炎症1-徐芳英.pdf

炎症(Inflammation)徐芳英浙江大学医学院 病理学与病理生理学系概述概述 炎症的概念具有血管系统的活体组织对各种损伤因子所发生的一种防御性反应。变质、渗出和增生 血管反应是炎症过程的中心环节。炎症的临床局部表现和全身反应炎症的临床局部表现和全身反应局部临床特征：红、肿、热、痛和功能障碍。全身反应：发热末梢血白细胞计数、类型的变化核左移Here is simple edema,or fluid collection within tissues.This is pitting edema because,on physical examination,you can press your finger into the skin and soft tissue and leave a depression.炎症反应的防御作用炎症反应的防御作用 清除消灭致病因子 液体的渗出可以稀释毒素 吞噬搬运坏死组织有助于再生和修复 使致病因子局限在炎症部位 不利因素：严重的过敏反应等This example of edema with inflammation is not trivial at all:there is marked laryngeal edema such that the airway is narrowed.This is life-threatening.Thus,fluid collections can be serious depending upon their location.炎症的原因炎症的原因 致炎因子：引起组织和细胞损伤，诱发炎症反应的因素。物理性因子 化学性因子 生物性因子：感染（infection）坏死组织 变态反应或异常免疫反应炎症的发生和炎症过程受致炎因子和机体自身状态两方面共同影响炎症的临床类型：超急性炎症：数小时至数天 急性炎症：数天至一个月 慢性炎症：数月至数年 亚急性炎症：一至数月炎症的基本病理变化炎症的基本病理变化 变质(alteration)、渗出(exudation)和增生(proliferation)早期以变质和渗出为主，后期以增生为主。三者相互联系变质（变质（alteration）炎症局部组织或细胞发生变性和坏死。是致炎因子引起的损伤过程 常见的变质性变化：细胞水肿、脂肪变性、细胞凝固性坏死或液化性坏死 粘液变性和纤维素性坏死增生（增生（proliferation）炎症局部组织内的细胞增生或再生，使细胞数目增多。实质细胞的增生（上皮、腺体等）间质细胞的增生（巨噬细胞、成纤维细胞、血管内皮细胞）渗出（渗出（exudation）炎症局部组织血管内的液体、蛋白质和细胞成分，通过血管壁进入组织、体腔、体表和粘膜表面的过程。是炎症最具特征性的变化 渗出液(exudate)和漏出液(transudate)的区别 在炎症早期或急性炎症时表现特别明显The components of acute and chronic inflammatory responses:circulating cells and proteins,cells of blood vessels,and cells and proteins of the extracellular matrix.渗出过程 血流动力学改变 血管通透性升高 液体渗出 白细胞渗出及其作用Seen here is vasodilation with exudation that has led to an outpouring of fluid with fibrin into the alveolar spaces,along with PMNs.炎症时血流动力学改变 血流量和血管口径的改变 首先是细动脉短暂收缩；继而发生血管扩张、血流加快、此时局部代谢增强、发红、发热。血流速度减慢，血液粘稠度增加。炎症早期的血管形态学改变血管通透性增加 血管内流体静力压增高 血浆胶体渗透压下降 间质胶体渗透压增加Blood pressure and plasma colloid osmotic forces in normal and inflamed microcirculation.A,Normal hydrostatic pressure(red arrows)is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end;the mean colloid osmotic pressure of tissues is approximately 25 mm Hg(green arrows),which is equal to the mean capillary pressure.hB,Acute inflammation.Arteriole pressure is increased to 50 mm Hg,the mean capillary pressure is increased because of arteriolar dilation,and the venous pressure increases to approximately 30 mm Hg.At the same time,osmotic pressure is reduced(averaging 20 mm Hg)because of protein leakage across the venule.The net result is an excess of extravasated fluid.血管通透性增加 内皮细胞收缩和/或穿胞作用增强 发生于细静脉 内皮细胞的收缩是由于炎症介质出现所致 内皮细胞的损伤 累及所有微循环血管，包括毛细血管、细动脉和细静脉 炎症早期白细胞黏附 新生毛细血管壁的高通透性造成局部水肿和积液Diagrammatic representation of five mechanisms of increased vascular permeability in inflammation Formation of transudates and exudates.A,Normal hydrostatic pressure(blue arrows)is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end;the mean colloid osmotic pressure of tissues is approximately 25 mm Hg(green arrows),which is equal to the mean capillary pressure.Therefore,the net flow of fluid across the vascular bed is almost nil.B,A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decrease pressure.C,An exudate is formed in inflammation because vascular permeability increases as a result of increased interendothelial spaces.