sCD74诱导CD44蛋白高表达在ARDS肺炎性损伤中的作用

Acute Respiratory Distress Syndrome (ARDS) is one of the critical complications. However, the mechanism of ARDS is still unclear. Our group has focused on the MIF and its receptor CD74 involved in the ARDS for a long time. We demonstrated the increased concentrations of sCD74 in serum of ARDS patients and its level was positively correlated with the lung inflammation. Also serum sCD74 could be used to determine prognosis of ARDS. CD44, a receptor of hyaluronan, has been demonstrated to participate in the inflammation of ARDS. Our preliminary experiments have confirmed that intratracheal instillation of sCD74 can induce lung inflammatory injury and promote high expression of CD44 in lung epithelial cells and vascular endothelial cells. sCD74 could also combine CD44 in vitro. Therefore, the main contents of the study are: (1) to confirm that sCD74 can induce the high expression of CD44 in lung epithelial cells and pulmonary vascular endothelial cells and find its signal pathway; (2) to dertermine whether sCD74 can promote the pulmonary imflammation through CD44; (3) to determine whether sCD74 can induce the cellular oxidative stress response through the promotion of CD44 high expression in the development of ARDS. The above research will provide new evidence for the study of the mechanism of inflammatory injury in ARDS lung tissue.

急性呼吸窘迫综合征(ARDS)是临床最危重的脏器并发症之一，其发病机制尚未完全阐明。本课题组长期聚焦于巨噬细胞移动抑制因子(MIF)及其膜受体CD74参与ARDS发病机制的研究，已证实可溶型CD74(sCD74)在ARDS患者中显著增高，与炎症因子表达呈正相关，可作为危险因素预测ARDS患者预后。CD44作为透明质酸的主要受体被证实参与肺部炎症反应。与本项目相关的预实验证实sCD74可以诱发肺组织炎性损伤，促进肺组织及其靶细胞高表达CD44，初步揭示sCD74可以与CD44结合。本项目拟主要研究:(1)明确sCD74诱导肺部靶细胞高表达CD44蛋白及其所依赖的信号通路；(2)明确sCD74是否通过CD44促进肺部炎症反应；(3)明确sCD74是否通过CD44促进肺部氧化应激反应，进而参与ARDS的发生发展。通过上述实验为ARDS肺炎性损伤的机制研究提供新的证据。

急性呼吸窘迫综合征（ARDS）是烧(创)伤患者最危重的并发症之一，其中炎症因子的级联放大效应所致的肺损伤加重在ARDS进展中扮演重要角色。可溶型CD74(sCD74)是细胞膜受体CD74胞外水解脱落片段，团队前期报道了sCD74存在于ARDS患者血清中，并且其含量和ARDS严重程度呈正相关。我们猜想伴随着ARDS进展中的sCD74，能否会如其他炎症因子加重肺损伤的发生。本课题研究了：①通过气道滴入和尾静脉注射sCD74，观察其对小鼠肺局部及全身有无炎性损伤影响（体内）；②通过sCD74和肺相关细胞共培养，观察其对肺相关细胞有无炎性损伤（体外）；③探究sCD74能否诱导CD44蛋白高表达；④探究sCD74是否通过CD44蛋白促进肺炎症反应的发生；⑤探究sCD74是否通过NF-κB通路参与肺炎症反应，探寻sCD74作用的上游靶点，阻断相关通路蛋白，寻找潜在干预靶点（机制）。通过上述研究，大体可得出以下结论：①气道滴入sCD74能够引起小鼠肺局部的炎症基因高表达和相应的炎症因子的分泌，但对于肺整体的炎性损伤作用和全身炎症反应影响较小；②sCD74能够促进肺相关细胞炎症基因表达增加，同时也能刺激巨噬细胞分泌炎症因子增多；③sCD74能够诱导CD44蛋白表达增多；④预实验研究发现sCD74促进肺炎症反应的发生和其诱导CD44蛋白高表达之间并无明显联系；⑤sCD74是通过激活NF-κB通路促进肺炎症反应的发生。通过上述研究揭示了sCD74通过NF-κB信号通路参与肺炎性损伤，为ARDS的防治提供新的理论依据。