-rich fluid into the interstitium The loss of protein reduces intravascular colloid osmotic pressure increases the colloid osmotic pressure of the interstit
18、ial fluid第19页/共78页Blood pressure and plama colloid osmotic forces in normal and inflammed microcirculation.第20页/共78页exudation:The escape of fluid,proteins,and blood cells from the vascular system into the interstitial tissue or body cavities.Exudate:an inflammatory extravascular fluid that has a hig
19、h protein concentration,cellular debris,and a higher gravity.It implies significant alteration in the normal permeability of small blood vessels in the area of injury.Transudate:a fluid with low protein content(most of which is albumin)and a lower gravity.It is essentially an ultrafiltrate of blood
20、plasma that results from osmotic or hydrostatic imbalance across the vessel wall.第21页/共78页2)Distinguish between exudate and transudate Transudate Exudate Vascular permeability Normal Increased Protein concentration 30g/L Protein type Albumin Kinds of protein Rivalta test Negative(-)Positive(+)Fibrin
21、 No Have Specific gravity 1.018 Cell number 1000106/L Autoagglutination No Yes Appearance Clear Cloudy第22页/共78页3)Functions of exudate:(1)Dilute local toxins reduce the injury to tissue(2)Bring in the nutritional substance for leukocytes carry off the metabolic products in infla foci(3)kill the patho
22、gen:Ab,complement(4)Fibrin mesh:limit the spreading of pathogenic organisms limit the removing of M第23页/共78页III.Leukocyte extravasation and phagocytosis1)Leukocyte extravasation:leukocyte pass through vascular wall into the site of injury.Divided into following steps:Margination and rolling Adhesion
23、 Transmigration and chemotaxis第24页/共78页 (1)Margination and rolling leukocyte in central axial column BV dilation,speed of blood flow margination rolling pavementing appearance第25页/共78页Leukocytic emigration 第26页/共78页(2)Adhesion:a.By binding of complementary adhesion molecules on the leukocyte and end
24、othelial surfacesb.Adhesion molecules:The immunoglobulin family:I(V)CAM-1 Integrins selectins第27页/共78页c.Mechanisms of adhesive process:i)Redistribution of adhesion molecules to the cell surface:For example:P-selectin Normally present in W-P body of EC Histamine thrombin,PAF Redistributed to the cell
25、 surface Binding to the receptor of leukocyte第28页/共78页ii)Induction of adhesion molecules synthesisSome inflammatory mediators,(IL-1,TNF)induced the synthesis and surface expression of endothelial adhesion molecules For example:In normal EC No expression of E-selectin IL-1 TNF Synthesis and express E
26、-selectin第29页/共78页iii)Increased avidity of binding For example:LFA-1 Present on neutrophils,monocyte,LC Not adhere to its ligand ICAM-1 on EC owing to leukocyte activation LFA-1 converted from a state of low-affinity binding to high affinity binding toward ICAM-1第30页/共78页Regulation of endothelial an
27、d leukocyte adhesion molecules.A,Redistribution of P-selectin.B,Cytokine activation of endothelium.C,Increased binding avidity of integrins 第31页/共78页(3)Transmigration and chemotaxis Injured venules or caps,leukocytes insert pseudopods into junction between ECs squeeze through interendothelial juncti
28、ons secrete collagenase decompose the BM escape into interstitial tissue 第32页/共78页pseudopod第33页/共78页Adhension and transmigration第34页/共78页第35页/共78页 Red cell diapedesis:a passive process,determine injured extent The type of leukocyte varies with the age of inflammatory lesion:i)Acute:neutrophils predo
29、minate during the first 624hs;are replaced by monocyte in 2448hsii)Chronic:LC,PC,monocyteLCPCNeutrophilsMC第36页/共78页 Basophil 12-15 mEosinophil 12-15m Neutrophil 12-15 mMonocyte 14-20 mLmphocyte 6-8 mRBC 7.5 m第37页/共78页第38页/共78页 The type of emigrating leukocyte varies with the types of stimulus:i)Vira
30、l infection:LC first C to arriveii)Hypersensitivity reaction Parasite infectioniii)Bacterial infection:neutrophilsEosinophils第39页/共78页 Chemotaxis:after extravasation leukocytes emigrate toward the chemical mediators along a chemical concentration gradient.Chemotactic agent:Exogenous:bacterial produc
31、ts Endogenous:complements(C5a)leukotriene B4(LTB4)cytokines:chemokine 第40页/共78页Chemotaxis第41页/共78页(4)The roles of leukocytes A critical function of inflammation is to deliver leukocytes to the site of injury and to activate the leukocytes to perform their normal functions in host defense.Phagocytosi
32、s(ingest offending agents)Immunological function(kill bacteria and other microbes,and get rid of necrotic tissue and foreign substances)Leukocyteinduced tissue injury第42页/共78页 Phagocytosis:Leukocyte emigrate to inflammatory focus engulf and kill or degradate the pathogenic organism and tissue debris
33、.第43页/共78页a.Types of phagocytes Neutrophils:1012um i)Azurophilic granules:Neutral proteinase and acidic hydrolase Digest and degradate debris,dead bacteriaMyeloperoxidase,phospholipase A2,lysozyme,and cation protein kill the bacteria第44页/共78页ii)Specific granules:Lysozyme,lactoferrin,Alkali phosphata
