RUNX1对急性肺损伤的影响研究

The mortality of acute lung injury(ALI) remains high at present. Genetic background plays an important role in ALI. Our previous results indicate that conditional knockout RUNX1 （runt-related transcription factor 1）in the lung results in high mortality in LPS induced mouse ALI model. A lung specific RUNX1 up-regulation mouse will be made with SP-C/rtTA/tetO7 system. Effect of up-regulation and down-regulation of RUNX1 on the prognosis of ALI induced by LPS or cecal ligation and puncture(CLP) will be investgated in the lung specific RUNX1 up-regulation and knockout mice. Effect of RUNX1 on lung stem cell differentiation and on the expression of inflammation cytokines will be investigated. Airway epithelial cell proliferation, apoptosis, migration will also be measured in vivo and in vitro after RUNX1 up-regulation or down-regulation. The relationship between RUNX1 level in bronchoalveolar lavage fluid (BALF) and prognosis of ALI/ARDS patients will be analyzed. This study will uncover the possible effect of RUNX1 on ALI prognosis and may demonstrate the potential mechanism of inflammation and lung tissue injury in ALI. The results will put new insight into ALI diagnosis and treatment, and also new insight into the function of RUNX1.

急性肺损伤（Acute lung injury，ALI）死亡率仍居高不下，其发生及预后与遗传背景相关。我们既往的研究发现LPS诱导的RUNX1（runt-related transcription factor 1）肺部定向基因敲除小鼠ALI死亡率高于对照组，但原因不明。本项目拟研究RUNX1肺部定向基因敲除与上调表达对ALI预后影响，通过检测肺部炎症反应、气道上皮细胞凋亡、肺部干细胞/祖细胞增殖与分化、TGFβ及MMPs通路变化，了解肺RUNX1上调表达与下调表达对ALI预后、肺部炎症、肺损伤及损伤修复的影响；检测气道上皮细胞上调与下调表达RUNX1后增殖与迁徙能力、分泌致炎症细胞因子情况进一步探讨RUNX1影响ALI的机制；分析ALI/ARDS患者BALF中RUNX1水平与预后的关系。通过上述研究，可明确RUNX1对ALI预后的影响并了解其可能机制，为ALI防治提供新的线索.

本项目研究发现，LPS诱导的RUNX1（runt-related transcription factor 1）肺部定向基因敲除小鼠ALI死亡率高于对照组，肺部肺部炎症反应明显，TGFβ及MMPs通路明显上调, 气道上皮细胞凋亡明显。上调与下调表达气道上皮细胞RUNX1后发现RUNX1对A549细胞增殖具有促进作用，但对迁徙能力能力无明显影响。下调RUNX1可促进LPS诱导的A549细胞分泌致炎症细胞因子。上述研究结果表明，肺部定向敲除 RUNX1可通过上调LPS诱导的气道上皮细胞致炎症细胞因子表达，促进肺部炎症反应，导致LPS诱导的ALI小鼠死亡率增加. .项目按计划完成了研究内容，发表SCI论文1篇，Medline收录论文1篇，培养硕士研究生1名，全面完成课题任务书要求。