MMP-12在环境因素加重RSV相关气道炎症及气道重塑中的作用及机制研究

Severe RSV infection early in life has been intimately associated with subsequent recurrent wheezing or asthma, however, the risk factors that affected the severity of RSV infection have not fully defined. Environmental facilitations such as lipopolysaccharide have been demonstrated to be able to promote asthma, but the role of environmental facilitations in RSV infection and the underlying mechanisms remain poorly revealed. Our previous study has found that airway inflammation and AHR could persist for a long time post RSV infection. When mice infected with RSV were further exposed to LPS, airway inflammation and AHR were further dramatically aggravated. Moreover, airway mucus secretion was also significantly increased. In parallel, MMP-12 induced by RSV infection was markedly increased following LPS treatment, and airway inflammation, AHR as well as airway hypersecretion were significantly alleviated by MMP-12 suppression. Here in the recent research,further studies are programmed to define the role of TLRs-MAPK signaling pathway in regulating MMP-12 production and to identify if MMP-12 could induce airway remodeling,persistent chronic airway inflammation and irreversible airflow limitation by targeting the mucus-related molecules such as Muc5ac.Such work will help to shed new light on the underlying mechanisms of recurrent wheezing and asthma induced by airway pathogen infection and and environmental pollutants exposure, and might lead to new promissing therapeutic strategies for chronic airway diseases.

生命早期重症呼吸道合胞病毒（RSV）感染与后期反复喘息和哮喘的发生密切相关，但影响RSV感染严重程度的危险因素及潜在机制尚不完全清楚。脂多糖（LPS）等环境因素可加重哮喘症状，但有关环境因素在RSV感染中的作用却知之甚少。前期预实验显示：RSV感染后期再暴露于LPS等环境因素后气道炎症、AHR、气道粘液分泌显著增加。环境因素可明显升高RSV感染诱导产生的MMP-12，阻断MMP-12后气道炎症、AHR及气道高分泌缓解。在此基础上，本项目拟进一步探明TLRs-MAPK信号通路在RSV与环境因素引起MMP-12过度分泌中的作用，并深入探讨MMP-12能否通过影响Muc5ac等粘液分泌相关分子的表达，引起气道重塑，最终导致慢性持续的气道炎症及不可逆的气流受限。研究结果将有助于阐明环境因素与病原感染相互作用引起反复喘息或哮喘的发生机制，为临床提供可能的干预靶点。

生命早期重症呼吸道合胞病毒（Respiratory syncytial virus, RSV）感染与后期反复喘息和哮喘的发生密切相关，但具体机制不清。课题组前期研究发现：RSV感染后期建立起以Th2类反应为主的类似哮喘的呼吸道局部微环境。文献报道脂多糖（lipopolysaccharide，LPS）等环境因素可通过促进Th2类反应诱导哮喘急性发作，但有关环境因素在RSV感染中的作用却知之甚少。本研究通过特异性阻断实验等证实RSV感染后期再暴露于LPS、CpG、Poly（I:C）、OVA等非特性环境刺激物后，气道炎症、气道高反应（airway hyper-responsiveness，AHR）及气道粘液分泌明显增强，但Th2类因子水平不升反降。而基质金属蛋白酶（matrix metalloproteinase，MMPs）或金属蛋白酶组织抑制剂（tissue inhibitors of metalloproteinases，TIMPs）显著升高， Toll样受体（TLRs）及其下游信号衔接分子ERK也显著高表达。阻断MMP12或TIMP-1后，粘液分泌相关基因Muc5ac及Gob5降低，气道炎症、AHR及气道高分泌缓解；阻断ERK后，MMP12、TIMP-1降低。提示环境因素可通过诱导“TLRs-ERK- MMP-12 / TIMP-1- Muc5ac / Gob5”这一炎症连锁反应加重RSV感染后期气道病变，研究结果进一步阐释了RSV感染引起反复喘息和哮喘发生的机制，为临床寻找防治病毒感染相关慢性气道炎症性疾病提供了新的靶点。本课题相关结果已发表1篇SCI，2篇CSCD，目前2篇SCI投稿中；培养博士研究生2名、硕士研究生1名；参与举办1次国际学术交流会议。