Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells.
Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells.
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DOI：
10.1002/hep.28432
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
Lee S
中科院分区：
文献类型：
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作者：
Oh Y;Park O;Swierczewska M;Hamilton JP;Park JS;Kim TH;Lim SM;Eom H;Jo DG;Lee CE;Kechrid R;Mastorakos P;Zhang C;Hahn SK;Jeon OC;Byun Y;Kim K;Hanes J;Lee KC;Pomper MG;Gao B;Lee S
肝纤维化是慢性肝病的常见结果，可导致肝硬化和肝细胞癌。目前还没有fda批准的靶向抗纤维化疗法。活化的肝星状细胞（aHSCs）是导致肝纤维化的主要细胞类型；因此，清除aHSCs，同时保留静止的hsc和其他正常细胞，是阻止和/或逆转肝纤维化/纤维化的合理策略。然而，没有有效的方法在纤维化期间特异性地消耗aHSCs而不产生全身毒性。aHSCs与死亡受体（dr）的表达升高相关，并对肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的细胞死亡变得敏感。重组TRAIL治疗可能是改善肝纤维化的潜在策略；然而，重组TRAIL的治疗应用由于其半衰期非常短而停止。为了克服这个问题，我们之前生成了PEGylated TRAIL (TRAILPEG)，它在啮齿动物中的半衰期比本地型TRAIL长得多。在这里，我们证明静脉注射TRAILPEG在非人灵长类动物中具有明显延长的半衰期，并且在人原代肝细胞中没有毒性。静脉注射TRAILPEG直接诱导体内aHSCs凋亡，并通过同时下调与aHSCs相关的多个关键纤维化标志物，改善四氯化碳诱导的大鼠纤维化/肝硬化。总之，基于trail的疗法可以作为肝纤维化/肝硬化和其他纤维化疾病的新疗法。
Liver fibrosis is a common outcome of chronic liver disease and leads to liver cirrhosis and hepatocellular carcinoma. No FDA-approved targeted anti-fibrotic therapy exists. Activated hepatic stellate cells (aHSCs) are the major cell types responsible for liver fibrosis; therefore, eradication of aHSCs, while preserving quiescent HSCs and other normal cells, is a logical strategy to stop and/or reverse liver fibrogenesis/fibrosis. However, there are no effective approaches to specifically deplete aHSCs during fibrosis without systemic toxicity. aHSCs are associated with elevated expression of death receptors (DRs) and become sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. Treatment with recombinant TRAIL could be a potential strategy to ameliorate liver fibrosis; however, the therapeutic application of recombinant TRAIL is halted due to its very short half-life. To overcome this problem, we previously generated PEGylated TRAIL (TRAILPEG) that has a much longer half-life in rodents than native-type TRAIL. Here, we demonstrate that intravenous TRAILPEG has a markedly extended half-life over native-type TRAIL in non-human primates and has no toxicity in primary human hepatocytes. Intravenous injection of TRAILPEG directly induces apoptosis of aHSCs in vivo and ameliorates carbon tetrachloride-induced fibrosis/cirrhosis in rats by simultaneously down-regulating multiple key fibrotic markers that are associated with aHSCs. In conclusion, TRAIL-based therapies could serve as new therapeutics for liver fibrosis/cirrhosis and possibly other fibrotic diseases.