1、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 with the process of repair lTwo major
2、mechanisms of host defense:Antibody Leukocyteslmajor components:1)Changes of hemodynamics 2)3)against microbes1.Alteration 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 ca
3、p beds increased blood flow inflammatory hyperemia (2)Related to the factors of:Body fluid:chemical mediator Nervous:axon reflection 3)Slowing of blood flow:increased permeability of the microvasculature outpouring of fluid into extracellular tissues concentration of RBC and increased viscosity of b
4、lood stasis of blood flowNormal blood flow Vasodilationincreased blood flowSlowing of blood flowStasis of blood flow Extravasation(fluid and leukocyte)Increased permeability the most important cause resulting in exudation of fluid and protein Mechanism of Increased permeability 1)EC retraction Forma
5、tion of endothelial gaps in venuleslImmediate transient response:occurs rapidly after 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 reorganiz
6、ationDelayed prolonged responsel induced by cytokines(IL-1,TNF,IFN-),lincreased permeability 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 trans
7、cytoplasmic channel VEGF,histamine,bradykinin,Increasing the number and the size of channels 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
8、 and repairedMild-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 enzymes6)High permeability of new capsduring repair,endothelial cells proliferate and form new blood
9、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 EClDiagrammatic representation of five mechanisms of increase
10、d vascular permeability in inflammation 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
11、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
12、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
13、e across the vessel wall.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 Autoagglutination No Yes Appearance Clear Cloudy(1)Dilut
14、e 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 organisms limit the removing of M1)Leukocyte extravasation:leukocyte pass th
15、rough 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 axial column BV dilation,speed of blood flow margination rolling pavementing appearanceLeukocytic emigration a.By bi
16、nding of complementary adhesion molecules on the leukocyte and endothelial surfacesb.Adhesion molecules:The immunoglobulin family:I(V)CAM-1 Integrins selectinsi)Redistribution of adhesion molecules to the cell surface:For example:P-selectin Normally present in W-P body of EC Histamine thrombin,PAF R
17、edistributed to the cell surface Binding to the receptor of leukocyteSome 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-selectin For example:LFA-1 P
18、resent 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-1Regulation of endothelial and leukocyte adhesion molecules.A,Redistribution of P-selectin.B,Cytokine activa
19、tion of endothelium.C,Increased binding avidity of integrins Injured venules or caps,leukocytes insert pseudopods into junction between ECs squeeze through interendothelial junctions secrete collagenase decompose the BM escape into interstitial tissue pseudopod Red cell diapedesis:a passive process,
20、determine 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
21、6-8 mRBC 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
22、 a chemical concentration gradient.Chemotactic agent:Exogenous:bacterial products Endogenous:complements(C5a)leukotriene B4(LTB4)cytokines:chemokine Phagocytosis(ingest offending agents)Immunological function(kill bacteria and other microbes,and get rid of necrotic tissue and foreign substances)Leuk
23、ocyteinduced tissue injury Phagocytosis:Leukocyte emigrate to inflammatory focus engulf and kill or degradate the pathogenic organism and tissue debris.Neutrophils:1012um i)Azurophilic granules:lNeutral proteinase and acidic hydrolase Digest and degradate debris,dead bacterialMyeloperoxidase,phospho
24、lipase A2,lysozyme,and cation protein kill the bacteriaLysozyme,lactoferrin,Alkali phosphatase,phospholipase A2 Macrophage:1224umi)Site distributed in CT,liver(kupffer C)spleen,LN,lung inflammatory focus:derived from blood monocyte kill bacteria Phagocytosis eliminate the dead bacteria,cells,debris,
25、foreign bodies that cant be digested Involves three steps:Recognition and attachment Engulfment killing or degradationi)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 op
26、sonins Fc fragment of IgG C3b collectins 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 phagocytic vacuole then
27、fuses with the limiting membrane of a lysosomal granuleresulting in discharge of the granules contents into the phagolysosome.OpsonizationPhagosome phagolysosomePhagocytosis of a particle(e.g.,bacterium)involves attachment and binding of Fc and C3b to receptors on the leukocyte membrane,engulfment,a
