骨髓X激酶(BMX)是非受体酪氨酸蛋白激酶TEC家族成员之一，近年研究发现它是TLRs信号通路的一个重要信号分子，但它在体内炎症反应中的作用仍知之甚少。肺巨噬细胞TLRs下游促炎性信号通路的活化可直接造成肺部炎症反应增强和严重烧伤急性肺损伤(ALI)的发生发展，我们预实验发现严重烧伤后肺脏BMX激酶活化，因此，我们推测BMX激酶可能通过激活促炎性信号通路活化肺巨噬细胞，促发炎症反应，参与严重烧伤ALI的发生发展。本研究拟采用小鼠严重烧伤ALI模型，以肺巨噬细胞为主要研究对象，应用BMX KO小鼠、RNA干扰等手段，观察肺巨噬细胞BMX激酶与严重烧伤ALI的相关性，并明确其与TLRs下游的MAPKs和NF-κB活化及细胞因子表达的关系，深入探讨BMX激酶调控肺巨噬细胞活化的分子机制。本项目的实施将有助于阐明严重烧伤后肺脏失控性炎症反应的发生机制，并为严重烧伤ALI的防治提供新的思路和线索。

Bone marrow kinase on chromosome X (BMX), a member of the TEC family of non-receptor tyrosine kinases, has been demonstrated to be an important molecular of TLRs signal pathway. However, little information has been regarding its role in the systemic inflammatory response. Activation of the downstream proinflammatory pathways of TLRs in pulmonary macrophages leads to the enhancement of inflammatory response in lung and the development and progress of acute lung injury (ALI) after burn trauma. Our preliminary experiments showed that BMX kinase was activated in the lung of severely burned mice. Therefore, we hypothesize that BMX can activate proinflammatory pathways in pulmonary macrophages, resulting in inflammatory response postburn, and involves the development and progress of ALI induced by severe burn. In this study, a mice model of severe burn-induced ALI is utilized. The main object of study is the pulmonary macrophage and BMX KO mice and RNA interference are also used. We aims to investigate the impact of pulmonary macrophage BMX kinase on the development and progress of ALI induced by severe burn, and study the relation of BMX to the activation of downstreams of TLRs including MAPKs and NF-κB and the expressions of cytokines as well. Based on the above experiments, the molecular mechanism of BMX kinase to regulate the activation of pulmonary macrophage will be deeply studied. The results of this study will clarify the mechanisms of uncontrolled pulmonary inflammatory response postburn, and provide new ideas and targets in the prevention and management of severe burn-induced ALI.

骨髓X 激酶(BMX)是非受体酪氨酸蛋白激酶TEC 家族成员之一，本课题采用小鼠严重烧伤ALI 模型，以巨噬细胞为主要研究对象，采用BMX 激酶特异性抑制剂BMX-IN-1作为干预手段，并应用RNA 干扰等手段进行了验证，明确BMX激酶与巨噬细胞促炎性细胞因子产生的关系，并明确其与TLRs下游的MAPKs 和NF-κB 活化之间的联系。研究结果显示：（1）BMX激酶通过TAK1-p38MAPK途径，促进了LPS诱导巨噬细胞产生促炎性细胞因子TNF-α和IL-1β的产生。（2）用不同浓度的LPS刺激巨噬细胞后发现TEC激酶的表达上调,并呈现出LPS浓度依赖性的变化关系，并在LPS浓度为1ug/ml时达到峰值，其后TEC激酶的表达开始出现下降。TEC激酶表达上升的过程与不同浓度LPS刺激有关，较高浓度的LPS所传导的信号更强，以致通过跨膜信号转导传至细胞内的信号更强，致编码TEC激酶的基因表达更多。（3）RNA干扰结果显示，LPS刺激巨噬细胞后，Tec激酶通过干预TAK1/ NF-κB通路影响各种细胞因子的产生和释放。（4）TLR2和TLR4在烧伤后巨噬细胞产生和释放炎性细胞因子的过程中发挥着不同作用。本项目探讨了BMX 激酶调控肺巨噬细胞活化的分子机制，进一步阐明了严重烧伤后失控性炎症反应的发生机制，并为严重烧伤SIRS 的防治提供新的思路和线索。