病理学课件：第二章 损伤的修复

1、第二章 损伤的修复（tissue repair）局部组织损伤后由邻近健康细胞复制分裂、填充、修补，全部或部分恢复机体受损组织细胞结构和功能的过程，称为修复（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) 纤维性修复(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 纲再生(Regeneration)细胞的生长和调控(control of cell growth and differentiation)纤维性修复(repair by connective tissue, fibrosis)创伤愈合(wound healing)概念：局部组织细胞损失后，由邻近同

4、种细胞通过分裂增殖以完成修复的现象，称为再生（regeneration）。有生理性和病理性再生。细胞周期及不同细胞的再生潜能 The ability of tissues to repair themselves is critically influenced by their intrinsic proliferative capacity. 第一节 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. 不稳定组织(labile tissues/Continuously Dividing Tissues.) 随时可从极短的G0期进入细胞周期G1期，不断分裂增殖（又称持续分裂细胞），替代凋亡或损伤细胞。 包括表皮、粘膜被覆上皮，淋巴、造血、间皮细胞等。These tissues can readily regenerate after injury as long as the pool of stem cells is preserved.2. 稳定组织(stable tissues): 生理状态

6、下不增殖，较长期处在G0期静止状态（又称静止细胞）。一旦同类细胞受损死亡，则可迅速重新进入G1期表现出较强的再生能力。 包括各种腺体和腺样器官的实质细胞、间叶细胞及其分化衍生的各种细胞。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.永久性组织(permanent tissues): 永久性处于G0期静止状态，不再进入下一个细胞增殖周期（故又称非分裂细胞）。包括神经元、心肌和骨骼肌。各种组织的再生过程1.上皮组织的再生：被覆上皮：通过创伤邻近部位的基底层

8、储备细胞及残留细胞分裂增生来完成再生。腺上皮：BM完整，可完全再生；BM破坏，难以完全再生。肝细胞再生：部分肝切除后，短期内可完全再生；肝细胞坏死小叶网状支架完整，可完全再生；小叶网状支架塌陷，网状纤维胶原化/肝细胞反复坏死及炎症刺激，纤维增生分隔形成不规则的肝细胞再生结节。 2.纤维组织的再生： 由成纤维细胞（fibroblast）分裂增殖，分泌前胶原蛋白等细胞外基质成分，并在间质中形成胶原纤维后变为纤维细胞。 3.软骨和骨组织的再生：软骨再生：软骨膜细胞增生转化为软骨母细胞，分泌软骨基质形成陷窝变为软骨细胞。软骨再生能力弱，缺损较大时纤维组织参与修复。骨组织再生：再生能力强，骨折后可完全修

9、复。 4血管的再生： 毛细血管以出芽方式进行再生。 小动脉、小静脉：通过毛细血管改建形成。 大血管修复：离断后需吻合，内膜复原，肌层瘢痕修复。 内皮细胞可分泌型胶原、层粘连蛋白和纤维粘连蛋白，构成基底膜的基板。周边成纤维细胞分泌型胶原及基质，组成基底膜的网板，本身则成为血管外膜细胞。 血管再生模式图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肌组织再生：横纹肌再生依肌膜是否存在及肌纤维是否完全断离而异。平滑肌、心肌、横纹肌断裂破坏后多由瘢痕修复。 6神经组织再生：脑及脊髓内神经细胞：多为胶质修复（胶质瘢痕）。外周NF：起源的神经细胞完好，可完全再生。若离断两端相隔超过2.5cm，或两端间有瘢痕组织等阻隔，则再生纤维不能到达远端，而与周围增生的结缔组织混杂成团，形成创伤性神经瘤，可产生顽固性疼痛。神经组织再生模式图 第二节 细胞生长的调控一、细胞再生与分化的分子机制 促进和抑制再生两种机制的动态消长，决定着组织再生能力的