28、nd fusion of lysosomes with phagocytic vacuoles,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 t
29、o the rapid activation of NADPH oxidase,which oxidizes 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 g
30、ranules of neutrophils contain the enzyme myeloperoxidase(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.Production of microbicidal reactive oxygen intermediates within phagoc
31、ytic vesicles.A.Bactericidal permeability increasing protein phospholipase activation phospholipid degradationB.Lysozyme:hydrolyzes the coat of BacteriaC.Cationic protein(eosinophils):limited bac.activity cytotoxic to many parasites.B cell PC Ab T cell lymphokine NKC:dissolve cell infected by virus
32、Leukocyteinduced tissue injury:During leukocyte activation,phagocytosis,lysosomal enzymes oxygen-derived active metabolites mediators(leukotriene,prostaglandin)cell tissue injury (1)Acquired:AIDS Th destroyed and M dysfunction (2)Others Defect in:leukocyte adhesion:recurrent bacterial infections and
33、 impaired 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 The vascular and cellular reactions of both acute and chronic inflam
34、mation 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 stimulusGeneral features:Endogenous IM origina
35、ted 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 precursor form activated by proteolytic cleavages Most mediators perform their biologic activity by binding to spec
36、ific 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 themselves.Secondary mediator Similar or different to the initial mediators Amplifying or opposing activities (counteracting
37、 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 are short-lived decay,inactivated,scavenged,inhibited Most mediators have the potential to cause harmful effects.1
38、)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 Stimuli that cause histamine release:l Physical injury:trauma,cold,heatl Immune reaction:IgE mast celll Fragments
39、 of complement:C3a,C5al Histamine-releasing protein(leukocyte)l Neuropeptides,substance Pl Cytokines:IL-1,IL-8(2)5-HT(5-hydrooxytryptamine)or serotonin Sites Platelets Enterochromaffin cells of intestine Function:increases vascular permeability Stimuli that cause 5-HT release:Collagen,thrombin Adeno
40、sine diphosphate(ADP)Platelet activating factor(PAF)(1)Prostaglandin(PG):Vasodilation;increased permeability;fever and pain(2)Leukotrienes(LT):Chemotactic agent of neutrophils Intense vasoconstriction and bronchospasm Increased vascular permeability(3)Lipoxins(LX):anti-inflammation Inhibit neutrophi
41、l chemotaxis and adhesion Stimulate monocyte adhesion Stimulate vasodilationlGeneration of arachidonic acid metabolites and their roles in inflammation.3).Cytokines:Types:l Cytokines that regulate LC function:IL-2,TGF-l Cytokines involved in natural immunity:TNF,IL-1l Cytokines that activate macroph
42、ages:IFN-,IL-12l Cytokines that stimulate hematopoiesis:IL-3,colony-stimulating Fl Chemokines:chemotactic activity for leukocyte Major cytokines:IL-1 and TNF,EC adherent to leukocyte neutrophils chemotaxis stroma release of proteinase Fever,cachexia,anorexiaEnhancelMajor effects of interleukin-1(IL-
43、1)and tumor necrosis factor(TNF)in inflammation.4).Platelet-activating factor(PAF):Sources Platelet,basophils,Mast cell,neutrophil Monocyte,EC Function:Activates platelet Vasodilation,increased permeability Vasoconstriction and bronchoconstriction Increase leukocyte adhesion,chemotaxis Neutrophils a
44、nd monocytes contain lysosomal granules various enzymes increased vascular permeability,chemotaxis,tissue damage1)Nitric oxide(NO)Sources EC(main),macrophage specific neurons in the brain Functions:A potent vasodilator SM relaxation Reduces pt aggregation and adhesion Inhibits mast cell-induced infl
45、ammation Serves as an endogenous regulator of leukocyte recuitmentFunctions of nitric oxide(NO)in blood vessels and macrophages.NO causes vasodilation,and NO free radicals are toxic to microbial and mammalian cells.NOS,nitric oxide synthase.2)Oxygen-derived active metabolites Released from neutrophi
46、ls and monocyte:Superoxide anion(O2-)Hydrogen peroxide(H2O2)Hydroxyl radical(OH-)Depend on the activation of the NADPH oxidative system Function:i)Low levels:increase expression of chemokines (IL-8),cytokines and endothelial,leukocyte adhesion molecules amplify the infla response destroy phagocytose
47、d microbesii)At high level:release of these potent mediators injury to EC,RBC parenchymal C Belong to a family of tachykinin in central and peripheral nervous systems,such as substance p(lung,intestine)Functions:Increased vascular Permeability Transmission of pain signal Regulation of blood pressure Stimulation of secretion by immune and endocrine cells79 结束语结束语
