COX2调控PGE2/EP介导重症中暑急性肺损伤的作用机制

重症中暑是一种高致残致死率的疾病，目前临床治疗效果仍不理想。我们在临床工作中发现，大多数中暑患者在出现呼吸衰竭前体温早已恢复正常，表明继发于热损伤外的其它机制可能介导了重症中暑肺损伤，机制目前尚未明确。本项目前期研究发现：重症中暑患者血浆中PGE2表达升高；重症中暑模型大鼠肺水肿，且有大量的炎性细胞富集，肺组织及血浆中PGE2也高表达。采用PGE2合成限速酶COX2特异性抑制剂Celecoxib可减少肺部炎症，减轻肺损伤。这些结果强烈提示，炎症性损伤可能是重症中暑急性肺损伤的关键因素，炎性介质PGE2可能发挥了重要作用。本项目拟从重症中暑动物模型、细胞模型和临床研究三个层面，阐明PGE2及其介导的上下游信号途径在重症中暑急性肺损伤中的作用及机制。该研究有望为揭示重症中暑急性肺损伤的分子病理机制及为Celecoxib老药新用提供重要的实验依据，也将为重症中暑临床治疗提供潜在的新靶点。

Severe heat stroke has a high morbidity and mortality, and the clinical treatment effect is still not satisfactory. In our clinical work, we found that most patients with heat stroke had returned to normal temperature before respiratory failure, indicating other mechanisms secondary to heat injury may lead to lung injury, but the specific mechanism is not yet clear. In the preliminary study of this project, the expression level of PGE2 was found to be up-regulated in the plasma of severe heat stroke patients; and pulmonary edema, alveolar inflammatory cell infiltration, and pulmonary prostaglandin E 2 and its synthesis rate-limiting enzyme cyclooxygenase 2 were found to be elevated in severe heat stroke model rats. The use of cyclooxygenase 2-specific inhibitor Celecoxib can reduce lung injury induced by severe heat stroke, and improve survival rate. These results strongly suggest that inflammatory injury may be a key factor in acute lung injury induced by severe heat stroke, and PGE2 may play a crucial role in this process. This project intends to further elucidate the functions and mechanisms of prostaglandin E2 and its upstream and downstream signaling pathways in lung injury induced by severe stroke through a series of molecular biological, cell biological and animal experimental methods. In addition, clinical intervention experiments are also designed to explore the clinical value of Celecoxib in the treatment of severe heat stroke. This study will provide theoretical foundation for revealing the pathological mechanisms of lung injury induced by severe heat stroke, and also will provide new ideas for the clinical prevention and treatment of severe heat stroke.