1、第四章 炎癥 炎癥的概念 具有血管系統的活體組織對各種損傷因 子所發生的一種防御性反應。 變質、滲出和增生 血管反應是炎癥過程的中心環節。 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：引起組織和細胞損傷，誘發炎 癥反應的因素。 物

4、理性因子 化學性因子 生物性因子-感染 壞死組織 變態反應或異常免疫反應 變質、滲出和增生 早期以變質和滲出為主，后期以增生 為主。 三者相互聯系 炎癥局部組織或細胞發生變性和壞死。 是致炎因子引起的損傷過程 常見的變質性變化： 細胞水腫、脂肪變性、細胞凝固性壞 死或液化性壞死-實質細胞 粘液變性和纖維素樣變性或壞死-間 質細胞 炎癥局部組織血管內的液體和細胞成 分，通過血管壁進入組織間質、體腔、 體表和粘膜表面的過程。 是炎癥最具特征性的變化 滲出液和漏出液的區別 在炎癥早期或急性炎癥時表現特別明 顯 mmmm3 3mmmm3 3 蛋白含量 30g/L 1.018 1.018 Rivalta

5、試驗 陽性 陰性 (漿液粘蛋白定性實驗) 凝固性 自凝 不自凝 透明度 混濁 澄清 稀釋中和毒素 白細胞吞噬搬運壞死組織，清除致病因子 帶來營養物質帶走代謝產物 抗體補體消滅病原體 纖維素交織成網，限制病原微生物擴散，有 利白細胞吞噬，后期成為修復支架，促進成 纖維細胞產生膠原纖維 滲出物中病原微生物和毒素隨淋巴液到達淋 巴結，刺激細胞免疫和體液免疫。 壓迫、阻塞和粘連、硬化 炎癥局部組織內的細胞增生或再生， 使細胞數目增多。 實質細胞的增生（上皮、腺體等） 間質細胞的增生（巨噬細胞、成纖維 細胞、血管內皮細胞） 局部臨床特征： 紅、腫、熱、痛和功能障礙。 全身反應：細胞因子（IL-1,IL-

6、6,TNF) 發熱 末梢血白細胞計數的變化（類白血病反應，核左 移） 急性期反應蛋白（CRP, 纖維蛋白原，血清淀粉 樣蛋白）合成增多 慢波睡眠增加 厭食，肌肉蛋白降解加速 根據致炎因子性質和機體對損傷刺激的反 應，分為急性炎癥和慢性炎癥。 急性炎癥：反應迅速，持續時間短，以滲 出性病變為主，浸潤炎癥細胞以中性粒 細胞為主 慢性炎癥：持續時間長，以增殖性病變為 主，浸潤炎癥細胞以淋巴和單核細胞為 主。 亞急性炎癥 血管反應 白細胞反應 炎癥介質 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 血流量和血管口徑的改變 首先是細動脈短暫收縮； 繼而發生血管擴張、 血流加快、 此時 局部代謝增強、發紅、發熱。 血流速度減慢，血液粘稠度增加。 炎癥早期的血管形態學改變 血管內流體靜力壓增高 血漿膠體滲透壓下降 間質膠體滲透壓增加 內皮細胞的病理變化 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. 內皮的完整性 1.內皮細胞收縮-毛細血管后靜脈 2.內皮細胞穿胞作用 細靜脈 3. 內皮細胞損傷脫落 累及所有微循環血管，包括毛細血管、細動 脈和細靜脈 炎癥早期白細胞黏附 4. 新生毛細血管壁的高通透性 稀釋毒素 帶來營養物質，帶走有害物質 帶來大量抗體、補體用以消滅病原體 纖維素有利于吞噬和修復 有利于產生體液和細胞免疫 壓迫、阻塞和粘連、硬化 炎癥環境中淋巴回流增加 炎癥刺激因子擴散 淋巴管炎，引流至淋巴結-反應性淋巴 結炎 臨床皮膚創口的硬性條索 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. 急性炎癥中的白細胞反應 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. 白細胞邊集 離開血管中心的軸流，到達血管的邊緣， 沿著內皮細胞表面滾動、附壁。 白細胞粘著 依靠細胞表面的黏附分子的作用來完成。 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. 阿米巴運動的形式 早期以中性粒細胞為主，此后是單核細 胞。 根據致炎因子的不同，分別以中性粒細 胞、淋巴細胞和嗜酸性粒細胞為主。 Regulation of endothelial and leukocyte adhesion molecules Increased bindin

