病理学：第四章 炎症

1、第四章 炎症 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。 The components of acute and chronic inflammatory responses: circulating cells and proteins, cells of blood vessels, and cells and proteins of the extracellular matrix. Julius Cohnheim (1839-1884) first used the microscope to obser

2、ve inflamed blood vessels in thin, transparent membranes. He wrote descriptions of inflammation that can hardly be improved on. In the 1880s, the Russian biologist Elie Metchnikoff discovered the process of phagocytosis. Metchnikoff and Paul Ehrlich (who developed the humoral theory of immunity) sha

3、red the Nobel Prize in 1908. Sir Thomas Lewis, who, on the basis of simple experiments studying the inflammatory response in skin, established the concept that chemical substances, such as histamine locally induced by injury, mediate the vascular changes of inflammation. 致炎因子：引起组织和细胞损伤，诱发炎 症反应的因素。 物

4、理性因子 化学性因子 生物性因子-感染 坏死组织 变态反应或异常免疫反应 变质、渗出和增生 早期以变质和渗出为主，后期以增生 为主。 三者相互联系 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-实质细胞 粘液变性和纤维素样变性或坏死-间 质细胞 炎症局部组织血管内的液体和细胞成 分，通过血管壁进入组织间质、体腔、 体表和粘膜表面的过程。 是炎症最具特征性的变化 渗出液和漏出液的区别 在炎症早期或急性炎症时表现特别明 显 mmmm3 3mmmm3 3 蛋白含量 30g/L 1.018 1.018 Rivalta

5、试验 阳性 阴性 (浆液粘蛋白定性实验) 凝固性 自凝 不自凝 透明度 混浊 澄清 稀释中和毒素 白细胞吞噬搬运坏死组织，清除致病因子 带来营养物质带走代谢产物 抗体补体消灭病原体 纤维素交织成网，限制病原微生物扩散，有 利白细胞吞噬，后期成为修复支架，促进成 纤维细胞产生胶原纤维 渗出物中病原微生物和毒素随淋巴液到达淋 巴结，刺激细胞免疫和体液免疫。 压迫、阻塞和粘连、硬化 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） 局部临床特征： 红、肿、热、痛和功能障碍。 全身反应：细胞因子（IL-1,IL-

6、6,TNF) 发热 末梢血白细胞计数的变化（类白血病反应，核左 移） 急性期反应蛋白（CRP, 纤维蛋白原，血清淀粉 样蛋白）合成增多 慢波睡眠增加 厌食，肌肉蛋白降解加速 根据致炎因子性质和机体对损伤刺激的反 应，分为急性炎症和慢性炎症。 急性炎症：反应迅速，持续时间短，以渗 出性病变为主，浸润炎症细胞以中性粒 细胞为主 慢性炎症：持续时间长，以增殖性病变为 主，浸润炎症细胞以淋巴和单核细胞为 主。 亚急性炎症 血管反应 白细胞反应 炎症介质 The major local manifestations of acute inflammation: (1) vascular dilation

7、; (2) extravasation of plasma fluid and protein; (3) leukocyte emigration and accumulation in the site of injury 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 内皮细胞的病理变化 Blood pressure and plasma colloid osmotic forces A, Normal h

8、ydrostatic 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. B, Acute inflammation. Arteriole pressure is

9、 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 o

10、f extravasated fluid. 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

11、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 decreased osmotic pressure. C, An exudate is formed in inflammation because vascular permeability increases

12、 as a result of increased interendothelial spaces. 内皮的完整性 1.内皮细胞收缩-毛细血管后静脉 2.内皮细胞穿胞作用 细静脉 3. 内皮细胞损伤脱落 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 4. 新生毛细血管壁的高通透性 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 纤维素有利于吞噬和修复 有利于产生体液和细胞免疫 压迫、阻塞和粘连、硬化 炎症环境中淋巴回流增加 炎症刺激因子扩散 淋巴管炎，引流至淋巴结-反应性淋巴 结炎 临床皮肤创口的硬性条索 edema, or fluid col

13、lection within tissues. 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. Here is an example of fluid collection into a body

14、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. Seen here is vasodilation with exudation that has led to an outpouring of fluid with fibrin into the alveolar spaces, along with PMNs. Here is an exam

15、ple 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. The diagram shown here illustrates the process of exudation, aided by endothelial cell contraction and vasodilati

16、on, which typically is most pronounced in venules. Chemical mediators producing endothelial contraction include: histamine, leukotrienes, bradykinin, platelet activating factor, and the C3a and C5a components from complement activation. Mediators of this process over a longer term include tumor necr

17、osis factor and interleukin-1. Chemical mediators that promote vasodilation include: histamine, prostaglandins, and nitric oxide. 急性炎症中的白细胞反应 The major local manifestations of acute inflammation, compared to normal. (1) Vascular dilation and increased blood flow (causing erythema and warmth), (2) ex

