病理學課件：第二章 損傷的修復

1、第二章 損傷的修復（tissue repair）局部組織損傷后由鄰近健康細胞復制分裂、填充、修補，全部或部分恢復機體受損組織細胞結(jié)構(gòu)和功能的過程，稱為修復（repair）。 Repair refers to the restoration of tissue architecture and function after an injury, sometimes called healing.再生(regeneration by parenchymal cells of the same type) 纖維性修復(repair by connective tissue, healing) Aft

2、er mild injury, which damages the epithelium but not the underlying tissue, resolution occurs by regeneration, but after more severe injury with damage to the connective tissue, repair is by scar formation. Critical to the survival of an organism is the ability to repair the damage caused by toxic i

3、nsults and inflammation.Repair involves the proliferation of various cells, and close interactions between cells and the extracellular matrix (ECM). 提 綱再生(Regeneration)細胞的生長和調(diào)控(control of cell growth and differentiation)纖維性修復(repair by connective tissue, fibrosis)創(chuàng)傷愈合(wound healing)概念：局部組織細胞損失后，由鄰近同

4、種細胞通過分裂增殖以完成修復的現(xiàn)象，稱為再生（regeneration）。有生理性和病理性再生。細胞周期及不同細胞的再生潛能 The ability of tissues to repair themselves is critically influenced by their intrinsic proliferative capacity. 第一節(jié) 再 生 (regeneration)Cell populations and cycle landmarks. Note the cell cycle stages (G0, G1, S, G2 and M), the G1 restrict

5、ion point, and the G1/S and G2/M checkpoints. 1. 不穩(wěn)定組織(labile tissues/Continuously Dividing Tissues.) 隨時可從極短的G0期進入細胞周期G1期，不斷分裂增殖（又稱持續(xù)分裂細胞），替代凋亡或損傷細胞。 包括表皮、粘膜被覆上皮，淋巴、造血、間皮細胞等。These tissues can readily regenerate after injury as long as the pool of stem cells is preserved.2. 穩(wěn)定組織(stable tissues): 生理狀態(tài)

6、下不增殖，較長期處在G0期靜止狀態(tài)（又稱靜止細胞）。一旦同類細胞受損死亡，則可迅速重新進入G1期表現(xiàn)出較強的再生能力。 包括各種腺體和腺樣器官的實質(zhì)細胞、間葉細胞及其分化衍生的各種細胞。Regeneration of human liver. Computed tomography scans of the donor liver in living-donor liver transplantation. A, The liver of the donor before the operation. Note the right lobe (outline), which will be r

7、esected and used as a transplant. B, Scan of the same liver 1 week after resection of the right lobe; note the enlargement of the left lobe (outline) without regrowth of the right lobe. 3.永久性組織(permanent tissues): 永久性處于G0期靜止狀態(tài)，不再進入下一個細胞增殖周期（故又稱非分裂細胞）。包括神經(jīng)元、心肌和骨骼肌。各種組織的再生過程1.上皮組織的再生：被覆上皮：通過創(chuàng)傷鄰近部位的基底層

8、儲備細胞及殘留細胞分裂增生來完成再生。腺上皮：BM完整，可完全再生；BM破壞，難以完全再生。肝細胞再生：部分肝切除后，短期內(nèi)可完全再生；肝細胞壞死小葉網(wǎng)狀支架完整，可完全再生；小葉網(wǎng)狀支架塌陷，網(wǎng)狀纖維膠原化/肝細胞反復壞死及炎癥刺激，纖維增生分隔形成不規(guī)則的肝細胞再生結(jié)節(jié)。 2.纖維組織的再生： 由成纖維細胞（fibroblast）分裂增殖，分泌前膠原蛋白等細胞外基質(zhì)成分，并在間質(zhì)中形成膠原纖維后變?yōu)槔w維細胞。 3.軟骨和骨組織的再生：軟骨再生：軟骨膜細胞增生轉(zhuǎn)化為軟骨母細胞，分泌軟骨基質(zhì)形成陷窩變?yōu)檐浌羌毎＼浌窃偕芰θ?，缺損較大時纖維組織參與修復。骨組織再生：再生能力強，骨折后可完全修

