Heme oxygenase-1 gene transfer prevents CD95/FasL-mediated apoptosis and improves liver allograft survival via carbon monoxide signaling pathway.
Heme oxygenase-1 gene transfer prevents CD95/FasL-mediated apoptosis and improves liver allograft survival via carbon monoxide signaling pathway.
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DOI：
10.1016/s0041-1345(02)02932-9
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发表时间：
2002-08
影响因子：
0.9
通讯作者：
B. Ke;X.‐D. Shen;R. Buelow;J. Melinek;F. Amersi;F. Gao;T. Ritter;H. Volk;R. Busuttil;J. Kupiec-Weglinski
中科院分区：
文献类型：
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作者：
B. Ke;X.‐D. Shen;R. Buelow;J. Melinek;F. Amersi;F. Gao;T. Ritter;H. Volk;R. Busuttil;J. Kupiec-Weglinski
CD95/FasL(CD95L)途径的细胞凋亡在同种异体移植排斥反应中起重要作用。血红素加氧酶1(HO-1)是一种应激反应细胞保护分子，在防止移植物排斥反应中可能是必不可少的。我们利用Ad-HO-1基因转移技术分析了HO-1在大鼠原位肝移植(OLT)模型中的作用。与Ad-CD95L+Ad-β-Gal对照组相比，Ad-CD95L+Ad-HO-1转染组对携带Fas的YAc-1靶细胞的杀伤活性和末端脱氧核苷酸转移酶介导的缺口末端标记阳性细胞(TUNEL+)的出现频率降低(p<；0.001)。Adho-1基因转移阻止了Lewis(LEW)大鼠(存活32天)暗刺鼠(DA)肝脏10天的排斥反应，并减少了细胞凋亡。与显示有严重急性排斥征象的Ad-β-Gal移植物不同，Ad-HO-1组的移植物表现出轻到中度的排斥反应和功能改善。用HO-1拮抗剂锡原卟啉(SnPP)辅助治疗后，上述有益作用被取消。与Ad-β-GAL对照相比，转导HO-1的移植物内HO-1和抗凋亡基因产物(BclXL/BAG-1)的表达增强，而辅助性T细胞1型细胞因子(IL-2和干扰素GAL)的表达选择性降低。为了传递HO-1下游介体之一的一氧化碳，同种异体原位肝移植受者暴露在二氯甲烷中。这样的治疗延长了存活至47天，减少了细胞凋亡，并保留了肝脏的结构和功能。因此，Ad-HO-1基因转移可阻止CD95/FasL介导的细胞凋亡，并通过下游的HO-1-CO信号通路显著延长同种异体移植的存活时间。
Apoptosis via the CD95/FasL (CD95L) pathway plays an important role in allograft rejection. Heme oxygenase 1 (HO-1), a stress-responsive cytoprotective molecule, may be essential in preventing graft rejection. We used Ad-HO-1 gene transfer to analyze HO-1-mediated effects in a rat allogeneic orthotopic liver transplantation (OLT) model. The cytotoxicity to Fas-bearing YAC-1 target cells and frequency of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-positive (TUNEL+) cellsin vitrowere diminished in Ad-CD95L + Ad-HO-1-transfected cells, as compared with Ad-CD95L + Ad-β-gal controls (p< 0.001). AdHO-1 gene transfer prevented <10-day rejection of dark agouti (DA) livers in Lewis (LEW) rats (survival >32 days), and diminished apoptosis. Unlike Ad-β-gal OLTs, which showed signs of severe acute rejection, OLTs in the Ad-HO-1 group exhibited mild to moderate rejection and improved function. These beneficial effects were abrogated after adjunctive treatment with tin protoporphyrin (SnPP), an HO-1 antagonist. Intragraft expression of HO-1 and antiapoptotic gene products (Bcl-xl/Bag-1) was enhanced in Ad-HO-1-transduced OLTs, in association with selectively depressed expression of helper T cell type 1 cytokines (interleukin 2 and interferonγ), as compared with Ad-β-gal controls. To deliver CO, one of the downstream HO-1 mediators, allogeneic OLT recipients were exposed to methylene chloride. Such treatment prolonged survival to >47 days, diminished apoptosis, and preserved hepatic architecture/function. Thus, Ad-HO-1 gene transfer prevents CD95/FasL-mediated apoptosis, and significantly prolongs allogeneic OLT survival via a downstream HO-1-CO signaling pathway.