液体渗出Vascular leakage induced by chemical mediators.A,This is a fixed and cleared preparation of a rat cremaster muscle examined unstained by transillumination.One hour before sacrifice,bradykinin was injected over this muscle,and colloidal carbon was given intravenously.Plasma,loaded with carbon,escaped,but most of the carbon particles were retained by the basement membrane of the leaking vessels,with the result that these became labeled black.Note that not all the vessels leak-only the venules.In B,a higher power,the capillary network is faintly visible in the background.渗出液与漏出液渗出液漏出液蛋白含量15-60g/L 15g/L细胞数0.5109/L 1.020 1.012Rivalta试验阳性阴性凝固性自凝不自凝透明度混浊澄清液体渗出的意义 稀释毒素 带来营养物质，带走有害物质 带来大量抗体、补体用以消灭病原体 有利于吞噬和修复 压迫、阻塞和粘连、硬化Here is an example of fluid collection into a body cavity,or an effusion.This is a right pleural effusion(in a baby).Note the clear,pale yellow appearance of the fluid.This is a serous effusion.Here is an example of the fibrin mesh in fluid with PMNs that has formed in the area of acute inflammation.It is this fluid collection that produces the tumor or swelling aspect of acute inflammation.白细胞渗出和吞噬作用白细胞渗出和吞噬作用 白细胞从血管内穿过管壁到达损伤部位的过程称为白细胞渗出 炎性细胞浸润：炎症反应最重要的组织形态学特征 炎症防御反应的中心环节白细胞的游出 聚集 作用白细胞游出的过程白细胞游出的过程 白细胞边集 离开血管中心的轴流，到达血管的边缘，沿着内皮细胞表面滚动、附壁。白细胞粘着 依靠细胞表面的黏附分子的作用来完成。白细胞游出白细胞游出 阿米巴运动的形式 早期以中性粒细胞为主，此后是单核细胞。根据致炎因子的不同，分别以中性粒细胞、淋巴细胞和嗜酸性粒细胞为主。内皮的活化内皮的活化白细胞在内皮细胞上的滚动白细胞在内皮细胞上的滚动白细胞粘着白细胞粘着白细胞游出白细胞游出The multistep process of leukocyte migration through blood vessels,shown here for neutrophils.The leukocytes first roll,then become activated and adhere to endothelium,then transmigrate across the endothelium,pierce the basement membrane,and migrate toward chemoattractants emanating from the source of injury.Different molecules play predominant roles in different steps of this process-selectins in rolling;chemokines in activating the neutrophils to increase avidity of integrins(in green);integrins in firm adhesion;and CD31(PECAM-1)in transmigration.This animation demonstrates the actions of neutrophils in the acute inflammatory process.Regulation of endothelial and leukocyte adhesion molecules.A,Redistribution of P-selectin.B,Cytokine activation of endothelium.C,Increased binding avidity of integrins Leukocyte activation.Different classes of cell surface receptors of leukocytes recognize different stimuli.The receptors initiate responses that mediate the functions of the leukocytes.Only some receptors are depicted Schematic and histologic sequence of events following acute injury.For sake of simplicity,edema is shown as an acute transient response,although secondary waves of delayed edema and neutrophil infiltration can also occur.红细胞漏出不同阶段、不同炎症，白细胞种类不同As in the preceding diagram,here PMNs that are marginated along the dilated venule wall(arrow)are squeezing through the basement membrane(the process of diapedesis)and spilling out into extravascular space.