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1、中国医科大学病理学英文课件6 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 injure
2、d factor eliminating and absorbing necrotic tissue3)The inflammatory responses is closely intertwined with the process of repair 4)Significance(1)Beneficial:without inflammation Infections would go unchecked injured organs might remain permanent festering sores wound would never heal(2)Harmful:hyper
3、sensitive reactions to drugs,toxins underlie common chronic diseases rheumatoid arthritis,atherosclerosis,and lung fibrosis fibrous repair disfiguring scars or fibrous bands that cause intestinal obstruction or limit the mobility of joints.2.Causes of inflammation1.Biologic factors:bacteria,Virus,fu
4、ngi,parasites the most common2.Chemical factors Exogenous:drugs,acid Endogenous3.Physical agents:trauma,burn 4.Allergic reaction:GN,TB lupus3.Basic pathologic changes1.Alteration Degeneration,necrosis of local tissue and cellslParenchymal C cellular swelling fatty change coagulative,liquefactive nec
5、rosislMesenchymal C mucoid change amyloid change fibrinoid necrosis hyaline change 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,hepat
6、ocyte Mesenchymal:fibroblast,EC,histocyte 4.Clinical types1)Acute 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
7、,fibrosis LC,PC,Macrophage infiltration病病 例例 六六病史：病史：男性，男性，4040岁，颈部患岁，颈部患“疖疖”，红、，红、肿、肿、热、痛，热、痛，1010天后局部红肿发展至手天后局部红肿发展至手掌大，体温掌大，体温3838，局部手术切开引流。，局部手术切开引流。当晚即恶寒、高热、头痛，次日体检发当晚即恶寒、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
8、述临床表现。Section 2.Acute inflammationlTwo major mechanisms of host defense:Antibody Leukocyteslmajor components:1)Changes of hemodynamics 2)Fluid exudationFluid exudation 3)Leukocyte extravasation and phagocytosisLeukocyte extravasation and phagocytosisagainst microbesI.Changes of hemodynamics1.Alterat
9、ion in vascular flow and caliber 1)Transient 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 (2)Related to the factors of:Body fluid:chemical mediator Nervous:ax
10、on reflection 3)Slowing of blood flow:increased permeability of the microvasculature outpouring of fluid into extracellular tissues concentration of RBC and increased viscosity of blood stasis of blood flowNormal blood flow Vasodilationincreased blood flowSlowing of blood flowStasis of blood flow Ex
11、travasation(fluid and leukocyte)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 venuleslImmediate transient response:occurs rapidly after
12、 exposure to the mediator and is usually reversible and short-lived(15 to 30 minutes)lmost common mechanism of vascular leakage and is elicited by:histamine,bradykinin,substance P,leukotriene2)Cytoskeletal reorganizationDelayed prolonged responsel induced by cytokines(IL-1,TNF,IFN-),lincreased perme
13、ability after a delay of 4 to 6 hours lasting for more than 24 hours linvolves venules as well as cap.lthe 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 c
14、hannels4)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 repaired5)Leukocyte-mediated endothelial injuryMild-t
15、o-moderate thermal injury,toxin,x-radiaton increased leucocyte infiltration involves venules as well as cap.Leukocyte adhere to EC activatedReleasing toxic species and proteolytic enzymes6)High permeability of new capsduring repair,endothelial cells proliferate and form new blood vessels New vessels
16、 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 EClDiagrammatic representation of five mechanisms of increased vascular permeabi
17、lity in inflammation 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 interstitial fluidBlood pressure and plama coll
18、oid osmotic forces in normal and inflammed microcirculation.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 high protein concentration,cellular debris,and a higher gra
19、vity.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 plasma that results from osmotic or hydrostatic imbalanc
20、e across the vessel wall.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 No Have Specific gravity 1.018 Cell number 1000106/L Autoaggluti
