Tissue Protection and Repair, Sanofi-Genzyme R&D Center, Framingham, Massachusetts, USA.
PLoS One. 2013;8(1):e54499. doi: 10.1371/journal.pone.0054499. Epub 2013 Jan 17.
Considerable evidence has demonstrated that transforming growth factor β (TGF-β) plays a key role in hepatic fibrosis, the final common pathway for a variety of chronic liver diseases leading to liver insufficiency. Although a few studies have reported that blocking TGF-β with soluble receptors or siRNA can prevent the progression of hepatic fibrosis, as yet no evidence has been provided that TGF-β antagonism can improve pre-existing hepatic fibrosis. The aim of this study was to examine the effects of a murine neutralizing TGF-β monoclonal antibody (1D11), in a rat model of thioacetamide (TAA)-induced hepatic fibrosis. TAA administration for 8 weeks induced extensive hepatic fibrosis, whereupon 1D11 dosing was initiated and maintained for 8 additional weeks. Comparing the extent of fibrosis at two time points, pre- and post-1D11 dosing, we observed a profound regression of tissue injury and fibrosis upon treatment, as reflected by a reduction of collagen deposition to a level significantly less than that observed before 1D11 dosing. Hepatic TGF-β1 mRNA, tissue hydroxyproline, and plasminogen activator inhibitor 1 (PAI-1) levels were significantly elevated at the end of the 8 week TAA treatment. Vehicle and antibody control groups demonstrated progressive injury through 16 weeks, whereas those animals treated for 8 weeks with 1D11 showed striking improvement in histologic and molecular endpoints. During the course of tissue injury, TAA also induced cholangiocarcinomas. At the end of study, the number and area of cholangiocarcinomas were significantly diminished in rats receiving 1D11 as compared to control groups, presumably by the marked reduction of supporting fibrosis/stroma. The present study demonstrates that 1D11 can reverse pre-existing hepatic fibrosis induced by extended dosing of TAA. The regression of fibrosis was accompanied by a marked reduction in concomitantly developed cholangiocarcinomas. These data provide evidence that therapeutic dosing of a TGF-β antagonist can diminish and potentially reverse hepatic fibrosis and also reduce the number and size of attendant cholangiocarcinomas.
大量证据表明，转化生长因子-β（TGF-β）在肝纤维化中起着关键作用，肝纤维化是导致肝功能不全的多种慢性肝病的最终共同途径。尽管有一些研究报道称，使用可溶性受体或 siRNA 阻断 TGF-β可以阻止肝纤维化的进展，但目前尚无证据表明 TGF-β 拮抗作用可以改善已存在的肝纤维化。本研究旨在研究一种鼠源性中和 TGF-β单克隆抗体（1D11）在硫代乙酰胺（TAA）诱导的肝纤维化大鼠模型中的作用。TAA 给药 8 周可诱导广泛的肝纤维化，然后开始并维持 1D11 给药 8 周。在两次时间点（1D11 给药前和给药后）比较纤维化程度，我们观察到治疗后组织损伤和纤维化明显消退，这反映在胶原沉积减少到显著低于 1D11 给药前的水平。TAA 治疗 8 周后，肝 TGF-β1 mRNA、组织羟脯氨酸和纤溶酶原激活物抑制剂 1（PAI-1）水平显著升高。在 16 周时，载体和抗体对照组表现出进行性损伤，而用 1D11 治疗 8 周的动物在组织学和分子终点方面表现出显著改善。在组织损伤过程中，TAA 还诱导胆管癌。在研究结束时，与对照组相比，接受 1D11 治疗的大鼠的胆管癌数量和面积明显减少，这可能是由于支持纤维化/基质的明显减少。本研究表明，1D11 可以逆转 TAA 延长给药引起的已存在的肝纤维化。纤维化的消退伴随着同时发生的胆管癌的显著减少。这些数据提供了证据，即 TGF-β 拮抗剂的治疗剂量可以减少并可能逆转肝纤维化，并减少伴随的胆管癌的数量和大小。
