整合素αvβ6在下呼吸道感染转归的免疫调节机制的研究

Lower respiratory infection is one of the most common diseases with high morbidity and mortality. As reported on the Lancet, lower respiratory infection was the 4th leading cause of death in 2010. The prognosis of lower respiratory disease is of diversity, such as delayed inflammation absorption and fibrosisgensis in some patients, especially in elderly. The outcomes of infectious diseases are decided by both pathogens and host immune status. Integrin αvβ6 is a transmembrane protein restricted to a subset of epithelial cells. Researches on intergrin αvβ6 have demonstrated that it functions as adherins receptors and signaling receptors,and plays critical roles in the behavior of epithelial cells, including survival, proliferation, maintenance of polarity, malignant transformation and activation of TGF-β1. We put forward hypotheses: intergrin αvβ6 could interact the epithelial cells with inflammatory effector cells, fibroblasts,and extracellular matrix by direct or indirect(outside-in and inside-out signalings) methods. We have planed to utilize αvβ6 and its monoclonal neutralizing antibody, to analyze its functions in lower respiratory infection, and the regulaiton roles of signaling cascades. Ultimately these experiments will provide a better understanding of the role of integrin αvβ6 in lower respiratory infection and may provide important insights into novel therapeutic strategies, and aplication values of clinial transformation capbility.

下呼吸道感染是常见疾病，发病率、病死率高；据Lancet杂志数据，2010年下呼吸道感染在全球死因顺位中居第4位。下呼吸道感染的转归呈多样化，部分患者可出现炎症吸收延迟、纤维化等；而其转归由致病源与宿主免疫状态共同决定。整合素αvβ6 可促进受损上皮细胞增殖、迁移，调节TGF-β1活化，间接调控炎症细胞趋化及细胞因子表达；其表达缺失可使博来霉素诱导的小鼠肺纤维程度明显减轻。因此我们假设：整合素αvβ6在呼吸道感染中亦可起到调节炎症、纤维化形成的发生发展，从而调节感染的转归；其机制可能是参与感染中气道上皮细胞与炎症效应细胞、成纤维细胞、细胞外基质的信号交流与调控。我们拟分析整合素αvβ6及其特异性抗体在下呼吸道感染中的功能及调节机制，为优化感染转归，提供新策略、理论基础及临床转化应用价值。