Institute of Molecular and Translational Medicine and Department of Medicine I, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
J Clin Invest. 2013 May;123(5):1887-901. doi: 10.1172/JCI66028. Epub 2013 May 1.
Fibrosis is an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. With protracted damage, fibrosis can progress toward excessive scarring and organ failure, as in liver cirrhosis. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development, with enormous potential but also high risks. Preclinical research has yielded numerous targets for antifibrotic agents, some of which have entered early-phase clinical studies, but progress has been hampered due to the relative lack of sensitive and specific biomarkers to measure fibrosis progression or reversal. Here we focus on antifibrotic approaches for liver that address specific cell types and functional units that orchestrate fibrotic wound healing responses and have a sound preclinical database or antifibrotic activity in early clinical trials. We also touch upon relevant clinical study endpoints, optimal study design, and developments in fibrosis imaging and biomarkers.
纤维化是对慢性损伤的固有反应，在发生广泛坏死或细胞凋亡时维持器官完整性。随着损伤的持续，纤维化可能会向过度瘢痕形成和器官衰竭发展，如肝硬化。迄今为止，纤维化的抗纤维化治疗代表了药物开发的一个尚未攻克的领域，具有巨大的潜力，但也存在很高的风险。临床前研究已经产生了许多抗纤维化药物的靶点，其中一些已经进入早期临床研究，但由于缺乏敏感和特异的生物标志物来衡量纤维化的进展或逆转，进展受到了阻碍。在这里，我们重点介绍针对肝脏的抗纤维化方法，这些方法针对的是特定的细胞类型和功能单位，它们协调纤维化的伤口愈合反应，并且在临床前数据库或早期临床试验中具有良好的抗纤维化活性。我们还涉及相关的临床研究终点、最佳研究设计以及纤维化成像和生物标志物的发展。