白细胞在损伤部位聚集 趋化作用和趋化因子 趋化作用（chemotaxis）是指白细胞沿炎症组织内分布的化学刺激物浓度差作定向移动。这些化学刺激物称为趋化因子(chemotactic agents)。趋化具有特异性，和细胞受体结合引起生化反应，细胞内微丝、微管收缩，细胞移动 外源性趋化因子：细菌产物 内源性趋化因子：补体成分、白细胞三烯和细胞因子白细胞在局部的作用白细胞在局部的作用 吞噬和免疫 吞噬作用是指白细胞游出到炎症灶，吞噬并杀伤或降解病原体以及组织碎片的过程。主要由嗜中性粒细胞和巨噬细胞完成吞噬过程吞噬过程 识别与附着 调理素：血清中的一类能增强吞噬细胞吞噬功能的蛋白质，如抗体Fc段、补体C3b 调理素化：细菌等颗粒状物与含调理素的血清接触并被包裹 吞入，形成吞噬溶酶体 杀伤或降解 依赖氧杀菌机制 不依赖氧杀菌机制A,Phagocytosis 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,followed by destruction of ingested particles within the phagolysosomes.Note that during phagocytosis,granule contents may be released into extracellular tissues.Production of microbicidal reactive oxygen intermediates within phagocytic vesicles.Events in the resolution of inflammation:(1)return to normal vascular permeability;(2)drainage of edema fluid and proteins into lymphatics or(3)by pinocytosis into macrophages;(4)phagocytosis of apoptotic neutrophils and(5)phagocytosis of necrotic debris;and(6)disposal of macrophages.Macrophages also produce growth factors that initiate the subsequent process of repair.Note the central role of macrophages in resolution.免疫作用免疫作用 主要有巨噬细胞、淋巴细胞和浆细胞。呈递抗原 产生淋巴因子和抗体 抗感染组织损伤作用组织损伤作用 释放溶酶体酶、活性氧自由基、前列腺素和白细胞三烯等。引起内皮细胞和组织损伤 造成组织溶解和破坏各种炎症细胞的作用各种炎症细胞的作用 中性粒细胞：急性炎症早期和化脓性炎 单核细胞：急性炎症后期、某些特殊微生物感染 淋巴细胞：病毒感染、梅毒 嗜酸性粒细胞：变态反应、寄生虫感染 浆细胞：慢性炎症Acute inflammation is marked by an increase in inflammatory cells.Perhaps the simplest indicator of acute inflammation is an increase in the white blood cell count in the peripheal blood,here marked by an increase in segmented neutrophils(PMNs).Following engulfment,the bacterium is contained within a phagosome,and lysosomal granules fuse with it,releasing their contents to form the phagolysosome seen here.Rapid activation of NADPH oxidase leads to generation of superoxide that is converted to hydrogen peroxide by spontaneous dismutation.Along with myeloperoxidase from the neutrophil azurophilic granules and halide ion,hydrogen peroxide is converted to HOCL that destroys the bacterium by halogenation.The red blood cells here are normal,happy RBCs.They have a zone of central pallor about 1/3 the size of the RBC.The RBCs demonstrate minimal variation in size(anisocytosis)and shape(poikilocytosis).A few small fuzzy blue platelets are seen.In the center of the field are a band neutrophil on the left and a segmented neutrophil on the right.Ultrastructure and contents of neutrophil granules,stained for peroxidase activity.The large peroxidase-containing granules are the azurophil granules;the smaller peroxidase-negative ones are the specific granules(SG).N,portion of nucleus;BPI,bactericidal permeability increasing protein.Maturation of mononuclear phagocytes.Here is a monocyte.It is slightly larger than a lymphocyte and has a folded nucleus.Monocytes can migrate out of the bloodstream and become tissue macrophages under the influence