Rac亚型调控哮喘性肺损伤的作用和机制研究

We previously demonstrated that both Rac1 and Rac2 were activated in lung tissue after LPS or cigarette smoking-induced pulmonary inflammation, and inhibition of Rac activities by NSC23766 significantly attenuated LPS or cigarette smoking-induced pulmonary inflammation, especially attenuated neutrophils migration toward chemokines and infiltration into the lung, improved inflammatory injury in lung tissue and decreased the release of inflammatory mediators, which played a very important role in COPD (Yao HY, et al. Biochim Biophys Acta. 2011;1810(7):666-74. and unpublished data). However, whether Rac GTPases were activated in asthma, the exact role of Rac subtypes in lung injury of asthma or the probable mechanism involved are all still unknown. Based on our premier finding that both Rac1 and Rac2 were activated in lung tissue in asthma model in mice, and NSC23766, the Rac inhibitor, reduced the exudation, migration, infiltration of eosinophils in the lung and ameliorated the airway hyperreactivity, we will figure out the role of the different subtypes of Rac in lung injury of asthma, and show the probable mechanism in this project. This study will provide us with the new theory that Rac could be a potential target in drug therapy in asthma.

我们以前的研究（Yao HY, et al. Biochim Biophys Acta. 2011;1810(7):666-74.及待发表数据）表明LPS或吸烟诱导的肺内炎症中，肺组织Rac1，Rac2被激活，Rac抑制剂NSC23766抑制Rac活性减少中性粒细胞的迁移及肺内浸润，改善肺组织炎症性损伤，减少炎症介质释放，减轻LPS及吸烟诱导的肺内炎症，在COPD中起重要作用。但是哮喘中Rac是否激活、Rac及其亚型在哮喘肺损伤过程中扮演的角色及可能调控机制尚不清楚。我们前期探索性的研究表明哮喘肺组织中Rac1、Rac2被激活，Rac抑制剂NSC23766显著减少小鼠哮喘模型中的嗜酸性粒细胞渗出、迁移及肺内浸润、改善气道高反应性，以此为依据，本项目进一步探索Rac各亚型调控哮喘性肺损伤中的重要地位及可能的分子机制。通过本研究，为Rac作为哮喘药物治疗靶点提供新的理论和实践依据。

哮喘是一种以气道高反应性为特征的慢性气道非特异性炎症性疾病，嗜酸性粒细胞浸润在哮喘进程中具重要作用。目前，大部分研究主要通过体外实验探讨Rac影响嗜酸性粒细胞的迁移以及炎症介质释放等调控炎症反应，Rac小G蛋白与哮喘之间的研究很少, 特别是Rac各亚型在哮喘中的具体角色以及Rac各亚型调控哮喘性肺损伤的分子机制，尚未深入研究。本研究表明，哮喘肺组织中Rac特别是Rac1被激活，Rac抑制剂NSC23766显著减少小鼠哮喘模型中的嗜酸性粒细胞渗出、迁移及肺内浸润、改善气道高反应性，降低哮喘模型中IL-4mRNA水平，提示Rac在OVA诱导的肺嗜酸性粒细胞炎症中的重要地位。粒细胞条件性敲除Rac1的转基因小鼠结果表明，粒细胞条件性敲除Rac1后哮喘模型炎症细胞渗出、浸润、炎症介质IL-4等释放及杯状细胞化生变化不大，可能与哮喘模型受多方面综合影响有关。另外，在离体研究中，我们明确了抑制Rac能减少嗜酸性粒细胞迁移，可一定程度地抑制RBL-2H3细胞p-p38，p-JNK的表达从而影响炎症介质释放。通过本项目研究，表明了Rac各亚型调控哮喘性肺损伤中的重要地位及可能的分子机制，为Rac作为哮喘药物治疗靶点提供新的理论和实践依据。.