11、强弱；再生增殖受基因活化与表达的调控，包括原癌基因（protooncogen）和细胞分裂周期基因（cell division cycle gene），决定细胞由静止期重新进入细胞周期的能力；细胞再生还受生长因子、抑素、细胞外基质等细胞外微环境因素的精密调控 。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. 细胞间信号的传递方式：自分泌(Autocrine signaling)旁分泌(Paracrine signaling)内分泌(Endocrine signaling)2. 细胞表面受体（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：是一个细胞外信号被识别后转变为细胞内信号，进而产生特异性细胞反应的过程，是由一系列蛋白激酶构成的调控细胞生长的网络。4.细胞周期和细胞分裂的调节： cyclin和CDK复合物，校验点（checkpoint）。5.生长因子: 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在组织修复和细胞再生中的作用（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、干细胞在组织修复和细胞再生中的作用 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. 干细胞（stem cell）：有胚胎干细胞（embryonic stem cell）和成体干细胞（adult stem cell）两大类。2. 胚胎干细胞具有全能分化（向三个胚层分化）的能力。起源于着床前期胚胎内细胞群。 3. 成体干细胞是存在于成体组织器官中的不成熟细胞，多向本身组织的各类型细胞分化，也可向无关类型的成熟细胞转向分化（transdifferenti

28、ation）4. 主要的成体干细胞在EGF、FGF、IL及其他诱导剂（人工干预因子）的作用下，分别产生神经元、血细胞、脂肪细胞、骨与软骨细胞等，实现病理状态下细胞组织的再生和修复。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. 第三节 纤维性修复纤维性修复（repair by connective tissue）：是指实质组织细胞破坏较多或受损组织细胞再生能力低下，不能完成同种细胞修复时，通过肉芽组织增生、溶解吸收坏死组织和异物、填补组织缺损、并逐渐转化为瘢痕组织的修复过程。 一、肉芽组织的形态及作用1.概念：肉芽组织（granulation tissue）是富含新生毛细血管和成纤维细胞的幼稚结缔组织，肉眼鲜红色、颗粒状、湿润柔软、形似鲜嫩的肉芽，故称肉芽组织。2.肉芽组织的成分及形态 成分：肉芽组织的主要成分是增生的成纤维细胞和新生的薄壁

31、毛细血管，伴炎性细胞浸润。 形态特点：新生毛细血管向损伤表面垂直生长，以小动脉为轴心，周围形成袢状弯曲的毛细血管网； 内皮细胞数量多、核大；巨噬细胞为主的炎性细胞浸润、也可见中性粒细胞和淋巴细胞；常有多量渗出液；可见肌成纤维细胞（myofibroblast），兼有SMC的超微结构、生化特点及收缩功能。3.肉芽组织的作用及结局 作用抗感染保护创面：通过巨噬细胞和中性粒细胞的吞噬水解消化清除感染与异物，保持创口洁净。 填补伤口及其组织缺损：成纤维细胞产生胶原纤维和基质填平伤口缺损，并为上皮组织的再生修复提供支撑。 机化或包裹：坏死、血栓、炎性渗出物及其它异物。 结局 成熟的结缔组织 形成瘢痕组织。

32、1.概念：瘢痕（scar）是由幼稚肉芽组织改建成熟，并有大量玻璃样变胶原纤维的老化纤维结缔组织。2.形态特征： 镜下，主要成分为大量平行或交错排列的玻璃样变胶原纤维束，很稀少的成纤维细胞和小血管。 大体上，瘢痕组织呈干燥收缩状态，颜色苍白或半透明，质地硬韧并缺乏弹性。二、瘢痕组织的形态及作用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.对机体的影响： 有利作用： 填补组织缺损，保持组织器官完整性； 抗拉力作用强，使创口愈合坚固。 不利方面： 瘢痕收缩； 瘢痕性粘连； 器官硬化、变形； 瘢痕过度增生，可形成瘢痕疙瘩(keloid)局部过度增 生的瘢痕组织突于皮肤表面形成肥大性瘢痕，并向周 围不规则生长扩延，

34、临床上称为蟹足肿。 可形成疝、动脉瘤、室壁瘤，比原结构薄弱、可能破 裂。 三、肉芽组织和瘢痕组织的形成过程及机制 1.血管生成（新生）的过程有两种类型：一种是由内皮细胞前体细胞或成血管细胞迁徙增殖形成新的血管结构，称为血管形成（vasculogenesis）；另一种是由组织中即存的成熟血管内皮细胞增殖游走形成小的血管，称为血管生成（angiogenesis）。血管新生过程受生长因子/受体、细胞和ECM间相互作用的调控。其中VEGF和血管生成素（angiopoietin, Ang）及其受体作用最为突出。 A, the mobilization of bone marrow endothelial precursor cells (EPCs), and, B, from preexisting vessels at the site of injury.2.纤维化 肉芽组织发生纤维化（fibrosis）的过程，就是成纤维细胞迁徙增殖和细