CEACAM1及其关键亚型在慢性阻塞性肺病急性加重中的调控作用及机制研究

Chronic Obstructive pulmonary disease (COPD) is a common chronic airway disease. The acute exacerbation of COPD (AECOPD) is closely related with poor prognosis. It is considered that the overload of bacteria may aggravate airway inflammation and subsequently induce AECOPD, but the key factor in the course remains unclear. In our previous study, CEACAM1 was found significantly up regulated in AECOPD and positively correlated with disease severity. Various types of cells express different isoforms of CEACAM1. CEACAM1-L was expressed dominantly in inflammatory cells while CEACAM1-S in airway epithelial cells. We also found that CEACAM1 could induce the production of inflammatory cytokines in airway epithelial cells. In this study, we hypothesized that CEACAM1-L may suppress the function of immunocytes, mediate immune escape and increase bacteria load in airway, while CEACAM1-S may induce inflammation of epithelial cells, and consequently trigger AECOPD. We will collect and measure blood or sputum samples from patients, construct rat models and cellular models of AECOPD, interfere CEACAM1 expression by siRNA, and up-regulate specific CEACAM1 isoform by over-expression plasmid, to verify the disease-specificity of CEACAM1, investigate the regulatory role of CEACAM1 isoforms in AECOPD and discuss the potential mechanism.

慢性阻塞性肺病(COPD)急性加重(AECOPD)与其不良预后密切相关。目前认为AECOPD可能与气道内细菌超负荷并诱导炎症反应相关，但其关键促发因子不明。我们前期研究发现CEACAM1水平与AECOPD严重程度正相关，其不同亚型（-L、-S）在炎症细胞与气道上皮细胞差异表达，且可诱导上皮细胞分泌炎症因子。本课题假设，炎症环境下CEACAM1一方面通过-L亚型抑制免疫细胞功能并介导病原体的免疫逃逸，另一方面通过-S亚型诱导气道上皮细胞分泌炎症因子而加重气道炎症，从而诱发AECOPD。通过临床标本检测、AECOPD大鼠模型构建、siRNA干扰及特定亚型过表达等方法，验证CEACAM1在AECOPD中的特异性，发现CEACAM1-L与气道细菌负荷及炎症细胞功能的关系，探索CEACM1-S诱导上皮炎症反应的相关通路，全面探讨CEACAM1及其关键亚型在AECOPD发生中的作用及可能机制。

慢性阻塞性肺病(COPD)急性加重(AECOPD)与疾病的不良预后密切相关。目前认为AECOPD的发生大多与细菌或病毒的感染相关，但其关键促发因子不明。本项目的研究结果表明，在AECOPD发生的过程中，CEACAM1表达特异升高，且与疾病病程密切相关。CEACAM1与气道内炎症因子释放、组织细胞的迁移、增殖与修复密切相关，并以CEACAM1-3S和CEACAM1-4S亚型起主导作用。PI3K-Akt信号通路在这一过程中起了关键作用，尤其是PI3K p110δ亚基，抑制PI3K p110δ可阻断炎症环境中CEACAM1的上调，从而阻断后续的一系列过程，因此我们提出，CEACAM1-S亚型及PI3K p110δ亚基可作为AECOPD预防和治疗的潜在靶点。