22、g avidity of integrins 整合素（Integrins）為跨膜異二聚體糖蛋白 ，由 與 亞單位組成，表達于多種細 胞表面，與配體結合介導白細胞與內皮細 胞，白細胞之間，以及白細胞與基質之間 粘附。 白細胞與內皮的粘附是由整合素與免疫球 蛋白超家族分子（ICAM-1、VCAM-1)介導 的。 2 integrins LFA-1 、Mac-1 (CD11a/CD18 、CD11b/CD18) 結合ICAM-1, 1 integrins (VLA-4) 結合 VCAM-1. 白細胞游出白細胞游出 白細胞游出是炎癥反應最重要的指征 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. 白細胞游出是炎癥反應最重要的指征 趨化作用和趨化因子 趨化作用（chemotaxis）是指白細胞 向化學刺激物作定向移動。 這些化學刺激物稱為趨化因子。 外源性 可溶性細菌產物，特別是含有N- 甲?；?/p>

24、氨酸末端氨基酸的多肽 內源性 (1) 補體成分尤其是C5a (2) 白細胞三烯B4 (LTB4) (3) 細胞因子 (如IL-8) 吸附具有特異性，和細胞受體結合引起 生化反應，細胞內微絲、微管收縮，細 胞移動 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. 白細胞活化 Toll樣受體(TLRs), 10 種哺乳類 TLRs，識別細菌 脂多糖，蛋白多糖，脂類，病毒雙鏈RNA。 G蛋白耦連受體，識別含有N-甲酰甲硫氨酸的細 菌短肽。 細胞因子受體，感染后產生，通過與白細胞表面 受體結合激活白細胞。最為重要的是 IFN-， 激活巨噬細胞。 調理素受體，

26、包裹微生物，增強吞噬細胞吞噬功 能的蛋白質，抗體IgGFc段，補體C3b,凝集素。 通過磷脂酶A2和鈣離子濃度升高 促進花生四烯酸代謝產物產生。 脫顆粒和釋放溶酶體酶，活性氧 產生。 釋放細胞因子，主要從活化的巨 噬細胞產生，促進炎癥反應。 調節粘附分子。 吞噬和免疫 吞噬作用是指白細胞游出到炎癥 灶，吞噬病原體以及組織碎片的 過程。 主要由嗜中性粒細胞和巨噬細胞 完成 識別與附著 吞入，形成吞噬溶酶體 殺傷或降解 依賴氧殺菌機制 不依賴氧殺菌機制 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. 非氧依賴途徑 溶酶體內細菌通透性增加蛋白-激活磷 脂酶降解細胞膜磷脂 溶菌酶水解細菌糖肽外衣 白細胞特異性顆粒中乳鐵蛋白，吞噬酸 性粒細胞主要堿性蛋白-寄生蟲 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、噬細胞、淋巴細胞和漿細胞。 呈遞抗原 產生淋巴因子和抗體 抗感染 白細胞活化過程中將產物釋放到細胞外間質 釋放溶酶體酶、活性氧自由基、前列腺素和 白細胞三烯，NETs(neutrophil extracellular traps)等。 引起內皮細胞和組織損傷 造成組織溶解和破壞 NETs 溶酶體酶釋放： 吞噬溶酶體完全封閉前與外界相通 不能被吞噬的物質引起白細胞胞膜運動 表面吞噬作用 吞噬的物質本身溶解溶酶體膜 中性粒細胞脫顆粒 粘附缺陷 吞噬溶酶體形成缺陷 殺菌活性障礙 骨髓白細胞生成障礙 白細胞激活障礙 導致嚴重反復的感染 中性粒細胞：急性炎癥早期和化膿性炎 單核細胞巨噬細胞： 急性炎癥后

