CD8~+ T细胞在系统性硬皮病组织纤维化中的作用

系统性硬皮病是一种累及皮肤和黏膜组织、内脏器官,引起组织纤维化和硬化性的慢性结缔组织病,主要分为局限肢端型和弥漫型,对患者身心健康及生活质量造成严重影响。其病因及发病机制仍在不断研究过程中,较为公认的结论包括CD8+T细胞参与调控成纤维细胞中胶原表达异常与硬皮病的发病相关,其中白介素13介导的CD8+T细胞参与的皮肤纤维化过程得到多方验证。本综述旨在总结和讨论CD8+T细胞在系统性硬皮病皮肤及皮下组织纤维化过程中的角色和作用机制。     

波动性高糖对肾小管上皮细胞Wnt／β-catenin信号途径的影响

肾脏纤维化分为肾小球硬化和肾小管间质纤维化（tubular interstitial fibrosis,TIF）,而TIF过程与肾损伤具有密切的关系。TIF是由于细胞外基质的过度沉积造成的,肌成纤维细胞是TIF发生发展过程中产生细胞外基质的主要细胞,该过程被成纤维细胞激活,涉及上皮细胞向肌成纤维细胞的转分化^[1-2]。Wnt／β-catenin信号途径涉及细胞增殖、肿瘤发生与转移的调控。β-catenin是Wnt信号途径的关键分子,在细胞的生长与分化过程中起着重要的作用,     

微小RNA介导心肌纤维化信号通路的研究进展

心肌纤维化以细胞外基质沉积为主要特征,是许多心血管疾病发展到一定阶段的共同病理变化.心肌纤维化过程中的一些微小RNA(microRNAs,miRNAs)表达异常,并通过对多种信号通路的调控,参与心肌成纤维细胞的活化和增殖过程,从而介导心肌纤维化的发生和发展.本文将综述这些miRNAs在心肌纤维化中的作用和机制,为心肌纤...     

肝纤维化发病机制中细胞和分子机制的研究进展

关于肝纤维化形成的复杂的细胞和分子联系已经有了相当多的研究进展。最近的数据表明,纤维化进程的终止和纤维分解途径的恢复可以逆转晚期肝纤维化甚至肝硬化。因此,需要更好地阐明参与肝纤维化的细胞和分子机制。HSC(肝星状细胞)的激活是肝纤维化发生的中心事件,此外还有产生基质的其他细胞来源,包括肝门区的成纤维细胞,纤维细胞和骨髓来源的肌纤维母细胞。这些细胞与其邻近细胞通过多种联系聚集产生纤维疤痕并造成持续性损伤。阐明不同类型的细胞的相互作用,揭示细胞因子对这些细胞的影响,理清活化HSC基因表达的调控,将有助于我们探索新的肝纤维化治疗靶点。此外,不同的病因有不同的致病途径,弄清这一点有助于针对特异性疾病治疗方法的发现。本文概述了肝纤维化的细胞和分子机制的最新研究进展,可能为未来治疗方法带来新的突破。     

1-磷酸鞘氨醇在肾脏纤维化中的作用及其调控

肾脏纤维化是原发或继发性肾脏病持续进展至终末期肾病的共同病理过程。1-磷酸鞘氨醇是一种具有生物活性的神经鞘脂类代谢物,参与组织纤维化的发生。研究发现,1-磷酸鞘氨醇在成纤维细胞转分化为肌成纤维细胞过程以及纤维化早期阶段炎症反应的诱导中发挥着关键作用。本文主要介绍1-磷酸鞘氨醇在肾脏纤维化中的作用及其调控,旨在更进一步认识肾脏纤维化发病机制,为肾脏纤维化疾病的预防及治疗提供新的靶向。     

心肌纤维化的信号转导机制及新型抑制剂的研究进展

心肌纤维化(myocardial fibrosis, MF)是心肌重构发生的重要病理过程,能够引起心脏衰竭甚至死亡。心肌组织中成纤维细胞异常增殖并转化为肌成纤维细胞以及心肌细胞外基质代谢紊乱导致沉积是心肌纤维化形成的主要病理基础。心肌纤维化发生的分子机制较复杂,已发现多种信号通路参与了心肌纤维化的发生。该文主要对参与调控心肌纤维化的信号转导机制进行了综述,并对新型信号抑制剂的研究进展进行了小结。     

