In vivo inhibition of rat stellate cell activation by soluble transforming growth factor β type II receptor:: A potential new therapy for hepatic fibrosis
In vivo inhibition of rat stellate cell activation by soluble transforming growth factor β type II receptor:: A potential new therapy for hepatic fibrosis
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DOI：
10.1073/pnas.96.22.12719
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发表时间：
1999-10-26
影响因子：
11.1
通讯作者：
Bissell, DM
中科院分区：
文献类型：
--
作者：
George, J;Roulot, D;Bissell, DM
转化生长因子β（TGF-β）是一种充分表征的细胞因子，其似乎在指导细胞对损伤的反应、驱动纤维化发生中起主要作用，并且因此潜在地是慢性损伤向纤维化的进展的基础。在这项研究中，我们报告了使用一种新的TGF-β受体拮抗剂来阻断大鼠胆总管结扎引起的纤维化。拮抗剂由含有TGF-β II型受体的细胞外部分的嵌合IgG组成。这种“可溶性受体”在损伤时注入;在一些实验中，它在损伤后4天给予，作为其逆转纤维形成的能力的测试。后者通过胶原蛋白的表达进行评估，无论是作为从对照或损伤的肝脏中分离的星状细胞中的mRNA，还是通过组织切片的定量组织化学。当在损伤时给予可溶性受体时，损伤肝星状细胞中I型胶原mRNA的表达是接受对照IgG的动物的26%（P < 0.0002）;当在损伤诱导后给予可溶性受体时，I型胶原表达是对照星状细胞中的35%（P < 0.0001）。通过定量组织化学，治疗组动物的肝纤维化是对照组的55%。我们的结论是，可溶性TGF-β受体是一种有效的抑制实验性肝纤维化在体内，值得临床评价作为一种新的代理控制慢性肝损伤的肝纤维化。
Transforming growth factor beta (TGF-beta) is a well characterized cytokine that appears to play a major role in directing the cellular response to injury, driving fibrogenesis, and, thus, potentially underlying the progression of chronic injury to fibrosis. In this study, we report the use of a novel TGF-beta receptor antagonist to block fibrogenesis induced by ligation of the common bile duct in rats. The antagonist consisted of a chimeric IgG containing the extracellular portion of the TGF-beta type II receptor. This "soluble receptor" was infused at the time of injury; in some experiments it was given at 4 days after injury, as a test of its ability to reverse fibrogenesis. The latter was assessed by expression of collagen, both as the mRNA in stellate cells isolated from control or injured liver and also by quantitative histochemistry of tissue sections. When the soluble receptor was administered at the time of injury, collagen I mRNA in stellate cells from the injured liver was 26% of that from animals receiving control IgG (P < 0.0002); when soluble receptor was given after injury induction, collagen I expression was 35% of that in control stellate cells (P < 0.0001). By quantitative histochemistry, hepatic: fibrosis in treated animals was 55% of that in controls. We conclude that soluble TGF-beta receptor is an effective inhibitor of experimental fibrogenesis in vivo and merits clinical evaluation as a novel agent for controlling hepatic fibrosis in chronic liver injury.