of cytokines.Note the many small smudgy blue platelets between the RBCs.In the center of the field is an eosinophil with a bilobed nucleus and numerous reddish granules in the cytoplasm.Just underneath it is a small lymphocyte.Eosinophils can increase with allergic reactions and with parasitic infestations.A normal mature lymphocyte is seen on the left compared to a segmented PMN on the right.An RBC is seen to be about 2/3 the size of a normal lymphocyte.At higher magnification,early abscessing pneumonia is shown.Alveolar walls are not clearly seen,only sheets of neutrophils.Of course,inflammatory reactions are not neatly categorized by cell type.A variety of inflammatory cell types may be present,though one may predominate.A focus of inflammation showing numerous eosinophils.A mononuclear inflammatory cell infiltrate extends from portal areas and disrupts the limiting plate of hepatocytes which are undergoing necrosis,the so-called piecemeal necrosis of chronic active hepatitis.Histopathology of a lymph node in a case of Typhoid Fever.Identify the segmented neutrophil,band neutrophil,lymphocyte,monocyte,eosinophil,basophil,and platelet in the imageA flat spread of omentum showing mast cells around blood vessels and in the interstitial tissue.Stained with metachromatic stain to identify the mast cell granules(dark blue or purple).The red structures are fat globules stained with fat stain.DisordersCells and Molecules Involved in InjuryAcuteAcute respiratory distress syndromeNeutrophilsAcute transplant rejectionLymphocytes;antibodies and complementAsthmaEosinophils;IgE antibodiesGlomerulonephritisAntibodies and complement;neutrophils,monocytesSeptic shockCytokinesVasculitisAntibodies and complement;neutrophilsChronicArthritisLymphocytes,macrophages;antibodiesAsthmaEosinophils,other leukocytes;IgE antibodiesAtherosclerosisMacrophages;lymphocytes?Chronic transplant rejectionLymphocytes;cytokinesPulmonary fibrosisMacrophages;fibroblasts炎症介质在炎症过程中的作用 炎症介质（inflammatory mediator)的概念 一系列介导炎症反应的化学因子 来自血浆（前体）和细胞（颗 粒）Chemical mediators of inflammation.EC,endothelial cells.细胞释放的炎症介质 血管活性胺 包括组胺和5羟色胺，又称血清素。组胺主要存在于肥大细胞中，使细动脉扩张和细静脉通透性增加。5HT主要存在于血小板和肠嗜铬细胞，作用与组胺类似。花生四烯酸代谢产物 包括前列腺素（PG）和白细胞三烯（LT）使炎症时血管扩张、水肿加剧，引起发热和疼痛；血管收缩、支气管痉挛以及血管通透性增加。临床上的对症治疗Biosynthesis of leukotrienes and lipoxins by cell-cell interaction.Activated neutrophils generate LTB4 from arachidonic acid-derived LTA4 by the action of 5-lipoxygenase,but they do not possess LTC4-synthase activity and consequently do not produce LTC4.In contrast,platelets cannot form LTC4 from endogenous substrates,but they can generate LTC4 and lipoxins from neutrophil-derived LTA4.白细胞产物 主要来自嗜中性粒细胞和单核细胞。活性氧代谢产物，与NO结合，影响炎症反应，损伤组织。溶酶体成分，促发炎症，组织破坏，直接降解C3和C5。细胞因子和化学因子 主要是由激活的淋巴细胞和单核巨噬细胞产生。调节淋巴细胞 调节自然免疫 激活巨噬细胞 刺激造血，调节白细胞生长、分化Major effects of interleukin-1(IL-1)and tumor necrosis factor(TNF)in inflammation.细胞因子引起巨噬细胞的活化血小板激活因子(PAF)来源于多种细胞，参与多方面炎症过程。影响血流动力学改变 增加血管通透性 促使白细胞与内皮细胞粘着 影响趋化作用 促使白细胞脱颗粒 一氧化氮(NO)：由内皮细胞、巨噬细胞和一些特定神经细胞产生。