脂氧素A4及其受体在脂肪栓塞综合征发病过程中的作用及机制

Fat embolism syndrome (FES) is characterized by high mortality but so far is only treated with symptomatic therapy. Some studies have shown that inflammation is one of the main pathogeneses of FES. Lipoxin A4 (LXA4) is an endogenous-derived anti-inflammatory substance which is discovered recently. It can alleviate inflammatory response and promote inflammation resolution, and so it is referred to as brake signal of inflammation. Our pilot study on the model of FES in rats showed that LXA4 could significantly reduce proinflammatory cytokine and improve blood oxygen saturation and survival rate, however, LXA4 receptor inhibitors BOC-2 offset these effects. Therefore we hypothesize that LXA4 may have a remission and therapeutic effect on FES by reducing inflammatory response. This study will (1) explore the variation of endogenous LXA4 in the process of FES (2) valuate the effects of LXA4 on the FES by increasing or opposing LXA4 in rats (3) observe the effect of LXA4 on inflammatory response in free fatty acid-treated pulmonary microvascular endothelial cells in rats with overexpression and gene silencing technology(4) investigate the signal pathway of LXA4 by using agonists and antagonists of MAPK, NF-κB and PI3K / Akt respectively. The objective of this study is to explore a new route for the treatment of FES.

脂肪栓塞综合征（FES）死亡率高，目前无特效治疗方法。研究显示游离脂肪酸引起的炎症反应是其主要病理机制之一。脂氧素A4（LXA4）是近年发现的炎症反应内源性刹车信号物质，具有抗炎、促炎症消退和促进组织修复等功能。我们前期研究发现在FES大鼠模型中，LXA4能明显减轻炎症反应，改善血氧饱和度和提高生存率，而LXA4受体拮抗剂BOC-2抵消了此效果。据此我们提出“LXA4及其受体可通过抑制炎症反应减轻FES的严重程度，从而对FES有治疗作用”的假设。本课题（1）明确FES过程中内源性LXA4的变化规律（2）通过增加或拮抗LXA4，观察其对FES的作用（3）使用基因过表达和沉默技术，观察LXA4对游离脂肪酸处理的大鼠肺微血管内皮细胞炎症反应的影响（4）分别利用MAPK、NF-κB及PI3K/Akt的激动剂和拮抗剂，探讨在FES中LXA4发挥抗炎作用的信号通路。旨在为FES的治疗提供一种新途径。

一、项目一般情况及目前完成情况：. 本课题通过在动物和细胞水平上建立的脂肪栓塞综合征生化损伤模型，研究脂氧素A4在其发病机制中的作用和对预后的影响。现已完成课题原设计的所有实验内容（除使用基因过表达和沉默技术，观察LXA4对游离脂肪酸处理过的大鼠肺微血管内皮细胞炎症反应的影响）。.二、目前取得成果：.（1）建立稳定的细胞和动物脂肪栓塞综合征生化损伤模型。.（2）同时在细胞和动物层面，证实LXA4在脂肪栓塞综合征病理模型中表达增多，且在一定范围内与脂肪栓塞炎症损伤的程度与时间有相关性。.（3）证实使用LXA4激动剂可减低脂肪栓塞综合征引起的肺损伤，该作用可被LXA4拮抗剂逆转。.（4）发现MAPKs信号转导途径参与脂肪栓塞综合征病理过程。.（5）在细胞和动物体内，LXA4通过抑制MAPKs信号通路减轻脂肪栓塞综合征引起的肺损伤。.（6）探讨了LXA4对脂肪栓塞综合征预后的影响。.（7）在本课题资助下共培养了1名博士研究生，2名硕士研究生(一名在读），现已在SCI期刊发表英文论著4篇。