XOR介导肺泡巨噬细胞极化在百草枯肺损伤中的作用及机制研究

百草枯(PQ)致急性肺损伤(ALI)是患者高死亡率的主因，然其机理不清。前期发现：1) PQ中毒患者血浆黄嘌呤水平增高，死亡组更高；2)PQ中毒死亡患者血浆PGE2显著增高；3)PQ中毒小鼠肺组织巨噬细胞渗出增加; 4)黄嘌呤氧化还原酶(XOR)抑制剂治疗显著减低PQ中毒小鼠的死亡率，减轻巨噬细胞浸润；5)PQ呈时间依赖地诱导巨噬细胞活化和迁移。由于肺泡巨噬细胞（AM）异常极化是ALI的始动环节，故认为：XOR介导AM极化是PQ中毒致ALI的关键机制。为此，首先验证XOR活性抑制和基因缺失对PQ中毒所致ALI的保护作用及其与小鼠肺巨噬细胞渗出的关系；采用单细胞测序技术确定XOR基因缺失对PQ中毒小鼠AMs极化的影响；最后确定XOR调控COX-2/mPGEs-1/PGE2通路异常是否是AM极化的关键通路。这为优化血液净化技术合并XOR抑制剂的治疗新方案，最终克服PQ中毒高死亡率提供实验依据。

Acute lung injury (ALI) induced by paraquat (PQ) mainly caused the high mortality in patients, but its mechanism is unclear. Our preliminary data showed that 1) the levels of plasma xanthine in patients with PQ intoxication increased significantly, and the mortality of the patients was also higher than that in the survival group. 2) The elevated number of lung macrophage infiltration were observed in the PQ-poisoned mice. 3) Plasma PGE2 level increased significantly in PQ-poisoned patients with both nonsurvivor group and survivor group, when compared with the controls. 4) Xanthine oxidoreductase (XOR) inhibitor treatment significantly reduced the mortality in PQ-poisoned mice, meanwhile reduced the lung macrophage infiltration. 5) PQ induced the macrophages activation and migration in a time dependent manner. Because the abnormal polarization of alveolar macrophages (AM) is initiating step of ALI, we hypothesized that XOR mediated the macrophages abnormal polarization through COX-2/mPGEs-1/PGE2 signaling pathway as an important mechanism for PQ-induced ALI. Therefore, we will firstly confirm whether both XOR inhibition and XOR gene knockout have a protective role in PQ-induced ALI mice and the close relationship between XOR and lung macrophages infiltration. Then, we will explore the effects of XOR knockout on the AM polarization. Finally, whether the XOR/COX-2/mPGEs-1/PGE2 signaling pathway plays a crucial role in abnormal AMs infiltration should be confirmed using the Single-Cell RNA-Sequence technique. Our studies lay the foundation for optimizing the new therapeutic regimen such as the blood purification techniques combined with XOD inhibitors in severe patients with PQ poisoning.