作用于血管平滑肌，使血管扩张 抑制血小板粘着和聚集 抑制肥大细胞引起的炎症反应 调节、控制白细胞向炎症灶的集中 减少微生物复制、导致组织的损伤 神经肽：P物质，增加血管通透性Functions of nitric oxide(NO)in blood vessels and macrophages,produced by two NO synthase enzymes.NO causes vasodilation,and NO free radicals are toxic to microbial and mammalian cells.NOS,nitric oxide synthase.MediatorSourcePrincipal ActionsCell-DerivedHistamineMast cells,basophils,plateletsVasodilation,increased vascular permeability,endothelial activationSerotoninPlateletsVasodilation,increased vascular permeabilityProstaglandinsMast cells,leukocytesVasodilation,pain,feverLeukotrienesMast cells,leukocytesIncreased vascular permeability,chemotaxis,leukocyte adhesion and activationPlatelet-activating factorLeukocytes,endothelial cellsVasodilation,increased vascular permeability,leukocyte adhesion,chemotaxis,degranulation,oxidative burstReactive oxygen speciesLeukocytesKilling of microbes,tissue damageNitric oxideEndothelium,macrophagesVascular smooth muscle relaxation;killing of microbesCytokines(e.g.TNF,IL-1)Macrophages,lymphocytes,endothelial cells,mast cellsLocal endothelial activation(expression of adhesion molecules),systemic acute-phase response;in severe infections,septic shockChemokinesLeukocytes,activated macrophagesChemotaxis,leukocyte activation体液中的炎症介质 激肽系统（kinin system）最终产物是缓激肽，增加血管的通透性 皮下注射可引起血管扩张、平滑肌收缩、引起疼痛 作用时间短暂，易被激肽酶灭活补体系统 由20种蛋白质组成 是机体抵抗病原微生物的重要因子 增加血管通透性、促使化学趋化作用和调理素化作用 C3a和C5a具有引起血管扩张、增加血管通透性的影响The activation and functions of the complement system.Activation of complement by different pathways leads to cleavage of C3.The functions of the complement system are mediated by breakdown products of C3 and other complement proteins,and by the membrane attack complex(MAC).凝血系统和纤溶系统 由XII因子启动 凝血系统：凝血酶、Xa 促使白细胞粘着和成纤维细胞增生 血管通透性增高 白细胞的趋化因子 促进白细胞渗出Interrelationships between the four plasma mediator systems triggered by activation of factor XII(Hageman factor).Note that thrombin induces inflammation by binding to protease-activated receptors(principally PAR-1)on platelets,endothelium,smooth muscle cells,and other cells.Plasma Protein-DerivedComplementPlasma(produced in liver)Leukocyte chemotaxis and activation,opsonization,vasodilation(mast cell stimulation)KininsPlasma(produced in liver)Increased vascular permeability,smooth muscle contraction,vasodilation,painProteases activated during coagulationPlasma(produced in liver)Endothelial activation,leukocyte recruitment炎症介质的相互作用 不同介质系统相互之间有着密切的联系 几乎所有介质均处于灵敏的调控和平衡体系中VasodilationProstaglandinsHistamine，NOIncreased vascular permeabilityHistamine and serotoninC3a and C5a(by liberating vasoactive amines from mast cells,other cells)BradykininLeukotrienes C4,D4,E4PAFSubstance PLeukocyte recruitment and activationTNF,IL-1ChemokinesC3a,C5aLeukotriene B4(Bacterial products,e.g.,N-formyl methyl peptides)FeverIL-1,TNFProstaglandinsPainProstaglandinsBradykininNeuropeptidesTissue damageLysosomal enzymes of leukocytesReactive oxygen species,NO