细胞衰老在高PEEP导致的膈肌萎缩中的病理作用及机制研究

膈肌是呼吸肌的重要组成部分。呼气末正压（positive end expiratory pressure，PEEP）几乎应用于所有机械通气的重症患者，以改善氧合和呼吸力学。但临床发现高PEEP机械通气会导致膈肌肌纤维萎缩，而相关的病理机制尚不清楚。本项目由此构建了高PEEP机械通气新西兰兔模型。预实验发现该模型的横膈肌组织中参与细胞衰老调控的关键分子p53和p21的表达量有显著的升高。进一步实时荧光定量PCR实验证实，细胞衰老相关的Pai1、IL-6、p16、MMP13等基因在转录水平的表达均有明显上调，提示细胞衰老是高PEEP机械通气引起膈肌肌纤维萎缩的病理基础之一。本项目拟在此基础上，确认细胞衰老在高PEEP机械通气模型中影响膈肌稳态中的病理作用；解析该模型中上调p53-p21信号轴的上游分子机理；还将尝试利用小分子化合物，对相关模型中的细胞衰老进行干预，以开发新的治疗手段。

Diaphragm is an important part of respiratory muscle. Positive end-expiratory pressure (PEEP) is used in almost all critically ill patients with mechanical ventilation to improve oxygenation and respiratory mechanics. However, it has been found that mechanical ventilation with high PEEP can lead to atrophy of diaphragm fibers, and the relevant pathological mechanism is not clear. In this study, we established a New Zealand rabbit model of mechanical ventilation using high PEEP. The results showed that the expression of p53 and p21, the key molecules involved in the regulation of cellular senescence, increased significantly in the diaphragmatic tissues of the model rabbits. Further real-time fluorescent quantitative PCR experiments showed that PAI1, IL-6, p16, MMP13 and other genes related to cellular senescence were significantly up-regulated at the transcription level, suggesting that cellular senescence is one of the pathological basis of diaphragm atrophy caused by high PEEP mechanical ventilation. On this basis, this study aims to determine the pathological role of cellular senescence in the diaphragmatic homeostasis of the animal model with high PEEP mechanical ventilation; analyze the upstream molecular mechanism of up regulation of p53-p21 signal axis in the model; and try to use small molecular compounds to intervene cellular senescence and develop new treatment methods in related models.