肝X受体对光气致急性肺损伤的保护作用及机制研究

Phosgene is a kind of high toxic class irritant gas, which has close relationship with people's production, life and national defense construction. The mechanism of phosgene induced acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is still not clear, and have no special treatment, so the fatality rate of phosgene poisoning is still high. Liver X receptors (LXRs) are the important members of the orphan nuclear receptor family, which are expressed in lung tissue, alveolar macrophages and epithelial cells. According to recent study of our research group, activated LXRs can alleviate oleic acid induced acute lung injury by reducing the expression of lung inflammation factors and the migration of neutrophil (PMN). Mer is one of the members of the tyrosine receptor family. Activated LXRs may be enhanced the expression of Mer, increase the phagocytosis of alveolar macrophage, so as to control the expedition of inflammation. We hypothesized that LXRs may have preventive effects on Phosgene induced acute lung injury. Therefore, this project will study the relationship among LXRs, Mer and ALI by using the phosgene poisoning model of rats. By giving LXRs agonists and antagonists, we will further verification the causal relationship among them. Through in vitro cell experiments, the molecular mechanisms of phosgene induced ALI will be dig out. The results of this project will not only help to resolve the underlying pathogenesis of ALI caused by phosgene, but also throw light on early effective intervention.

光气（phosgene）中毒后发生急性肺损伤（ALI）的具体机制至今仍不明确，也无特效的治疗方法，故病死率较高。肝X受体（LXRs）在肺组织、肺泡巨噬细胞和上皮细胞都有表达。本课题组研究显示,被激活的LXRs可以通过减少炎症因子表达、减少中性粒细胞（PMN）迁移来减轻油酸导致的急性肺损伤。激活的LXRs可能会通过酪氨酸受体Mer(c-Mer Nyk Eyk)表达的增强，提高肺泡巨噬细胞的吞噬功能，进而阻止炎症的继续扩大。我们推测：LXRs可能对光气导致的肺损伤有保护作用。因此，本课题拟用光气染毒大鼠模型来研究LXRs、Mer与ALI的关系；通过给予LXRs激动剂和拮抗剂进一步验证其因果关系；通过体外细胞实验，研究LXRs、 Mer基因、巨噬细胞、PMN等的变化规律及光气导致ALI的分子机制。研究结果不仅可以解析光气致ALI的发病机制，而且为进一步探讨光气中毒的早期干预提供理论基础。

光气（phosgene）中毒后发生急性肺损伤（ALI）的具体机制至今仍不明确，也无特效的治疗方法，故病死率较高。肝X受体（LXRs）在肺组织、肺泡巨噬细胞和上皮细胞都有表达。本课题组前期研究显示，被激活的LXRs可以通过减少炎症因子表达、减少中性粒细胞（PMN）迁移来减轻油酸导致的小鼠急性肺损伤，推测其可能对其他原因导致的ALI亦有保护作用。本课题构建了光气染毒大鼠模型，摸索出LXRs激动剂GW3965、抑制剂SR9243对大鼠的最佳浓度分别为10mg/kg和30mg/kg，对大鼠巨噬细胞作用的最佳剂量30μmol／L和60μmol／L；光气染毒可以引起肝内淤血、肝重量增加和转氨酶增高，这些变化可能与低氧血症和血液流变学变化导致的氧化应激、肝细胞损伤有关。光气染毒可导致肾脏重量的增加、血肌酐和尿素氮水平的升高和肾小管变形。前期研究数据表明，光气染毒会导致大鼠全血黏度，血浆黏度明显升高，红细胞压积上升，而红细胞变形指数下降；同时，血小板的数量急剧、持续降低。血液流变学的变化是全身性的，对肝脏、肾脏势必产生影响；血黏度的增加、红细胞的增多和变形能力的下降、血小板的增多可以导致脏器内微血栓形成、血流瘀滞，肝组织缺血；低氧血症导致肝组织缺氧，引起组织水肿、血管内水分外渗，需氧量大的脏器重量增加会更为明显；缺血缺氧环境可能导致肝脏、肾脏内的氧化应激反应，进而损伤实质细胞，引起脏器功能异常和结构改变。光气中毒后可以引起肝、肾等肺外器官功能的变化，后者对患者的病程和预后有一定的影响，这为光气中毒的治疗提供了有益的线索。课题组即将完成的实验是，用LXRs激动剂GW3965、抑制剂SR9243分别干预健康大鼠和巨噬细胞，除常规方法外，运用基因组学和蛋白组学方法，探索LXRs、相关基因、巨噬细胞、PMN等的变化规律及光气导致ALI的分子机制。研究结果不仅可以解析光气致ALI的发病机制，而且为进一步探讨光气中毒的早期干预提供理论基础。