Molecular hydrogen as a potential treatment of chronic rejection after experimental lung transplantation

肺移植(LTX)已成为治疗终末期肺部疾病的有效方法。然而，尽管改进了手术技术、供体器官保存方案和免疫抑制方案，但慢性排斥反应(CR)是闭塞性毛细支气管炎(BO)和血管病变的严重并发症，限制了同种异体移植物的长期存活。CR的发生似乎与多种因素有关。除了急性排斥反应(AR)和淋巴细胞性毛细支气管炎外，氧化应激在CR的发生发展中起着核心作用。然而，仍然缺乏合适的治疗选择。分子氢(H2)治疗的许多动物实验已经在各种疾病领域进行。然而，有关氢治疗LTX后CR的研究仍然缺乏。通过分子氢清除自由基可以起到预防或治疗的作用。本研究的目的是探讨H2作为实验性肺移植后CR的一种治疗选择的有效性。在大鼠单侧原位肺移植模型(WKY中的F344)中，设计了四个研究组来研究H2治疗CR的效果。在该动物模型中，除饮用富含氢气的饮用水外，还应吸入使用氢气(在室内空气中占2%)，并通过腹腔注射富含氢气的生理盐水溶液。第一组仅基于氢气对CR的影响。在另外两组中，根据目前治疗LTX后CR的临床情况，使用免疫抑制剂(霉酚酸酯和伊波利莫司)作为H2的联合治疗。由于在动物实验中已知多种受体酪氨酸激酶抑制剂(RTK-I)联合应用可降低CR，所以最终的研究组是RTK-I与分子H2的联合应用。除了实验性LTX后用H2治疗CR的问题外，本研究还将继续为阐明LTX后CR的病理机制做出贡献。

Lung transplantation (LTx) has become an effective clinical treatment for patients with end-stage pulmonary diseases. However, in spite of improved surgical techniques, donor organ preservation solutions and immunosuppression regimes, chronic allograft rejection (CR), is a severe complication in the form of obliterative bronchiolitis (BO) and vasculopathy and limits longterm allograft survival. Multiple factors seem to be responsible for the development of CR. Besides acute rejections (AR) and lymphocytic bronchiolitis, oxidative stress plays a central role in the development of CR. However, suitable therapeutic options are still lacking. Many animal experiments with molecular hydrogen (H2) therapy were already carried out in a variety of disease fields. However, studies about the treatment of CR after LTx with H2 are still missing. Scavenging of free radicals by molecular hydrogen may act preventively or therapeutically. The aim of this study is to investigate the efficency of H2 as a therapeutical option of CR after experimental LTx.In a one-sided, orthotopic lung transplant model in rats (F344 in WKY) four study groups are designed to investigate the treatment of CR by means of H2. In this animal model, H2 should be used inhalatively (2% in a room air chamber) in addition to H2-enriched drinking water as well as via an intraperitoneal injection with H2-enriched physiological saline solution.The first group is based on the effect of H2 on CR alone. In two other groups, based on the current clinical situation to treat the CR after LTx, immunosuppressants (mycophenolate mofetil and everolimus) are used as a combination therapy with H2. Since it is known that the combination of various receptor tyrosine kinase inhibitors (RTK-I) reduced CR in animal experiments, the final study group is a combination of RTK Is with molecular H2. In addition to the question of the treatment of the CR by means of H2 after experimental LTx, this study will continue to contribute to the clarification of the pathological mechanism of the CR after LTx.