Schuppan D, Koda M, Bauer M, Hahn E G
Medizinische Klinik I, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
Acta Gastroenterol Belg. 2000 Oct-Dec;63(4):366-70.
Chronic diseases of the liver, pancreas, intestine, kidneys, skin and lungs are usually accompanied by scarring. Loss of organ function is often progressive despite the use of immunosuppressive, antiviral or antiinflammatory agents. Therefore, well tolerated antifibrotic therapies are urgently needed. The targets for such therapies are activated mesenchymal cells that synthesize an excess of matrix proteins and resemble the myofibroblasts of healing wounds. These cells derive from normally quiescent fibroblasts or smooth muscle cells and from stellate cells of liver and pancreas. Their activation is triggered and maintained by mechanical stress and several fibrogenic modulators and cytokines. Some agents inhibit myofibroblast proliferation and collagen synthesis in vitro, but only few of them are effective in vivo. Potential antifibrotic drugs have been tested mainly in models of liver fibrosis. In the suitable rat model of biliary fibrosis, an antifibrotic effect was demonstrated for silymarin, a defined mixture of flavonoids, and to a lesser degree for pentoxifylline. A spin-off of the large multicenter trials for hepatitis C is the finding that interferon-alpha given for 6-12 months may halt or reverse fibrosis, even in virological non-responders. This has to be proven in prospective randomized trials. Specific inhibitors of the endothelin-A-receptor which are orally available can suppress liver collagen accumulation by 40-60%. Other strategies aim at inhibition of the profibrogenic cytokines TGF-beta or connective tissue growth factor. Effective drug targeting to the fibrogenic liver cells is now possible by use of cyclic peptides that bind to receptors which are specifically upregulated on activated stellate cells. Blockade of such activation receptors can induce stress-relaxation which reverts the fibrogenic cells to a fibrolytic, collagen degrading phenotype. Fibrosis has been discovered as a novel target for the pharmaceutical industry. This implies the use of combinatorial chemistry and an automatized screening machinery, greatly speeding up the design and selection of specific antifibrotic agents. Combined with the rapidly evolving validation of serological markers of fibrogenesis and fibrolysis unforeseen progress in the treatment of organ fibrosis can be expected.
肝脏、胰腺、肠道、肾脏、皮肤和肺部的慢性疾病通常伴有瘢痕形成。尽管使用了免疫抑制剂、抗病毒药物或抗炎药物，器官功能丧失往往仍在进展。因此，迫切需要耐受性良好的抗纤维化疗法。此类疗法的靶点是活化的间充质细胞，这些细胞合成过量的基质蛋白，类似于愈合伤口的肌成纤维细胞。这些细胞来源于正常静止的成纤维细胞或平滑肌细胞，以及肝脏和胰腺的星状细胞。它们的活化由机械应力以及多种促纤维化调节剂和细胞因子触发并维持。一些药物在体外可抑制肌成纤维细胞增殖和胶原蛋白合成，但其中只有少数在体内有效。潜在的抗纤维化药物主要在肝纤维化模型中进行了测试。在合适的大鼠胆管纤维化模型中，水飞蓟宾（一种确定的黄酮类混合物）显示出抗纤维化作用，己酮可可碱的作用则较弱。丙型肝炎大型多中心试验的一个附带发现是，给予6至12个月的α干扰素可能会阻止或逆转纤维化，即使在病毒学无应答者中也是如此。这必须在前瞻性随机试验中得到证实。口服可用的内皮素-A受体特异性抑制剂可使肝脏胶原蛋白积累减少40%至60%。其他策略旨在抑制促纤维化细胞因子转化生长因子-β或结缔组织生长因子。现在，通过使用与活化星状细胞上特异性上调的受体结合的环肽，有可能将药物有效靶向到纤维化的肝细胞。阻断此类活化受体可诱导应力松弛，使纤维化细胞恢复为纤维溶解、胶原蛋白降解的表型。纤维化已被发现是制药行业的一个新靶点。这意味着要使用组合化学和自动化筛选机制，从而大大加快特定抗纤维化药物的设计和选择。结合纤维生成和纤维溶解血清学标志物的快速发展的验证，预计在器官纤维化治疗方面会取得意想不到的进展。
