Regulation of glutathione redox status in lung and liver by conditioning regimens and keratinocyte growth factor in murine allogeneic bone marrow transplantation
Regulation of glutathione redox status in lung and liver by conditioning regimens and keratinocyte growth factor in murine allogeneic bone marrow transplantation
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DOI：
10.1097/00007890-200110270-00004
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发表时间：
2001-10-27
期刊：
影响因子：
6.2
通讯作者：
Blazar, BR
中科院分区：
文献类型：
--
作者：
Ziegler, TR;Panoskaltsus-Mortari, A;Blazar, BR
背景资料。活性氧(ROS)和谷胱甘肽(GSH)耗竭是骨髓移植(BMT)后器官损伤的重要原因。角质形成细胞生长因子(KGF)改善小鼠骨髓移植模型移植物抗宿主病(GVHD)相关器官损伤。B10.BR小鼠接受全身照射(第1天)+环磷酰胺(Cy)120 mg/kg/天，第3天和第2天，然后在第0天移植C57BL/6骨髓+脾细胞作为GVHD致病T细胞的来源。KGF(每天5毫克/公斤皮下注射[S.C.])或在-6、-5、-4天给予生理盐水。分别于第0、5天测定肺、肝GSH和氧化GSH二硫化物(GSSG)水平，计算谷胱甘肽氧化还原电位(E-h)。第5天测定脏器丙二醛(MDA)含量，作为ROS介导的脂质过氧化指标。在肺组织中，TBI+BMT氧化GSH E-h，增加丙二醛。Cy进一步氧化肝脏中的肺GSH E-h，BMT方案均不改变GSH氧化还原状态和丙二醛。KGF可抑制脑损伤+Cy后肺组织GSH的降低，降低肺组织中丙二醛的含量。KGF可提高脑创伤后肝脏GSH水平和GSH E-h水平，升高脑损伤后GSH E-h水平。在小鼠异基因骨髓移植中，TBI氧化肺GSH氧化还原池，Cy在骨髓移植后5天加剧这种反应。相反，在这些实验条件下，肝脏GSH氧化还原状态保持不变。KGF治疗可减轻Cy诱导的肺GSH下降，减轻BMT后肺组织脂质过氧化反应，改善肝脏GSH氧化还原指数。KGF可能在预防或减轻骨髓移植中GSH耗竭和ROS介导的器官损伤方面起到治疗作用。
Background. Reactive oxygen species (ROS) and glutathione (GSH) depletion contribute to organ injury after bone marrow transplantation (BMT). Keratinocyte growth factor (KGF) ameliorates graft-versus-host disease (GVHD)-associated organ injury in murine BMT models.Methods. B10.BR mice received total body irradiation (TBI; day -1) +/- cyclophosphamide (Cy; 120 mg/kg/day i.p., days -3 and -2), then were transplanted on day 0 with C57BL/6 bone marrow + spleen cells as a source of GVHD-causing T cells. KGF (5 mg/kg/day subcutaneously [s.c.]) or saline was given on days -6, -5, and -4. Lung and liver GSH and oxidized GSH disulfide (GSSG) levels were measured on days 0 and 5 and glutathione redox potential (E-h) calculated. Organ malondialdehyde (MDA) was determined on day 5 as an index of ROS-mediated lipid peroxidation.Results. In lung, TBI+BMT oxidized GSH E-h and increased MDA. Cy further oxidized lung GSH E-h In liver, neither BMT regimen altered GSH redox status or MDA. KGF prevented the decrease in lung GSH after TBI+Cy and decreased lung MDA after both TBI and TBI + Cy. KGF increased liver GSH levels and GSH E-h after TBI and GSH E-h after TBI+Cy.Conclusions. In murine allogeneic BMT, TBI oxidizes the lung GSH redox pool and Cy exacerbates this response by 5 days post-BMT. In contrast, liver GSH redox status is maintained under these experimental conditions. KGF treatment attenuates the Cy-induced decrease in lung GSH, decreases post-BMT lung lipid peroxidation, and improves liver GSH redox indices. KGF may have a therapeutic role to prevent or attenuate GSH depletion and ROS-mediated organ injury in BMT.