Bissell D M
University of California, San Francisco, USA.
Exp Mol Med. 2001 Dec 31;33(4):179-90. doi: 10.1038/emm.2001.31.
Cells termed myofibroblasts are prominent in the injury response of all epithelial tissues. They exhibit proliferation, migration, production of collagen and other extracellular matrix (ECM) molecules, and contraction, all for containing the injury and closing the wound. When the injury is limited in time, the final stage of the repair involves a dismantling of the cellular apparatus and restoration of normal tissue structure. With multiple cycles of repair, however, there is net accumulation of ECM, to the detriment of tissue structure and function. Repair-related ECM coalesces into fibrous bundles and, over time, undergoes changes that render it resistant to degradation. The result is a scar. In the skin, a scar may have cosmetic importance only. In the liver, however, extensive scarring is the setting for unregulated growth and neoplasia; also, fibrous bands disrupt normal blood flow, leading to portal hypertension and its complications. With regard to therapy for fibrosis, the first consideration is elimination of the injury factor. However, given that many liver diseases do not have effective therapies at present, strategies targeting fibrogenesis per se are under development. The main source of myofibroblast-like cells and ECM production in the liver is the perisinusoidal stellate cell, which responds to injury with a pleiotypic change termed activation. Activation is orchestrated by cytokines and the ECM itself. Among the cytokines involved in this process, transforming growth factor-beta (TGF-beta) is particularly prominent. The early changes in ECM include de novo production of a specific "fetal" isoform of fibronectin, which arises from sinusoidal endothelial cells. It is stimulated by TGF-beta and acts directly on stellate cells to promote their activation. Based on these and other advances in understanding the fundamentals of the injury response, several strategies now exist for altering fibrogenesis, ranging from agents that block TGF-beta to traditional Chinese herbal extracts. Arrest of fibrogenesis, even with underlying cirrhosis, is likely to extend life or prolong the time to transplant. Whether it reduces the risk of hepatocellular carcinoma remains to be proven. Although TGF-beta antagonists are effective anti-fibrogenic agents, they will require detailed safety testing because of the finding that several forms of epithelial neoplasia are associated with altered regulation of TGF-beta.
被称为肌成纤维细胞的细胞在所有上皮组织的损伤反应中都很突出。它们表现出增殖、迁移、产生胶原蛋白和其他细胞外基质（ECM）分子以及收缩，所有这些都是为了控制损伤并闭合伤口。当损伤在时间上受到限制时，修复的最后阶段涉及细胞装置的拆解和正常组织结构的恢复。然而，经过多次修复循环后，ECM会有净积累，这对组织结构和功能不利。与修复相关的ECM聚集成纤维束，随着时间的推移，会发生变化使其难以降解。结果就是形成瘢痕。在皮肤中，瘢痕可能仅具有美容方面的重要性。然而，在肝脏中，广泛的瘢痕形成是不受控制的生长和肿瘤形成的背景；此外，纤维束会破坏正常血流，导致门静脉高压及其并发症。关于纤维化的治疗，首要考虑的是消除损伤因素。然而，鉴于目前许多肝脏疾病尚无有效的治疗方法，针对纤维化本身的策略正在研发中。肝脏中肌成纤维细胞样细胞和ECM产生的主要来源是窦周星状细胞，它对损伤的反应是发生一种称为激活的多型性变化。激活是由细胞因子和ECM本身精心调控的。在参与这一过程的细胞因子中，转化生长因子-β（TGF-β）尤为突出。ECM的早期变化包括由窦状内皮细胞产生一种特定的“胎儿”型纤连蛋白。它受到TGF-β的刺激，并直接作用于星状细胞以促进其激活。基于对损伤反应基本原理的这些以及其他进展，现在有几种改变纤维化形成的策略，从阻断TGF-β的药物到传统的中草药提取物。即使存在潜在的肝硬化，阻止纤维化形成也可能延长寿命或延长移植时间。它是否能降低肝细胞癌风险仍有待证实。尽管TGF-β拮抗剂是有效的抗纤维化药物，但由于发现几种上皮性肿瘤与TGF-β调节改变有关，它们需要进行详细的安全性测试。
