Relaxin decreases the severity of established hepatic fibrosis in mice.
Relaxin decreases the severity of established hepatic fibrosis in mice.
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DOI：
10.1111/liv.12247
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Tuma DJ
中科院分区：
文献类型：
--
作者：
Bennett RG;Heimann DG;Singh S;Simpson RL;Tuma DJ
肝纤维化的特征是胶原沉积过多、细胞外基质降解减少以及肝星状细胞活化。激素松弛素在治疗许多组织的纤维化方面显示出希望，但松弛素对已形成的肝纤维化的作用尚不清楚。本研究的目的是确定松弛素对建立肝纤维化后体内模型的影响。通过四氯化碳处理使雄性小鼠纤维化4周，然后用两剂松弛素（25或75微克/千克/天）或媒介物处理4周，并持续施用四氯化碳。松弛素在两个剂量下均显着降低总肝胶原蛋白和平滑肌肌动蛋白含量，并在较高剂量下抑制胶原蛋白 I 的表达。松弛素增加基质金属蛋白酶 MMP13 和 MMP3 的表达，减少 MMP2 和金属蛋白酶组织抑制剂 2 (TIMP2) 的表达，并增加胶原蛋白降解活性的总体水平。松弛素减少小鼠肝星状细胞中 TGFβ 诱导的 Smad2 核定位。结果表明，尽管存在持续的肝损伤，但松弛素可减少已形成的肝纤维化中的胶原蛋白沉积和 HSC 活化。这种纤维化的减少与纤维状胶原降解酶 MMP13 表达增加、TIMP2 表达减少、胶原降解活性增强以及 TGFβ 信号传导受损有关，这与松弛素对活化成纤维细胞的作用一致。结果表明，松弛素可能是治疗已形成的肝纤维化的有效疗法。
Hepatic fibrosis is characterized by excess collagen deposition, decreased extracellular matrix degradation, and activation of the hepatic stellate cells. The hormone relaxin has shown promise in the treatment of fibrosis in a number of tissues, but the effect of relaxin on established hepatic fibrosis is unknown. The aim of this study was to determine the effect of relaxin on an in vivo model after establishing hepatic fibrosis. Male mice were made fibrotic by carbon tetrachloride treatment for 4 weeks, followed by treatment with two doses of relaxin (25 or 75 ug/kg/day) or vehicle for 4 weeks, with continued administration of carbon tetrachloride. Relaxin significantly decreased total hepatic collagen and smooth muscle actin content at both doses, and suppressed collagen I expression at the higher dose. Relaxin increased the expression of the matrix metalloproteinases MMP13 and MMP3, decreased expression of MMP2 and tissue inhibitor of metalloproteinases 2 (TIMP2), and increased the overall level of collagen degrading activity. Relaxin decreased TGFβ-induced Smad2 nuclear localization in mouse hepatic stellate cells. The results suggest that relaxin reduced collagen deposition and HSC activation in established hepatic fibrosis despite the presence of continued hepatic insult. This reduced fibrosis was associated with increased expression of the fibrillar collagen-degrading enzyme MMP13, decreased expression of TIMP2, and enhanced collagen degrading activity, and impaired TGFβ signaling, consistent with relaxin's effects on activated fibroblastic cells. The results suggest that relaxin may be an effective treatment for the treatment of established hepatic fibrosis.
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