吸入氢气调节BMPR2表达、防治慢阻肺的作用和机制研究

chronic obstructive pulmonary disease (COPD) is a common and frequently occurring disease with high disability rate and high mortality.At present,there is no effective treatment to prevent the occurrence and development of COPD. Inflammation and oxidative stress are the main pathogenesis of COPD,so the treatment of anti-inflammatory and anti-oxidative may be the focus of future research on the prevention and treatment of COPD.In the present study,Hydrogen gas is one of the most potential anti-inflammatory and antioxidant. In the early stage of hydrogen treatment in patients with severe stable COPD in clinical trials,we found that inhaled hydrogen gas can improve the symptoms and quality of life of patients , reduce airway inflammatory factors and levels of oxidation.And then our previous study in genomic science about vitro and population show that the mutation of bone morphogenetic protein type II receptor (BMPR2) is an important risk factor for COPD; exposure to cigarette smoke can reduces expression level of BMPR2 in cells through pathway of IL-6-miRNA20a. According to the result of previous researches,this study will use animal experiments and cell culture in vitro to research weather inhalation of hydrogen can affect the occurrence and development of COPD by the change of IL-6-miRNA20a-BMPR2 signal pathway ,which is induced under regulating cigarette smoke.The significance of this study lies in two aspects: demonstrate the role of inhaled hydrogen gas in the prevention and treatment of COPD and its possible mechanism, to provide a new method for the prevention and treatment of COPD.

慢性阻塞性肺疾病是一种高致残率和高死亡率的多发病，目前尚没有一种有效的治疗可以从根本上阻止慢阻肺的发生、发展。炎症反应、氧化应激是慢阻肺的主要发病机制。氢气是目前研究中最具潜力的抗炎、抗氧化剂之一。我们在前期氢气治疗慢阻肺的临床实验中发现：吸入氢气可以改善慢阻肺患者的症状，降低气道炎症和氧化水平。我们前期的体外和人群基因组学研究也发现：骨形成蛋白Ⅱ型受体（BMPR2）功能突变是慢阻肺发病的重要危险因素；香烟烟雾暴露通过IL-6-miRNA20a通路降低细胞中BMPR2的表达水平从而增加慢阻肺发生的风险。本研究将在前期实验的基础上应用小鼠模型和体外细胞实验等手段探讨氢气是否通过调节IL-6-miRNA20a-BMPR2信号通路影响慢阻肺的发生和发展。本研究的意义在于：论证氢气在慢阻肺防治中的作用及可能的机制，为慢阻肺的防治提供一种新的策略。

慢性阻塞性肺疾病是一种高致残率和高死亡率的多发病，目前尚没有一种有效的治疗手段可以从根本上阻止慢阻肺的发生、发展。炎症反应、氧化应激是慢阻肺的主要发病机制。氢气是目前研究中最具潜力的抗炎、抗氧化剂之一。本课题将野生型小鼠暴露于香烟烟雾中共90天，制作慢阻肺小鼠模型，从第60天开始实验组吸入40%H2，每天2次，每次1小时。对照组吸入空气。空白组小鼠正常饲养，不予烟熏和吸氢等任何干预。第91天进行观察指标的检测。结果发现：H2吸入改善香烟烟雾引起的慢阻肺小鼠肺功能减退：与空白组小鼠比较，对照组小鼠的肺功能明显改变，包括肺活量(TLC)、功能残气量（FRC）、肺阻抗、FEV100和阻力指数(RI)升高，FEV100/fvc的比值下降，肺顺应性下降。予氢气干预后肺功能可基本恢复正常。H2吸入减轻香烟烟雾引起的慢阻肺小鼠肺组织结构破坏:暴露于香烟烟雾导致小鼠细支气管壁厚度显著增加；肺泡结构破坏明显，形成肺气肿；肺动脉管壁增厚重建。但与对照组比较，H2吸入减少了气管壁厚度的增加量，减轻肺气肿的程度，减轻肺动脉管壁增厚。H2吸入减少香烟烟雾引起的慢阻肺小鼠气道炎症介质和炎症细胞:对照组小鼠的肺泡灌洗液炎症介质IL-6，TNF-α，KC和炎症细胞较空白组明显升高，吸入氢气可明显减轻炎症介质和炎症细胞的浓度。对照组肺组织的ERK1/2和NF-κB浓度明显高于空白组，吸入H2后ERK1/2和NF-κB浓度大大降低。另外我们比较在人支气管上皮细胞培养液中加入H2O2和同时加入H2O2和饱和氢水后培养液中各炎症因子的浓度。结果显示：在人支气管上皮细胞培养液中加入H2O2，培养液中IL-6，IL-8，ERK1/2和NF-κB的浓度明显增加，同时加入H2O2和饱和氢水的培养基中IL-6，IL-8，ERK1/2和NF-κB的浓度增加不明显。该研究结果提示吸入氢气可以改善慢阻肺小鼠模型的肺功能、减轻肺气肿，减少肺结构破坏，减轻气道炎症细胞和炎症介质，为慢阻肺的防治提供了一种新的手段。其作用机制可能与抑制ERK1/2和NF-κB通路有关。