NFAT5-SGK1信号途径调节海水吸入型肺损伤时肺水肿液清除的作用和机制研究

Seawater inhalation results in hypertonic and hypoxic stimulations to lungs, and further leads to seawater inhalation induced acute lung injury (SW-ALI) with very complicated pathogenesis. Researches on mechanisms of pulmonary edema during SW-ALI mainly focused on how seawater induces edema, while fewer studies concerned about edema fluid removal mechanisms. Clearance of fluid in the alveoli depends on normal expression and function of epithelial sodium channel (ENaC) and Na+/K+-ATP enzyme (NKA). It has been confirmed that serum and glucocorticoid regulated kinase 1 (SGK1) played critical role in modulating expression and function of ENaC and NKA, while the regulatory mechanisms of ENaC and NKA in lungs suffering from SW-ALI is still not clear. NFAT5 is the only known transcription factor in mammals sensitive to osmotic stimulations, and it has been reported to modulate SGK1 expression in various tissues and cells. Our previous results indicated that abnormal activation and expression of NFAT5 pathway regulated seawater inhalation induced pulmonary inflammation and hypertonic adaptation through modulating NF-κB and downstream molecules. The present research intends to further explore the mechanisms of NFAT5-SGK1 pathway in regulating pulmonary edema during SW-ALI via interfering expression and function of ENaC and NKA. Results from the present project will help to illuminate the pathological mechanisms of SW-ALI and provide theoretical evidences for the development of novel clinical treatments for SW-ALI.

海水吸入后造成高渗和低氧双重刺激，引起发病机制复杂的海水吸入型肺损伤（SW-ALI）；SW-ALI时肺水肿相关研究多关注于海水引起肺水肿的机制，而水肿液清除机制的研究少见。肺泡内液体清除依赖上皮钠通道（ENaC）和Na+/K+-ATP酶（NKA）正常的表达和功能；高渗状态下，血清和糖皮质激素调节激酶1（SGK1）调控多种组织和细胞中ENaC及NKA表达，而SW-ALI时肺组织中ENaC和NKA的调控机制尚不明确。NFAT5是哺乳动物体内唯一已知对渗透压敏感的转录因子，调控多种细胞中SGK1的表达。我们前期的研究表明NFAT5干预NF-κB及下游分子的表达，调控SW-ALI时肺部炎症和高渗适应。本项目拟进一步研究NFAT5-SGK1调控ENaC和NKA表达及功能，进而影响SW-ALI时肺水肿的机制。本研究将为SW-ALI发病机制提供新的认识，为SW-ALI临床治疗新策略的研发提供理论依据。

本项目主要目标是探讨NFAT5/TonEBP信号通路在海水吸入型肺损伤发病机制中的作用，项目执行时限为2019年1月至2021年12月。在开展本项目的过程中，课题组围绕预定研究目标，深入探讨NFAT5/TonEBP信号通路在海水吸入型肺损伤（SW-ALI）发病机制中的作用和意义，明确不同渗透压液体吸入后p38 MAPK信号通路对NFAT5/TonEBP及下游分子表达的调控作用。配方海水、高渗NaCl溶液和LPS刺激都能够引起细胞中p38 MAPK信号通路的异常活化；配方海水和高渗NaCl溶液对NFAT5/TonEBP及其下游分子表达的影响更为明显，但同比例的配方海水对NFAT5/TonEBP的影响强于高渗NaCl溶液；这说明NFAT5/TonEBP为核心的信号通路是SW-ARDS发病机制中的独特环节。并且，明确了NFAT5/TONEBP通过调节Na+, K+-ATP酶（NKA）的活性和表达调控SW-ALI时肺水肿的发生。.在完成既定研究目标的同时，本课题组在项目经费的资助下开展了肺部疾病诊断方案临床研究，相关内容发表SCI论文1篇，中文论文3篇，申请发明专利1项。此外，在项目经费资助下开展了FUNDC1依赖的线粒体自噬对血管内皮细胞衰老的调控作用，撰写英文论文1篇，正在投稿中。.在人才培养方面，本项目培养博士后1名（马李杰，项目负责人），硕士研究生2名（吴鹏飞、张庭秀，项目参与人）。