9、復。 4血管的再生： 毛細血管以出芽方式進行再生。 小動脈、小靜脈：通過毛細血管改建形成。 大血管修復：離斷后需吻合，內(nèi)膜復原，肌層瘢痕修復。 內(nèi)皮細胞可分泌型膠原、層粘連蛋白和纖維粘連蛋白，構(gòu)成基底膜的基板。周邊成纖維細胞分泌型膠原及基質(zhì)，組成基底膜的網(wǎng)板，本身則成為血管外膜細胞。 血管再生模式圖Mechanism of angiogenesis. In tissue repair, angiogenesis occurs mainly by growth factordriven outgrowth of residual endothelium, sprouting of new ves

10、sels, and recruitment of pericytes to form new vessels. 5肌組織再生：橫紋肌再生依肌膜是否存在及肌纖維是否完全斷離而異。平滑肌、心肌、橫紋肌斷裂破壞后多由瘢痕修復。 6神經(jīng)組織再生：腦及脊髓內(nèi)神經(jīng)細胞：多為膠質(zhì)修復（膠質(zhì)瘢痕）。外周NF：起源的神經(jīng)細胞完好，可完全再生。若離斷兩端相隔超過2.5cm，或兩端間有瘢痕組織等阻隔，則再生纖維不能到達遠端，而與周圍增生的結(jié)締組織混雜成團，形成創(chuàng)傷性神經(jīng)瘤，可產(chǎn)生頑固性疼痛。神經(jīng)組織再生模式圖 第二節(jié) 細胞生長的調(diào)控一、細胞再生與分化的分子機制 促進和抑制再生兩種機制的動態(tài)消長，決定著組織再生能力的

11、強弱；再生增殖受基因活化與表達的調(diào)控，包括原癌基因（protooncogen）和細胞分裂周期基因（cell division cycle gene），決定細胞由靜止期重新進入細胞周期的能力；細胞再生還受生長因子、抑素、細胞外基質(zhì)等細胞外微環(huán)境因素的精密調(diào)控 。The normal size of cell populations is determined by a balance of cell proliferation, cell death by apoptosis, and emergence of new differentiated cells from stem cells.

12、1. 細胞間信號的傳遞方式：自分泌(Autocrine signaling)旁分泌(Paracrine signaling)內(nèi)分泌(Endocrine signaling)2. 細胞表面受體（cell surface receptor, CSR）：The binding of a ligand to its cell surface receptor leads to a cascade of secondary intracellular events that culminate in transcription factor activation or repression, leadi

13、ng to cellular responses. Receptor, in biochemistry, is a protein molecule that receives and responds to a neurotransmitter, or other substance。Patterns of extracellular signaling, demonstrating autocrine, paracrine, and endocrine signalingReceptors with tyrosine kinase activity, Dimeric transmembra

14、ne molecules; ligand binding causes stable dimerization with subsequent phosphorylation of the receptor subunits, activate other intracellular proteins (e.g., RAS, phosphatidylinositol 3-PI3 kinase, phospholipase C PLC-), leading to entry into the cell cycle and cell cycle progression, or induction

15、of other transcriptional programs. RAS activates mitogen-activated protein (MAP) kinase cascade, which is involved in the intracellular signaling of many growth factors, including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte

16、 growth factor (HGF).Receptors without intrinsic enzymatic activityMonomeric transmembrane molecules; ligand interaction induces an intracellular conformational change that allows association with intracellular protein kinases called Janus kinases (JAKs). Phosphorylation of JAKs activates cytoplasmi

17、c transcription factors called STATs (signal transducers and activators of transcription), which shuttle directly into the nucleus. Ligands for these receptors include many cytokines, the interferons, colony-stimulating factors, growth hormone, and erythropoietin.G-protein-coupled receptorsContain s

18、even transmembrane -helix segments and are also known as seven transmembrane G-protein-coupled receptors. After ligand binding, the receptors associate with intracellular guanosine triphosphate (GTP)-binding proteins (G proteins) that contain guanosine diphosphate (GDP). Binding of the G proteins ca

