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

肺移植已成为临床治疗终末期肺部疾病的有效手段。然而，尽管改进了手术技术，供体器官保存溶液和免疫抑制机制，慢性同种异体移植排斥反应（CR）是一种严重的并发症，以闭塞性细支气管炎（BO）和血管病变的形式出现，并限制了同种异体移植的长期存活。CR的发生与多种因素有关，除急性排斥反应（AR）和淋巴细胞性细支气管炎外，氧化应激在CR的发生中起着核心作用，但目前尚缺乏合适的治疗方案。分子氢疗法的许多动物实验已经在各种疾病领域进行。然而，关于LTx后用H2治疗CR的研究仍然缺失。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LTx后CR的治疗选择的有效性。在大鼠单侧原位肺移植模型（WKY F344）中，设计了四个研究组来研究H2对CR的治疗作用。在该动物模型中，除了富H2的饮用水外，还应吸入H2（在室内气室中使用2%），并通过腹腔注射富H2生理盐水溶液。第一组仅基于H2对CR的影响。另外两组，根据目前临床治疗LTx后CR的情况，采用免疫抑制剂（霉酚酸酯和依维莫司）联合H2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）联合使用降低了CR，所以最后的研究组是RTK is与分子H2的联合使用。除了实验性LTx后H2治疗CR的问题外，本研究将继续有助于阐明LTx后CR的病理机制。

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.