肝纤维化中肌成纤维细胞的作用及TGF-β/Smads通路的研究进展

肌成纤维细胞(myofibrobasts)是一种多起源的异质性细胞,在肝纤维化过程和愈伤反应(wound-healing response)中扮演重要角色.TGF-β /Smads通路作为体内重要的信号调节通路,对肝纤维化过程具有关键的调节作用,现已成为国内外近年来的研究热点.对肌成纤维细胞的来源以及影响其分化的因素,TGF-β /Smads通路与调控的研究进展,以及肝纤维化的治疗进行了较为全面的综述,并就肝纤维化今后研究的主要发展方向进行了展望.     

肝纤维化发生发展及逆转过程中肝巨噬细胞亚群分类

肝纤维化是由持续性损伤修复反应引起的,导致肝组织内细胞外基质异常沉积,进一步引发肝脏结构和肝功能异常改变的一种病理过程.已有大量研究表明,肝纤维化在去除损伤因素后是可以逆转的.肝星状细胞作为主要的效应细胞,合成和分泌各种胶原和细胞外基质,一直被认为是肝纤维化发生发展的中心环节.最近的研究发现,巨噬细胞作为主要的调节细胞,能同时调节肝星状细胞的功能和基质胶原的降解,促进肝纤维化的形成.而在肝纤维化逆转过程中,促使活化的肝星状细胞凋亡和纤维胶原的降解,促进肝纤维化的逆转.目前已有研究表明,巨噬细胞亚群在肝纤维化发生发展及逆转中具有双向调控作用,但是对于动物模型体内还没有系统的研究巨噬细胞亚群的分类.本文对巨噬细胞亚群的分类研究做一个全面的综述,对肝脏巨噬细胞在肝纤维化中分子机制的进一步研究具有一定的参考价值和借鉴意义.     

肾小管上皮细胞在肾损伤局部微环境中的免疫调节作用

诸多原因可造成肾脏损伤,而肾小管损伤和肾间质纤维化是各种病因所致慢性肾脏病发展至终末期肾病的共同途径.炎症免疫反应是肾损伤的主要病理生理机制,并受局部微环境的精细调控.在此基础上,经历了一个损伤-修复平衡或失衡过程,从而决定着肾组织损伤与修复的走向.肾小管上皮细胞(renal tubular epithelial cell,RTEC)是兼有免疫调节作用且生物学功能十分活跃的细胞,其在肾损伤的局部微环境形成及调控中发挥重要作用.在肾损伤初始及随后的损伤修复中,RTEC不仅合成分泌各种黏附分子、趋化因子及炎症介质,招募单核/巨噬细胞、淋巴细胞等炎症细胞浸润;亦可转分化为免疫细胞或成纤维细胞,启动、参与并调控局部炎症免疫反应,行使免疫防御和损伤修复作用,在损伤因素持续存在且组织修复失衡状况下,积极参与免疫损伤以及肾间质纤维化的演变过程.因此从这个意义上说,RTEC可能是决定肾损伤趋于修复或肾纤维化最终结局的关键因素.     

microRNA调控心肌纤维化研究进展

心肌纤维化(myocardial fibrosis)是指致病因素导致心肌细胞外基质(extracellular matrix,ECM)合成和降解失衡,促使细胞外基质异常增多和过度积聚的病理过程。近年研究发现,miRNA可通过调节成纤维细胞的增殖和转化、细胞因子的分泌和胶原代谢参与心肌纤维化的发病过程。本文就近年关于miRNA参与和调控心肌纤维化的发生过程的研究进展进行综述,为心肌纤维化疾病的诊断和治疗提供理论参考。     

Cytokeratin-positive subserosal myofibroblasts in gastroduodenal ulcer; another type of myofibroblasts

