硫化氢通过抑制内质网应激保护高氧肺损伤的研究

Continuous exposure of animals to oxygen at pressures ranging from more than 50 kPa causes hyperoxia-induced acute lung injury.One of the major effects of hyperoxia is the injury and death of pulmonary epithelium, which is accompanied by increased levels of pulmonary proinflammatory cytokines and excessive leukocyte infiltration. A great amount of reactive oxygen species(ROS) were produced by hyperoxia exposure, which induce oxidative damage and endoplasmic reticulum stress(ERS). ERS induces apoptosis through a specific pathway. Recent findings by our group have suggested that exogenous hydrogen sulfide produced by NaHS administration protect lung from hyperoxia-induced injury characterized by reducing the ratio of apoptotic cells. While the precise mechanisms of this effect has not been clarified. The goal of this study is to investigate the relationship between ERS and hyperoxic lung injury and the protective effect of hydrogen sulfide through inhibition of endoplasmic reticulum stress. Together, we try to search for new protective measures aimed at preventing hyperoxic pulmonary injuries based on intervention of the ERS pathway.

机体长时间吸入分压大于50 kPa的氧会导致高氧肺损伤,主要表现为肺泡上皮细胞的损伤及死亡，同时伴随大量炎性因子的释放和中性粒细胞浸润。其发生机制主要为高分压氧进入体内后，产生大量活性氧，超过机体的清除能力，造成氧化损伤。而大量活性氧可以触发内质网应激（ERS），后者可启动下游凋亡途径导致细胞凋亡。我们前期研究发现，外源性硫化氢供体NaHS可以减轻高氧性肺损伤，减少高分压氧暴露造成的肺上皮细胞凋亡，但是，上述作用的分子机制尚需进一步探讨。本项目拟在整体和细胞水平研究ERS在高氧性肺损伤中的作用机制；研究硫化氢是否通过减轻ERS而发挥肺损伤保护作用。通过上述研究，明确ERS在高氧性肺损伤中的作用及机制，并基于ERS探讨硫化氢的高氧肺损伤保护机制，可能为高氧肺损伤的防治提供新思路和理论依据。

长时间暴露于大于 50kPa 高分压氧导致高氧肺损伤。主要表现为肺泡上皮细胞的损伤和死亡，同时伴随大量炎性因子的释放和中性粒细胞浸润。其发生机制主要为高氧进入体内产生大量活性氧，超过机体清除能力造成氧化损伤，进而触发内质网应激。本课题研究发现外源性硫化氢减轻高氧诱导的肺损伤，减轻肺水肿和炎性损伤，减少高氧造成的肺上皮细胞凋亡。硫化氢的保护效应与内质网应激通路有关，后续将继续深入研究二者的关系。