21、nation No Yes Appearance Clear Cloudy3)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 pathogen:Ab,complement(4)Fibrin mesh:limit the spreading of pathogenic organism
22、s limit the removing of MIII.Leukocyte extravasation and phagocytosis1)Leukocyte extravasation:leukocyte pass through vascular wall into the site of injury.Divided into following steps:Margination and rolling Adhesion Transmigration and chemotaxis (1)Margination and rolling leukocyte in central axia
23、l column BV dilation,speed of blood flow margination rolling pavementing appearanceLeukocytic emigration (2)Adhesion:a.By binding of complementary adhesion molecules on the leukocyte and endothelial surfacesb.Adhesion molecules:The immunoglobulin family:I(V)CAM-1 Integrins selectinsc.Mechanisms of a
24、dhesive 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 surface Binding to the receptor of leukocyteii)Induction of adhesion molecules synthesisSome inflammatory mediators,(I
25、L-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-selectiniii)Increased avidity of binding For example:LFA-1 Present on neutrophils,monocyte,LC Not adhere to its ligand ICAM-1 o
26、n EC owing to leukocyte activation LFA-1 converted from a state of low-affinity binding to high affinity binding toward ICAM-1Regulation of endothelial and leukocyte adhesion molecules.A,Redistribution of P-selectin.B,Cytokine activation of endothelium.C,Increased binding avidity of integrins(3)Tran
27、smigration and chemotaxis Injured venules or caps,leukocytes insert pseudopods into junction between ECs squeeze through interendothelial junctions secrete collagenase decompose the BM escape into interstitial tissue pseudopodAdhension and transmigration Red cell diapedesis:a passive process,determi
28、ne injured extent The type of leukocyte varies with the age of inflammatory lesion:i)Acute:neutrophils predominate during the first 624hs;are replaced by monocyte in 2448hsii)Chronic:LC,PC,monocyteLCPCNeutrophilsMC Basophil 12-15 mEosinophil 12-15m Neutrophil 12-15 mMonocyte 14-20 mLmphocyte 6-8 mRB
29、C 7.5 m The type of emigrating leukocyte varies with the types of stimulus:i)Viral infection:LC first C to arriveii)Hypersensitivity reaction Parasite infectioniii)Bacterial infection:neutrophilsEosinophils Chemotaxis:after extravasation leukocytes emigrate toward the chemical mediators along a chem
30、ical concentration gradient.Chemotactic agent:Exogenous:bacterial products Endogenous:complements(C5a)leukotriene B4(LTB4)cytokines:chemokine Chemotaxis(4)The roles of leukocytes A critical function of inflammation is to deliver leukocytes to A critical function of inflammation is to deliver leukocy
31、tes to the site of injury and to activate the leukocytes to perform the site of injury and to activate the leukocytes to perform their normal functions in host defense.their normal functions in host defense.Phagocytosis(ingest offending agents)Immunological function(kill bacteria and other microbes,
32、and get rid of necrotic tissue and foreign substances)Leukocyteinduced tissue injury Phagocytosis:Leukocyte emigrate to inflammatory focus engulf and kill or degradate the pathogenic organism and tissue debris.a.Types of phagocytes Neutrophils:1012um i)Azurophilic granules:lNeutral proteinase and ac
33、idic hydrolase Digest and degradate debris,dead bacterialMyeloperoxidase,phospholipase A2,lysozyme,and cation protein kill the bacteriaii)Specific granules:Lysozyme,lactoferrin,Alkali phosphatase,phospholipase A2 Macrophage:1224umi)Site distributed in CT,liver(kupffer C)spleen,LN,lung inflammatory f
34、ocus:derived from blood monocyte kill bacteriaii)Functions:Phagocytosis eliminate the dead bacteria,cells,debris,foreign bodies that cant be digested b.Process of phagocytosis:Involves three steps:Recognition and attachment Engulfment killing or degradation Recognition and attachment:i)Opsonins:a ki
35、nd of protein in serum which enhances the efficiency of phagocytosis ii)Opsonization:microorganism contact with the serum contained opsonins and are coatediii)Major opsonins Fc fragment of IgG C3b collectins Engulfment Engulfment Binding of opsonized particle to the Fc receptor of phagocytic leukocy