18、travasation and deposition of plasma fluid and proteins (edema), and (3) leukocyte emigration and accumulation in the site of injury. 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 swe

19、lling aspect of acute inflammation. This animation demonstrates the actions of neutrophils in the acute inflammatory process. 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。 The multistep process of leukocyte migration through blood vessels, shown here for neutrophils. The leukocyte

20、s 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 r

21、olling; chemokines in activating the neutrophils to increase avidity of integrins (in green); integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. 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。 Regulation of endothelial and leukocyte adhesion molecules Increased bindin

22、g avidity of integrins 整合素（Integrins）为跨膜异二聚体糖蛋白 ，由 与 亚单位组成，表达于多种细 胞表面，与配体结合介导白细胞与内皮细 胞，白细胞之间，以及白细胞与基质之间 粘附。 白细胞与内皮的粘附是由整合素与免疫球 蛋白超家族分子（ICAM-1、VCAM-1)介导 的。 2 integrins LFA-1 、Mac-1 (CD11a/CD18 、CD11b/CD18) 结合ICAM-1, 1 integrins (VLA-4) 结合 VCAM-1. 白细胞游出白细胞游出 白细胞游出是炎症反应最重要的指征 Schematic and histologic s

23、equence 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. 白细胞游出是炎症反应最重要的指征 趋化作用和趋化因子 趋化作用（chemotaxis）是指白细胞 向化学刺激物作定向移动。 这些化学刺激物称为趋化因子。 外源性 可溶性细菌产物，特别是含有N- 甲酰基蛋

24、氨酸末端氨基酸的多肽 内源性 (1) 补体成分尤其是C5a (2) 白细胞三烯B4 (LTB4) (3) 细胞因子 (如IL-8) 吸附具有特异性，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 Seen here is vasodilation with exudation that has led to an outpouring of fluid with fibrin into the alveolar spaces, along with PMNs. As in the preceding diagram, here PMNs that are marginated

25、along the dilated venule wall (arrow) are squeezing through the basement membrane (the process of diapedesis) and spilling out into extravascular space. 白细胞活化 Toll样受体(TLRs), 10 种哺乳类 TLRs，识别细菌 脂多糖，蛋白多糖，脂类，病毒双链RNA。 G蛋白耦连受体，识别含有N-甲酰甲硫氨酸的细 菌短肽。 细胞因子受体，感染后产生，通过与白细胞表面 受体结合激活白细胞。最为重要的是 IFN-， 激活巨噬细胞。 调理素受体，

26、包裹微生物，增强吞噬细胞吞噬功 能的蛋白质，抗体IgGFc段，补体C3b,凝集素。 通过磷脂酶A2和钙离子浓度升高 促进花生四烯酸代谢产物产生。 脱颗粒和释放溶酶体酶，活性氧 产生。 释放细胞因子，主要从活化的巨 噬细胞产生，促进炎症反应。 调节粘附分子。 吞噬和免疫 吞噬作用是指白细胞游出到炎症 灶，吞噬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 识别与附着 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 b

27、inding 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 o

28、f microbicidal reactive oxygen intermediates within phagocytic vesicles. 非氧依赖途径 溶酶体内细菌通透性增加蛋白-激活磷 脂酶降解细胞膜磷脂 溶菌酶水解细菌糖肽外衣 白细胞特异性颗粒中乳铁蛋白，吞噬酸 性粒细胞主要碱性蛋白-寄生虫 防御素 Events in the resolution of inflammation: (1) return to normal vascular permeability; (2) drainage of edema fluid and proteins into lymphatics

29、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. 主要有巨

30、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 白细胞活化过程中将产物释放到细胞外间质 释放溶酶体酶、活性氧自由基、前列腺素和 白细胞三烯，NETs(neutrophil extracellular traps)等。 引起内皮细胞和组织损伤 造成组织溶解和破坏 NETs 溶酶体酶释放： 吞噬溶酶体完全封闭前与外界相通 不能被吞噬的物质引起白细胞胞膜运动 表面吞噬作用 吞噬的物质本身溶解溶酶体膜 中性粒细胞脱颗粒 粘附缺陷 吞噬溶酶体形成缺陷 杀菌活性障碍 骨髓白细胞生成障碍 白细胞激活障碍 导致严重反复的感染 中性粒细胞：急性炎症早期和化脓性炎 单核细胞巨噬细胞： 急性炎症后

31、期、慢性 炎症 尤其是肉芽肿性炎症，某些特殊微生 物感染 淋巴细胞： T 淋巴细胞识别巨噬细胞传递 的抗原，释放淋巴因子，产生细胞免疫。 B 淋巴细胞转化成浆细胞产生多种抗体，参 与体液免疫。 嗜酸性粒细胞： 变态反应、寄生虫感染 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 bl