To investigate the distribution and origin of alpha-smooth muscle actin (ASMA)-positive stromal cells in the perforation of human gastroduodenal ulcers. Perforative lesions of 24 surgically resected gastroduodenal ulcers were examined immunohistochemically for ASMA, HCD, CD34, CD31, CAM5.2 and HMW-CK, and double staining of ASMA and CAM5.2 was also performed. In addition, to determine the cell source of collagen, in situ hybridization of collagen I mRNA was performed. In the normal gastroduodenal wall, the reticular network of CD34-positive stromal cells was identified in the muscularis mucosa, submucosa, muscular propria, and subserosa. In the subepithelial area, many myofibroblasts were observed, whereas no CD34-positive stromal cells were seen. In areas neighboring ulcerative lesions, no CD34-positive stromal cells were observed, but a significant number of myofibroblasts were present there. In the deep layer of ulceration, numerous fusiform or stellate stromal cells strongly positive for ASMA and CAM5.2 were observed in the subserosal area around the perforation. In the same site, many cells co-expressing ASMA and CAM5.2 were identified by double staining. In contrast, in the surface layer of ulceration, stromal cells expressing only ASMA were observed. The cytokeratin-positive subserosal myofibroblastic cell in human gastroduodenal ulcer is a novel type of myofibroblast.     

Origins and functions of liver myofibroblasts

Myofibroblasts combine the matrix-producing functions of fibroblasts and the contractile properties of smooth muscle cells. They are the main effectors of fibrosis in all tissues and make a major contribution to other aspects of the wound healing response, including regeneration and angiogenesis. They display the de novo expression of α-smooth muscle actin. Myofibroblasts, which are absent from the normal liver, are derived from two major sources: hepatic stellate cells (HSCs) and portal mesenchymal cells in the injured liver. Reliable markers for distinguishing between the two subpopulations at the myofibroblast stage are currently lacking, but there is evidence to suggest that both myofibroblast cell types, each exposed to a particular microenvironment (e.g. hypoxia for HSC-MFs, ductular reaction for portal mesenchymal cell-derived myofibroblasts (PMFs)), expand and exert specialist functions, in scarring and inflammation for PMFs, and in vasoregulation and hepatocellular healing for HSC-MFs. Angiogenesis is a major mechanism by which myofibroblasts contribute to the progression of fibrosis in liver disease. It has been clearly demonstrated that liver fibrosis can regress, and this process involves a deactivation of myofibroblasts, although probably not to a fully quiescent phenotype. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.     

Reversible differentiation of myofibroblasts by MyoD

Myofibroblasts participate in tissue repair processes in diverse mammalian organ systems. The deactivation of myofibroblasts is critical for termination of the reparative response and restoration of tissue structure and function. The current paradigm on normal tissue repair is the apoptotic clearance of terminally differentiated myofibroblasts; while, the accumulation of activated myofibroblasts is associated with progressive human fibrotic disorders. The capacity of myofibroblasts to undergo de-differentiation as a potential mechanism for myofibroblast deactivation has not been examined. In this report, we have uncovered a role for MyoD in the induction of myofibroblast differentiation by transforming growth factor-β1 (TGF-β1). Myofibroblasts demonstrate the capacity for de-differentiation and proliferation by modulation of endogenous levels of MyoD. We propose a model of reciprocal signaling between TGF-β1/ALK5/MyoD and mitogen(s)/ERK-MAPK/CDKs that regulate myofibroblast differentiation and de-differentiation, respectively. Our studies provide the first evidence for MyoD in controlling myofibroblast activation and deactivation. Restricted capacity for de-differentiation of myofibroblasts may underlie the progressive nature of recalcitrant human fibrotic disorders.     