34、se,phospholipase A2 Macrophage:1224umi)Site distributed in CT,liver(kupffer C)spleen,LN,lung inflammatory focus:derived from blood monocyte kill bacteria第45页/共78页ii)Functions:Phagocytosis eliminate the dead bacteria,cells,debris,foreign bodies that cant be digested 第46页/共78页b.Process of phagocytosis
35、:Involves three steps:Recognition and attachment Engulfment killing or degradation第47页/共78页 Recognition and attachment:i)Opsonins:a kind of protein in serum which enhances the efficiency of phagocytosis ii)Opsonization:microorganism contact with the serum contained opsonins and are coatediii)Major o
36、psonins Fc fragment of IgG C3b collectins第48页/共78页 Engulfment Binding of opsonized particle to the Fc receptor of phagocytic leukocyte Pseudopods to create a deep pocket complete enclosure of the particle within a phagosome created by the plasma membrane of the cell The limiting membrane of this pha
37、gocytic vacuole then fuses with the limiting membrane of a lysosomal granuleresulting in discharge of the granules contents into the phagolysosome.第49页/共78页Process of phagocytosisOpsonizationattachmentattachmentEngulfmentEngulfmentPhagosome phagolysosomePhagocytosis of a particle(e.g.,bacterium)invo
38、lves attachment and binding of Fc and C3b to receptors on the leukocyte membrane,engulfment,and fusion of lysosomes with phagocytic vacuoles,followed by destruction of ingested particles within the phagolysosomes.第50页/共78页 killing or degradation:i)Phagolysosome release many enzymesii)Killing is acco
39、mplished largely by oxygen-dependent mechanism第51页/共78页The generation of reactive oxygen intermediates is due to the rapid activation of NADPH oxidase,which oxidizes NADPH and,in the process,reduces oxygen to superoxide anion.Superoxide is then converted into hydrogen peroxide(H2O2).The H2O2 generat
40、ed by the NADPH oxidase system is generally not able to efficiently kill microbes by itself.The azurophilic granules of neutrophils contain the enzyme myeloperoxidase(MPO),which,in the presence of a halide such as Cl-,converts H2O2 to hypochlorite(HOCl).The H2O2-MPO-halide system is the most efficie
41、nt bactericidal system in neutrophils.第52页/共78页Oxygen-dependent mechanism第53页/共78页Oxygen-dependent mechanismProduction of microbicidal reactive oxygen intermediates within phagocytic vesicles.第54页/共78页iii)Oxygen-independent mechanismA.Bactericidal permeability increasing protein phospholipase activa
42、tion phospholipid degradationB.Lysozyme:hydrolyzes the coat of BacteriaC.Cationic protein(eosinophils):limited bac.activity cytotoxic to many parasites.第55页/共78页 Immunological function:B cell PC Ab T cell lymphokine NKC:dissolve cell infected by virus Leukocyteinduced tissue injury:During leukocyte
43、activation,phagocytosis,lysosomal enzymes oxygen-derived active metabolites mediators(leukotriene,prostaglandin)cell tissue injury第56页/共78页(5)Defect in leukocyte function (1)Acquired:AIDS Th destroyed and M dysfunction (2)Others Defect in:leukocyte adhesion:recurrent bacterial infections and impaire
44、d wound healing phagolysosome function:neutropenia(decreased numbers of neutrophils),defective degranulation,and delayed microbial killing bone marrow suppression:leading to reduced production of leukocytes Severe infection第57页/共78页IV.Inflammatory mediators The vascular and cellular reactions of bot
45、h acute and chronic inflammation are mediated by chemical factors that are derived from plasma proteins or cells and are produced in response to or activated by the inflammatory stimulus.Concept:A series of chemical agents produced in response to or activated by the inflammatory stimulus第58页/共78页Gen
46、eral features:Endogenous IM originated from plasma or cells Cell-derived mediators:Sequestered in intracellular granules that need to be secreted Synthesized in response to a stimulus 第59页/共78页 Plasma-derived mediators:present in precursor form activated by proteolytic cleavages Most mediators perfo
47、rm their biologic activity by binding to specific receptors on target cells.Some have direct enzymatic activity mediated oxidative damage 第60页/共78页 One chemical mediator can stimulate the release of others mediators by target cell themselves.Secondary mediator Similar or different to the initial med
48、iators Amplifying or opposing activities (counteracting the initial mediators)第61页/共78页 A mediator can act on one or few target cell types different effects depend on cell and tissue types.Once activated and released from cell,most of these mediators are short-lived decay,inactivated,scavenged,inhib
49、ited Most mediators have the potential to cause harmful effects.第62页/共78页1.Mediators released by cells1)Vasoactive amines(1)Histamine:Sites:Mast cell granules(the major site)Basophils and platelets Functions dilation of arterioles increase permeability of venules chemotaxis to eosinophils 第63页/共78页
50、Stimuli that cause histamine release:Physical injury:trauma,cold,heat Immune reaction:IgE mast cell Fragments of complement:C3a,C5a Histamine-releasing protein(leukocyte)Neuropeptides,substance P Cytokines:IL-1,IL-8第64页/共78页(2)5-HT(5-hydrooxytryptamine)or serotonin Sites Platelets Enterochromaffin c