19、uses the exchange of GDP with GTP, resulting in activation of the proteins. Receptors in this category constitute the largest family of plasma membrane receptors (more than 1500 members have been identified) and include those for epinephrine, vasopressin, serotonin, histamine, and glucagon, as well

20、as the chemokines.3. signal transduction system：是一個細胞外信號被識別后轉(zhuǎn)變?yōu)榧毎麅?nèi)信號，進而產(chǎn)生特異性細胞反應的過程，是由一系列蛋白激酶構(gòu)成的調(diào)控細胞生長的網(wǎng)絡。4.細胞周期和細胞分裂的調(diào)節(jié)： cyclin和CDK復合物，校驗點（checkpoint）。5.生長因子: growth factors, whose major role is to promote cell survival and proliferation and which are important in regeneration and healing. Most gro

21、wth factors have pleiotropic effects; that is, in addition to stimulating cellular proliferation, they stimulate migration, differentiation and contractility, and enhance the synthesis of specialized proteins (such as collagen in fibroblasts). An overview of the major types of cell surface receptors

22、 and their principal signal transduction pathways leading to transcription factor activation. 二、ECM在組織修復和細胞再生中的作用（Roles of the Extracellular Matrix） 1. The major components of the ECM： The ECM serves several important functions:It provides mechanical support to tissues, this is the role of collagens

23、 and elastin.It acts as a substrate for cell growth and the formation of tissue microenvironments.It regulates cell proliferation and differentiation; proteoglycans bind growth factors and display them at high concentration, and fibronectin and laminin stimulate cells via cellular integrin receptors

24、. Proteoglycans in the ECM and on cells act as reservoirs for growth factors. Heparan sulfate binds FGF-2 secreted into the ECM. Any subsequent injury to the ECM can release FGF-2, which stimulates the recruitment of inflammatory cells, fibroblast activation, and new blood vessel formation. Syndecan

25、 is a cell surface proteoglycan with a transmembrane core protein and attached extracellular glycosaminoglycan side chains. The glycosaminoglycan chains can also bind free FGF-2 from the ECM and mediate interactions with cell surface FGF receptors. The cytoplasmic tail of syndecan attaches to the in

26、tracellular actin cytoskeleton and helps maintain the architecture of epithelial sheets.三、干細胞在組織修復和細胞再生中的作用 Stem cells are characterized by two important properties: self-renewal capacity and asymmetric replication. Asymmetric replication of stem cells means that after each cell division, some proge

27、ny enter a differentiation pathway, while others remain undifferentiated, retaining their self-renewal capacity. 1. 干細胞（stem cell）：有胚胎干細胞（embryonic stem cell）和成體干細胞（adult stem cell）兩大類。2. 胚胎干細胞具有全能分化（向三個胚層分化）的能力。起源于著床前期胚胎內(nèi)細胞群。 3. 成體干細胞是存在于成體組織器官中的不成熟細胞，多向本身組織的各類型細胞分化，也可向無關(guān)類型的成熟細胞轉(zhuǎn)向分化（transdifferenti

28、ation）4. 主要的成體干細胞在EGF、FGF、IL及其他誘導劑（人工干預因子）的作用下，分別產(chǎn)生神經(jīng)元、血細胞、脂肪細胞、骨與軟骨細胞等，實現(xiàn)病理狀態(tài)下細胞組織的再生和修復。Steps involved in therapeutic cloning using embryonic stem (ES) cells for cell therapy.5. Induced pluripotent stem cells: By introducing four genes (Oct3/4、Sox2、c-Myc and Klf4) together, mature cells return to

29、a stem cell state. The resulting induced pluripotent stem cells (iPS cells) could develop into mature cell types such as fibroblasts, nerve cells and gut cells. Genes that confer stem cell properties are introduced into a patients differentiated cells, give rise to stem cells, which can be induced t