32、ood, 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

33、 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 zon

34、e 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

35、 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 mon

36、onuclear 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 fie

37、ld 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 rig

38、ht. 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

39、 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 acti

40、ve 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 image below: DisordersCells and Molecules Involved in Injury Acute Acute respiratory distress syndrome Neutroph

41、ils Acute transplant rejection Lymphocytes; antibodies and complement AsthmaEosinophils; IgE antibodies GlomerulonephritisAntibodies and complement; neutrophils, monocytes Septic shockCytokines VasculitisAntibodies and complement; neutrophils Chronic ArthritisLymphocytes, macrophages; antibodies Ast

42、hmaEosinophils, other leukocytes; IgE antibodies AtherosclerosisMacrophages; lymphocytes? Chronic transplant rejection Lymphocytes; cytokines Pulmonary fibrosisMacrophages; fibroblasts 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(主要在肝脏合成，前体形式存在，蛋白酶 水解激活）和细胞（胞内颗粒储存，需要时释放或 刺激下即刻合成） 通过靶细胞表面特异性抗体发

43、挥作用，或本身具有 酶活性或氧化损伤 可刺激产生次级炎症介质 可作用于一种或多种靶细胞，产生不同作用 半衰期短，很快降解灭活或被拮抗因子抑制，清除 大多数对正常组织具有潜在危害 Chemical mediators of inflammation. EC, endothelial cells. 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。 A flat spread of omentum showing mast cells around blood vessels and i

44、n 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. 花生四烯酸代谢产物，包括前列腺素 （PG）、白细胞三烯（LT）和脂质素 (lipoxins) 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。 脂质素炎症抑制因子 临床上的对症治疗的靶点 Generat

45、ion of arachidonic acid metabolites and their roles in inflammation. The molecular targets of action of some anti-inflammatory drugs are indicated by a red X. COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid. Biosynthesis of leukotrienes and lipoxins b

46、y 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 gene

47、rate LTC4 and lipoxins from neutrophil-derived LTA4. The Nobel Prize in Physiology or Medicine 1982 for their discoveries concerning prostaglandins and related biologically active substances. Sune K. Bergstrm Bengt I. Samuelsson John R. Vane 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

48、破 坏，直接降解C3和C5。 主要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 对不同炎症细胞有趋化作用 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 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

49、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. Media

50、torSourcePrincipal Actions Cell-Derived HistamineMast cells, basophils, platelets Vasodilation, increased vascular permeability, endothelial activation SerotoninPlateletsVasodilation, increased vascular permeability ProstaglandinsMast cells, leukocytesVasodilation, pain, fever LeukotrienesMast cells

51、, leukocytesIncreased vascular permeability, chemotaxis, leukocyte adhesion and activation Platelet- activating factor Leukocytes, endothelial cells Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst Reactive oxygen species LeukocytesKilling

52、 of microbes, tissue damage Nitric oxideEndothelium, macrophages Vascular smooth muscle relaxation; killing of microbes Cytokines (e.g. TNF, IL-1) Macrophages, lymphocytes, endothelial cells, mast cells Local endothelial activation (expression of adhesion molecules), systemic acute-phase response; i

53、n severe infections, septic shock ChemokinesLeukocytes, activated macrophages Chemotaxis, leukocyte activation 激肽系统（kinin system） 补体系统 （complement system) 凝血和纤溶系统 （coagulation and fibrinolytic system) 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 Vascular leakage induce

54、d 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 t

55、he 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. 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

56、、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 C3b 调理素化作用 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 b

57、y the membrane attack complex (MAC). 补体系统的活化可分为早期和晚期两个阶 段。 早期阶段由经典、替代，凝集素途径三条 通路导致C3蛋白水解。 晚期阶段为活化C3后导致的其他补体系统 成分活化。 C3激活为最重要一步。 The classical pathway is triggered by fixation of C1 to antibody (IgM or IgG) that has combined with antigen, and proteolysis of C2 and C4, and subsequent formation of a C4

58、b2b complex that functions as a C3 convertase. The alternative pathway can be triggered by microbial surface molecules (e.g., endotoxin, or LPS), complex polysaccharides, and cobra venom. It involves a distinct set of plasma components (properdin, and factors B and D). In this pathway, the spontaneo

59、us cleavage of C3 that occurs normally is enhanced and stabilized by a complex of C3b and a breakdown product of Factor B called Bb; the C3bBb complex is a C3 convertase. In the lectin pathway, mannose-binding lectin, a plasma collectin, binds to carbohydrate-containing proteins on bacteria and viru

60、ses and directly activates C1; the remaining steps are as in the classical pathway. The C3 convertases break down C3 into C3b, which remains attached to the surface where complement is activated, and a smaller C3a fragment that diffuses away. 经典激活途径经典激活途径替代激活途径替代激活途径MBLMBL途径途径 激活物质激活物质抗原抗体复合物抗原抗体复合物