31、期、慢性 炎癥 尤其是肉芽腫性炎癥，某些特殊微生 物感染 淋巴細胞： T 淋巴細胞識別巨噬細胞傳遞 的抗原，釋放淋巴因子，產生細胞免疫。 B 淋巴細胞轉化成漿細胞產生多種抗體，參 與體液免疫。 嗜酸性粒細胞： 變態反應、寄生蟲感染 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 炎癥介質（inflammatory mediator)的概念 一系列介導炎癥反應的化學因子 來自血漿(主要在肝臟合成，前體形式存在，蛋白酶 水解激活）和細胞（胞內顆粒儲存，需要時釋放或 刺激下即刻合成） 通過靶細胞表面特異性抗體發

43、揮作用，或本身具有 酶活性或氧化損傷 可刺激產生次級炎癥介質 可作用于一種或多種靶細胞，產生不同作用 半衰期短，很快降解滅活或被拮抗因子抑制，清除 大多數對正常組織具有潛在危害 Chemical mediators of inflammation. EC, endothelial cells. 血管活性胺 包括組胺和5羥色胺，又稱血清素。 組胺主要存在于肥大細胞中，使細動 脈擴張和細靜脈通透性增加。 5HT主要存在于血小板和腸嗜鉻細 胞，作用與組胺類似。 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. 花生四烯酸代謝產物，包括前列腺素 （PG）、白細胞三烯（LT）和脂質素 (lipoxins) 使炎癥時血管擴張、水腫加劇，引起發 熱和疼痛； 血管收縮、支氣管痙攣以及血管通透性 增加。 脂質素炎癥抑制因子 臨床上的對癥治療的靶點 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 主要來自嗜中性粒細胞和單核細胞。 活性氧代謝產物，與NO結合，影 響炎癥反應，損傷組織。 溶酶體成分，促發炎癥，組織

48、破 壞，直接降解C3和C5。 主要由激活的淋巴細胞和單核巨噬細 胞產生。 調節淋巴細胞 調節自然免疫 激活巨噬細胞 對不同炎癥細胞有趨化作用 刺激造血，調節白細胞生長、分化 Major effects of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in inflammation. 細胞因子引起巨噬細胞的活化 來源于多種細胞，參與多方面炎癥過 程。 影響血流動力學改變 增加血管通透性 促使白細胞與內皮細胞粘著 影響趨化作用 促使白細胞脫顆粒 一氧化氮(NO) 由內皮細胞、巨噬細胞和一些特定神經 細胞產生。 作用于血管平滑肌，使血管

49、擴張 抑制血小板粘著和聚集 抑制肥大細胞引起的炎癥反應 調節、控制白細胞向炎癥灶的集中 減少微生物復制、導致組織的損傷 神經肽：P物質，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 激肽系統（kinin system） 補體系統 （complement system) 凝血和纖溶系統 （coagulation and fibrinolytic system) 激肽系統（kinin system） 最終產物是緩激肽，增加血管的通透性 皮下注射可引起血管擴張、平滑肌收縮、 引起疼痛 作用時間短暫，易被激肽酶滅活 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種蛋白質組成 是機體抵抗病原微生物的重要因子 增加血管通透性

56、、促使化學趨化作用和調理素 化作用 C3a和C5a具有引起血管擴張、增加血管通透性 的影響 C3b 調理素化作用 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). 補體系統的活化可分為早期和晚期兩個階 段。 早期階段由經典、替代，凝集素途徑三條 通路導致C3蛋白水解。 晚期階段為活化C3后導致的其他補體系統 成分活化。 C3激活為最重要一步。 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. 經典激活途徑經典激活途徑替代激活途徑替代激活途徑MBLMBL途徑途徑 激活物質激活物質抗原抗體復合物抗原抗體復合物