30、o differentiate into various lineages. 第三節(jié) 纖維性修復纖維性修復（repair by connective tissue）：是指實質(zhì)組織細胞破壞較多或受損組織細胞再生能力低下，不能完成同種細胞修復時，通過肉芽組織增生、溶解吸收壞死組織和異物、填補組織缺損、并逐漸轉(zhuǎn)化為瘢痕組織的修復過程。 一、肉芽組織的形態(tài)及作用1.概念：肉芽組織（granulation tissue）是富含新生毛細血管和成纖維細胞的幼稚結(jié)締組織，肉眼鮮紅色、顆粒狀、濕潤柔軟、形似鮮嫩的肉芽，故稱肉芽組織。2.肉芽組織的成分及形態(tài) 成分：肉芽組織的主要成分是增生的成纖維細胞和新生的薄壁

31、毛細血管，伴炎性細胞浸潤。 形態(tài)特點：新生毛細血管向損傷表面垂直生長，以小動脈為軸心，周圍形成袢狀彎曲的毛細血管網(wǎng)； 內(nèi)皮細胞數(shù)量多、核大；巨噬細胞為主的炎性細胞浸潤、也可見中性粒細胞和淋巴細胞；常有多量滲出液；可見肌成纖維細胞（myofibroblast），兼有SMC的超微結(jié)構(gòu)、生化特點及收縮功能。3.肉芽組織的作用及結(jié)局 作用抗感染保護創(chuàng)面：通過巨噬細胞和中性粒細胞的吞噬水解消化清除感染與異物，保持創(chuàng)口潔凈。 填補傷口及其組織缺損：成纖維細胞產(chǎn)生膠原纖維和基質(zhì)填平傷口缺損，并為上皮組織的再生修復提供支撐。 機化或包裹：壞死、血栓、炎性滲出物及其它異物。 結(jié)局 成熟的結(jié)締組織 形成瘢痕組織。

32、1.概念：瘢痕（scar）是由幼稚肉芽組織改建成熟，并有大量玻璃樣變膠原纖維的老化纖維結(jié)締組織。2.形態(tài)特征： 鏡下，主要成分為大量平行或交錯排列的玻璃樣變膠原纖維束，很稀少的成纖維細胞和小血管。 大體上，瘢痕組織呈干燥收縮狀態(tài)，顏色蒼白或半透明，質(zhì)地硬韌并缺乏彈性。二、瘢痕組織的形態(tài)及作用A, Granulation tissue showing numerous blood vessels, edema, and a loose ECM containing occasional inflammatory cells. Collagen is stained blue by the tri

33、chrome stain; minimal mature collagen can be seen at this point. B, Trichrome stain of mature scar, showing dense collagen with only scattered vascular channels.3.對機體的影響： 有利作用： 填補組織缺損，保持組織器官完整性； 抗拉力作用強，使創(chuàng)口愈合堅固。 不利方面： 瘢痕收縮； 瘢痕性粘連； 器官硬化、變形； 瘢痕過度增生，可形成瘢痕疙瘩(keloid)局部過度增 生的瘢痕組織突于皮膚表面形成肥大性瘢痕，并向周 圍不規(guī)則生長擴延，

34、臨床上稱為蟹足腫。 可形成疝、動脈瘤、室壁瘤，比原結(jié)構(gòu)薄弱、可能破 裂。 三、肉芽組織和瘢痕組織的形成過程及機制 1.血管生成（新生）的過程有兩種類型：一種是由內(nèi)皮細胞前體細胞或成血管細胞遷徙增殖形成新的血管結(jié)構(gòu)，稱為血管形成（vasculogenesis）；另一種是由組織中即存的成熟血管內(nèi)皮細胞增殖游走形成小的血管，稱為血管生成（angiogenesis）。血管新生過程受生長因子/受體、細胞和ECM間相互作用的調(diào)控。其中VEGF和血管生成素（angiopoietin, Ang）及其受體作用最為突出。 A, the mobilization of bone marrow endothelial precursor cells (EPCs), and, B, from preexisting vessels at the site of injury.2.纖維化 肉芽組織發(fā)生纖維化（fibrosis）的過程，就是成纖維細胞遷徙增殖和細