36、te 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 phagocytic vacuole then fuses with the limiting membrane of a lysosomal granuleresulting in discharge of the granules contents into the
37、 phagolysosome.Process of phagocytosisOpsonizationattachmentattachmentEngulfmentEngulfmentPhagosome phagolysosomePhagocytosis of a particle(e.g.,bacterium)involves attachment and binding of Fc and C3b to receptors on the leukocyte membrane,engulfment,and fusion of lysosomes with phagocytic vacuoles,
38、followed by destruction of ingested particles within the phagolysosomes.killing or degradation:i)Phagolysosome release many enzymesii)Killing is accomplished largely by oxygen-dependent mechanismlThe generation of reactive oxygen intermediates is due to the rapid activation of NADPH oxidase,which ox
39、idizes NADPH and,in the process,reduces oxygen to superoxide anion.lSuperoxide is then converted into hydrogen peroxide(H2O2).The H2O2 generated by the NADPH oxidase system is generally not able to efficiently kill microbes by itself.lThe azurophilic granules of neutrophils contain the enzyme myelop
40、eroxidase(MPO),which,in the presence of a halide such as Cl-,converts H2O2 to hypochlorite(HOCl).lThe H2O2-MPO-halide system is the most efficient bactericidal system in neutrophils.Oxygen-dependent mechanismOxygen-dependent mechanismProduction of microbicidal reactive oxygen intermediates within ph
41、agocytic vesicles.iii)Oxygen-independent mechanismA.Bactericidal permeability increasing protein phospholipase activation phospholipid degradationB.Lysozyme:hydrolyzes the coat of BacteriaC.Cationic protein(eosinophils):limited bac.activity cytotoxic to many parasites.Immunological function:B cell P
42、C Ab T cell lymphokine NKC:dissolve cell infected by virus Leukocyteinduced tissue injury:During leukocyte activation,phagocytosis,lysosomal enzymes oxygen-derived active metabolites mediators(leukotriene,prostaglandin)cell tissue injury(5)Defect in leukocyte function (1)Acquired:AIDS Th destroyed a
43、nd M dysfunction (2)Others Defect in:leukocyte adhesion:recurrent bacterial infections and impaired wound healing phagolysosome function:neutropenia(decreased numbers of neutrophils),defective degranulation,and delayed microbial killing bone marrow suppression:leading to reduced production of leukoc
44、ytes Severe infectionIV.Inflammatory mediators The vascular and cellular reactions of both 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 chem
45、ical agents produced in response to or activated by the inflammatory stimulusGeneral 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 Plasma-derived mediators:present in
46、precursor form activated by proteolytic cleavages Most mediators perform their biologic activity by binding to specific receptors on target cells.Some have direct enzymatic activity mediated oxidative damage One chemical mediator can stimulate the release of others mediators by target cell themselve
47、s.Secondary mediator Similar or different to the initial mediators Amplifying or opposing activities (counteracting the initial mediators)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
48、 are short-lived decay,inactivated,scavenged,inhibited Most mediators have the potential to cause harmful effects.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 ven
49、ules chemotaxis to eosinophils Stimuli that cause histamine release:l Physical injury:trauma,cold,heatl Immune reaction:IgE mast celll Fragments of complement:C3a,C5al Histamine-releasing protein(leukocyte)l Neuropeptides,substance Pl Cytokines:IL-1,IL-8(2)5-HT(5-hydrooxytryptamine)or serotonin Site
50、s Platelets Enterochromaffin cells of intestine Function:increases vascular permeability Stimuli that cause 5-HT release:Collagen,thrombin Adenosine diphosphate(ADP)Platelet activating factor(PAF)2)Arachidonic acid metabolites:(1)Prostaglandin(PG):Vasodilation;increased permeability;fever and pain(2