分子氢对异基因造血干细胞移植后慢性移植物抗宿主病的治疗作用及机制研究

The incidence of chronic graft-versus-host-disease is rising year by year, which has become the leading cause of non-transplantation related death and has become the most difficult complication of allogeneic hematopoietic stem cell transplantation to deal with. Inflammation and fibrosis play dominant roles in the pathogenesis of chronic graft-versus-host-disease. Studies have shown that molecular hydrogen has anti-inflammatory, antioxidant, anti-fibrosis effects. Therefore, we hypothesized that molecular hydrogen may have therapeutic effects on chronic graft-versus-host-disease. Recently, we firstly reported the therapeutic effects of hydrogen on acute graft-versus- host disease and carried out preliminary experiments on the therapy effects of hydrogen on chronic graft-versus-host disease. Based on the experimental results previously, we will study the therapeutic effects of hydrogen on chronic graft-versus- host disease, including the survival rate of mice with chronic graft-versus-host disease and its therapeutic effects on skin, intestine, liver lesions. We will also study the mechanism of its therapeutic effects by multiple experiments on cytokines, lymphocyte subsets, DNA damage and repair, cell cycle, cell apoptosis, oxidative damage, cell signaling pathways, cell activation, et al. This project will provide new ideas on the treatment of chronic graft-versus-host disease and has important theoretical values and potential application prospects on the study of hematopoietic stem cell transplantation and hematology.

慢性移植物抗宿主病的发病率正逐年上升，已成为异基因造血干细胞移植后患者非移植相关死亡的主要原因，并已成为异基因造血干细胞移植最难处理的并发症。炎性因子失衡和纤维化在慢性移植物抗宿主病的发病机制中占据了主导性作用。研究表明分子氢具有抗炎、抗纤维化、抗氧化作用，因此我们推测分子氢对慢性移植物抗宿主病可能具有治疗作用。近年，我们在国际上首先报道了分子氢对急性移植物抗宿主病的治疗作用，并开展了分子氢治疗慢性移植物抗宿主病的初步实验。本项目将在前期实验的基础上，系统研究分子氢对小鼠慢性移植物抗宿主病的治疗作用，包括对小鼠生存率、皮肤、肠道、肝脏病变的影响；另将从细胞因子、淋巴细胞亚群、DNA分子损伤与修复、细胞周期、细胞凋亡、氧化损伤、细胞信号通路、细胞活化等多个层面，系统探讨其作用机制。本项目将为慢性移植物抗宿主病的治疗提供新思路，对造血干细胞移植及血液病学研究具有重要的理论价值及潜在的应用前景。

研究背景：慢性移植物抗宿主病（chronic graft-versus-host disease, cGVHD）是异基因造血干细胞移植后一种十分常见的并发症，已成为移植后非移植相关死亡的主要原因及异基因造血干细胞移植最难处理的并发症。目前对慢性GVHD的治疗方案均有较大弊端，国际上仍推荐临床试验作为治疗慢性GVHD的首选，急需寻找到更好的治疗慢性GVHD的方案。前期研究发现分子氢具有抗炎、抗氧化、抗纤维化作用。因此，我们推测分子氢对异基因造血干细胞移植后慢性GVHD可能具有潜在的治疗价值。这一问题过去从未见研究报道，极有必要开展探索。一旦研究成功，这无疑会对突破慢性GVHD的研究瓶颈带来新的希望。.研究内容：1.慢性GVHD小鼠模型的建立；2.富氢溶液在小鼠体内分布规律及其药代动力学；3.富氢溶液对小鼠cGVHD的治疗作用规律；4.富氢溶液对小鼠cGVHD治疗作用的机制研究。.重要结果：1.分子氢能够提高慢性GVHD小鼠生存率；2.分子氢能够改善慢性GVHD小鼠临床评分；3.分子氢能够改善慢性GVHD小鼠皮肤病理改变；4.分子氢能够降低慢性GVHD小鼠皮肤血红素加氧酶-1(HO-1)和烟酰胺腺嘌呤二核苷酸（磷）酸:醌受体氧化还原酶1(NQO1)蛋白表达水平；5.分子氢能够降低慢性GVHD小鼠皮肤Caspase-3蛋白表达水平；6.分子氢能够降低慢性GVHD小鼠皮肤组织中Fas和FasL基因表达水平；7.分子氢能够降低慢性GVHD小鼠体内B细胞活化因子（BAFF）水平。.科学意义：本研究证实了分子氢可通过抗氧化、抗凋亡、抗炎等作用提高慢性GVHD小鼠的存活率，改善了其临床症状。我们认为，该研究为慢性GVHD的治疗提供新的选择，为进一步的临床研究铺平了道路。