Thrombin inhibits migration of human hepatic myofibroblasts

Several lines of data recently pointed out a role of the serine proteinase thrombin in liver fibrogenesis, but its mechanism of action is unknown. The aim of this study was to evaluate the effect of thrombin on the migration of human liver myofibroblasts. We show here that thrombin inhibits both basal migration and platelet-derived growth factor (PDGF)-BB-induced migration of myofibroblasts. By using a thrombin antagonist, a protease-activated receptor (PAR)-1 mimetic peptide, and a PAR-1 antibody, we show that this effect is dependent on the catalytic activity of thrombin and on PAR-1 activation. Thrombin's effect on basal migration was dependent on cyclooxygenase 2 (COX-2) activation because it was blocked by the COX-2 inhibitors NS-398 and nimesulide, and pharmacological studies showed that it was relayed through prostaglandin E(2) and its EP(2) receptor. On the other hand, thrombin-induced inhibition of PDGF-BB-induced migration was not dependent on COX-2. We show that thrombin inhibits PDGF-induced Akt-1 phosphorylation. This effect was consecutive to inhibition of PDGF-beta receptor activation through active dephosphorylation. Thus thrombin, through two distinct mechanisms, inhibits both basal- and PDGF-BB-induced migration of human hepatic liver myofibroblasts. The fine tuning of myofibroblast migration may be one of the mechanisms used by thrombin to regulate liver fibrogenesis.     

Inhibition of myofibroblasts by skin grafts.

The myofibroblast population was studied by electron microscopy in rat wounds healing by (1) contraction of granulation tissue, (2) by coverage with split-skin grafts, and (3) by coverage with full-thickness skin grafts. In all 3 types of wounds, myofibroblasts appeared early and reached a peak number at two weeks after wounding. At this time, 40 to 50 percent of the wound fibroblasts had myofibroblast characteristics. The granulating wounds contracted rapidly and completely, and had long persistence of myofibroblasts. Split-skin grafted wounds contracted less and had a more rapid decrease in myofibroblasts. The wounds covered with full thickness skin grafts had a minimum of contraction with a very rapid decrease in the number of myofibroblasts until by 4 weeks no myofibroblasts were present. Full-thickness skin grafts thus appeared to influence contracting wounds not by preventing the formation of myofibroblasts, but by speeding up completion of their life cycle.     

Role of myofibroblasts at the invasion front

Tumor progression occurs within a microecosystem, where cancer cells and myofibroblasts exchange proteinases and cytokines that promote growth directly through stimulation of proliferation and survival, as well as invasion through local proteolysis of the extracellular matrix and stimulation of motility. Myofibroblasts maintain the capacity of fibroblasts to induce differentiation. Fibroblasts are the main source of tumor-associated myofibroblasts. The transition to myofibroblasts also occurs in noncancerous situations. This transition is modulated by mechanical stress and cytokines, amongst which transforming growth factor-beta. The cross-talk between cancer cells and myofibroblasts illustrates the microecosystem of tumor invasion. In order to consider myofibroblasts as a possibly new target for cancer therapy, further characterization of the molecular cross-talk between myofibroblasts and cancer cells is required.     

Myofibroblasts. II. Intestinal subepithelial myofibroblasts

Intestinalsubepithelial myofibroblasts (ISEMF) and the interstitial cells ofCajal are the two types of myofibroblasts identified in the intestine.Intestinal myofibroblasts are activated and proliferate in response tovarious growth factors, particularly the platelet-derived growth factor(PDGF) family, which includes PDGF-BB and stem cell factor (SCF),through expression of PDGF receptors and the SCF receptorc-kit. ISEMF have been shown to playimportant roles in the organogenesis of the intestine, and growthfactors and cytokines secreted by these cells promote epithelial restitution and proliferation, i.e., wound repair. Their role in thefibrosis of Crohn's disease and collagenous colitis is beinginvestigated. Through cyclooxygenase (COX)-1 and COX-2 activation, ISEMF augment intestinal ion secretion in response to certain secretagogues. By forming a subepithelial barrier toNa⁺ diffusion, they create ahypertonic compartment that may account for the ability of the gut totransport fluid against an adverse osmotic gradient. Through theparacrine secretion of prostaglandins and growth factors (e.g.,transforming growth factor-), ISEMF may play a role incolonic tumorigenesis and metastasis. COX-2 in polyp ISEMF may be atarget for nonsteroidal anti-inflammatory drugs (NSAIDs), whichwould account for the regression of the neoplasms infamilial adenomatous polyposis and the preventive effect of NSAIDs inthe development of sporadic colon neoplasms. More investigation isneeded to clarify the functions of these pleiotropic cells.