PD-L1/PD-1信号通过调控肺区域免疫应答在支气管肺发育不良中的作用及机制

Abnormal pulmonary regional immunity caused by prenatal risk factors is one of the most important reasons for poor prognosis of BPD. While, how pulmonary regional immunity is affected by prenatal risk factors and contributes to pathogenesis of BPD is largely unclear. Previous study has demonstrated PD-L1/PD-1 signaling is a critical regulator of pulmonary regional immunity. Our study identified that perinatal stage is the critical period of regional immune function maturation, and expression of PD-L1/PD-1 signaling molecular was significant increased during this period which was affected by prenatal infection. These results indicated that prenatal infection is likely to affect PD-L1/PD-1 signaling molecular expression which results in immune dysfunction and abnormal inflammatory response in BPD. In present study, this hypothesis will be tested by using BPD animal model and peripheral blood samples of newborn. This study will provide important insights in understanding the mechanism of inflammation in BPD, which is helpful for the early diagnosis and treatment.

孕期高危因素影响肺发育，导致肺区域的免疫应答异常，是BPD等疾病预后不良的重要原因之一。但孕期高危因素对肺区域免疫功能的影响及影响机制是怎样的？肺区域免疫功能异常在BPD发病过程中怎样发挥重要作用，目前不清楚。研究表明，PD-L1在肺区域免疫功能健全中非常重要。我们前期的研究发现：围产期是肺区域免疫功能健全的关键时期，PD-L1/PD-1信号分子在这一时期表达显著上升，而孕期感染可影响其表达。这些发现提示孕期感染可能通过影响PD-L1/PD-1信号途径，导致肺发育期区域免疫功能不健全，造成异常的炎症应答，在BPD的发生中起关键作用。因此，本研究将利用小鼠BPD模型，研究孕期感染对PD-L1/PD-1信号通路及肺区域免疫细胞的影响，探索其异常在BPD发生中的作用及机制，并利用实验室已收集的新生儿血液标本，探索血清中该信号通路关键蛋白表达变化与BPD发生的相关性，为疾病的早期预警提供潜在靶标。

健全的肺区域免疫功能是在肺发育过程中逐渐形成和完善的，其异常是BPD等慢性肺部疾病预后不良的重要原因。本研究我们利用体外细胞培养，小鼠动物实验及临床样本，研究了PD-L1等B7家族负性共刺激分子在围产期肺发育及区域免疫功能建立过程中的作用，探索其表达异常与BPD发生的相关性。重要发现主要有以下两个方面：1.发现了在围产期肺发育及区域免疫功能建立过程中非常重要的分子，如PD-L1等B7家族负性共刺激分子，claudin18；2.发现血浆Th2趋化因子（eotaxin2，MCP4）表达升高与BPD发病密切相关，早期检测早产儿血浆eotaxin2，MCP4含量，对后期BPD发病有较好的预测作用。