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1、Targeting Liver Fibrosis: Strategies for Development and Validation of Antifibrotic Therapies针对肝纤维化：抗纤维化治疗的发展和检验的策略We have made striking progress in our understanding of the biochemistry and cell biology that underlies liver fibrosis and cirrhosis, including the development of strategies and agents
2、to prevent and reverse fibrosis.我们已经在现今的生物化学和细胞生物学上构成肝脏纤维变性和肝硬变的原因，包括预防和逆转肝纤维化策略和因子的发展方面取得了显著的进展。 However, translation of this knowledge into clinical practice has been hampered by但是，把这种理论应用到临床实践上受到了阻碍： (1) the limitation of many in vitro and in vivo models to confirm mechanisms and to test antifibr
3、otic agents, （1）许多体外和体内模型机制的确认和抗纤维化因子试验方面的限制。and (2) the lack of sensitive methodologies to quantify the degree of liver fibrosis and the dynamics of fibrosis progression or reversal in patients.（2）缺乏量化肝纤维化程度和肝纤维化的动态进展以及患者肝纤维化逆转的敏感方法。Furthermore, whereas cirrhosis and subsequent decompensation are a
4、ccepted hard clinical endpoints, fibrosis and fibrosis progression alone are merely plausible surrogates for future clinical deterioration. 此外，尽管肝硬化和随后的失代偿期被认为是临床终末阶段，但是肝纤维化和肝纤维化进程仅仅是未来临床恶化似乎可信的代名词。 In this review we focus on an optimized strategy for preclinical antifibrotic drug development and hi
5、ghlight the current and future techniques that permit noninvasive assessment and quantification of liver fibrosis and fibrogenesis.这篇综述，主要总结了为临床前抗肝纤维化药物开发优化策略，突出当前和未来可能的非侵入性评估和量化肝纤维化以及纤维形成的技术。The availability of such noninvasive methodologies will serve as the pacemaker for the clinical development
6、and validation of potent antifibrotic agents.这种非侵入性方法的可用性将成为临床开发和确定有效抗纤维化作用的领头者。 Fibrosis is an excessive wound healing response that occurs in most forms of chronic liver disease and results in the deposition of scar tissue, 肝纤维化是一种发生在大多数慢性肝病过度的伤口愈合的反应,导致了瘢痕组织沉积i.e., excess extracellular matrix (EC
7、M).也就是细胞外基质的过度沉积。 With ongoing liver damage, fibrosis may progress to cirrhosis, which is characterized by a distortion of the liver vasculature and architecture, 随着持续的肝损伤，纤维化可发展为血管和组织结构重塑的肝硬化。and which is the major determinant of morbidity and mortality in patients with liver disease, 肝病患者发病率和死亡率的主
8、要决定因素 predisposing to liver failure and primary liver cancer.诱发肝衰竭和原发性肝癌 Causal treatment, 病因治疗 e.g., 例如antiviral therapy for chronic hepatitis B and C,抗病毒药物治疗慢性乙型肝炎和丙型肝炎 or weight loss and exercise for nonalcoholic steatohepatitis (NASH)非酒精性脂肪肝的减肥和运动疗法can retard or prevent liver fibrosis progressio
9、n.可延缓或阻止肝纤维化的进展However, many patients either do not respond to causal treatment or are diagnosed with advanced fibrosis or cirrhosis.然而, 许多病人或者不重视病因治疗，或者已经被诊断为晚期肝纤维化或肝硬化Because fibrosis and especially cirrhosis are the major predictors of liver-related morbidity and mortality,因为纤维变性和特别是肝硬变是 和肝脏相关疾病发
10、病率和死亡率的主要前兆。there is an urgent need to develop, test, and monitor antifibrotic treatments that can prevent, halt, or even reverse liver fibrosis or cirrhosis.目前迫切需要开发，测试和监测可以预防、制止，甚至逆转肝纤维化或肝硬化的抗纤维化治疗方法。Although we have made impressive progress in our understanding of the mechanisms that underlie the
11、 pathogenesis of liver fibrosis in the past two decades, 虽然在过去20年里，我们已经在肝纤维化的发病机制方面取得了令人瞩目的进展， translation of this knowledge into antifibrotic therapies has ground to a halt short of clinical trials. 但是把这些理论应用于抗肝纤维化治疗的临床试验上已陷于一个短暂的停顿。In this review we will focus on current challenges and pitfalls in
12、 the development of antifibrotic drugs, and on strategies to overcome the obstacles toward their clinical validation.本文主要讨论当前在抗肝纤维化药物的研制方面的问题和易犯的错误，以及克服临床验证障碍的策略。Promising Targets for Antifibrotic Therapies有前景的抗肝纤维化治疗目标Hepatic fibrosis results from a dynamic process,characterized by a preponderance
13、of fibrogenesis (the excess synthesis and deposition of ECM), over its removal(fibrolysis). 肝纤维化是一个动态过程,以纤维形成(ECM过量的合成和沉积)大于其清除(纤维溶解)。Thus, even advanced fibrosis and possibly cirrhosis can regress once the fibrogenic trigger is eliminated and fibrolysis prevails over fibrogenesis.因此,一旦引起纤维化的病因被去除或者
14、纤维溶解超过纤维形成，甚至晚期肝纤维化和肝硬化都可以逆转。The complex biology of hepatic stellate cells and myofibroblasts (collectively termed HSC),肝星状细胞和肌纤维母细胞（都称为HSC）the major producers of excessive ECM in liver fibrogenesis,在肝脏纤维化过程中主要生成过多的细胞外基质 has been covered extensively in recent reviews. 在最近综述中已被广泛报道 Other profibrogeni
15、c nonparenchymal cells act upstream of activated HSC (summarized in Table 1).其他非实质细胞，在上游激活HSC （表1总结）表一Targets for antifibrotic therapies are cells, signaling pathways, and molecules critical for fibrosis progression or reversal.抗纤维化治疗的靶点有细胞，信号转导通路和在肝纤维化形成或逆转过程中的关键性分子 They can therefore address (1) HSC activation and recruitment, (2) activation of cells upstream of HSC activation, (3) profibrogenic growth factors, cytokines and other mediators, (4) intracellular profibrogenic pathways in HSC and cells upstream oftheir activation, and (5) stimulation of fi
