慢性阻塞性肺病(COPD)是一种难治的慢性气道炎性疾病，发病机制复杂，治疗药物有限。目前，磷酸二酯酶(PDE)抑制剂通过调控细胞内环核苷酸水平，成为控制COPD炎症药物的新选择；此外，“炎性衰老”学说认为气道细胞早衰可放大细胞炎症表型，使气道炎症自我扩展和持久化，抗衰老蛋白SIRT1或可逆转这一过程。因此，对于SIRT1和PDEs的双重药理活性纠正很可能是对抗COPD炎症的有效策略。SIRT1对气道慢性炎症的调节机制尚未阐明，它与环核苷酸-PDE信号通路之间的联系，国内外鲜有报道。本项目重点研究PDEs抑制作用和SIRT1激活作用是否可协同调节气道细胞炎性反应，改善气道功能。课题将采用多种细胞和动物COPD模型，研究PDEs与SIRT1的相互调节，同时根据化合物羧胺三唑抑制PDEs、激活SIRT1的双重药理作用，探讨其治疗COPD的潜能，为发展新型小分子抗COPD药物提供理论和实践依据。

Chronic obstructive pulmonary disease (COPD) is a refractory chronic airway inflammatory disease, with complex pathogenesis and limited therapeutic drugs. Currently, phosphodiesterase (PDE) inhibitors become new drug candidates for controlling COPD inflammation by regulating intracellular cyclic nucleotide levels; Moreover, “inflammatory aging” hypothesis for COPD believes the premature aging of airway cells enlarges the inflammatory phenotype and results in self-expanded and persistent airway inflammation. And anti-aging protein SIRT1 may be able to reverse the process. Therefore, the dual pharmacological correction targeting PDEs and SIRT1 activities is likely to be an effective strategy for COPD. The regulatory mechanism of SIRT1 in COPD has not yet been clarified. Few studies investigating the linkage of SIRT1 and cyclic nucleotide-PDEs signaling pathway are published at home and abroad. The focus of this project is to clear the effects of PDEs inhibition and SIRT1 activation on airway inflammation and whether they can improve airway function synergistically. This project will conduct a thorough study on the mutually regulatory mechanism between cyclic nucleotides/PDEs and SIRT1 signaling pathway using various immune cell lines, endothelial cell lines and rat model of chronic obstructive pulmonary disease. In addition, based on the non-selective inhibitory effect and stimulating effect of CAI on PDEs and SIRT1 separately, an in-depth study will be conducted to explore the therapeutic potential and mechanism of CAI on COPD and provide theoretical and practical basis for the development of new small molecule anti-COPD drugs.