骨髓来源的CXCR2阳性单核细胞在高血压性视网膜血管损伤中作用及分子机制

Retinal vascular injury is the main pathological feature of retinopathy. Macrophage aggregation and inflammatory response play an important role in hypertensive retinal vascular injury. Chemokine receptor CXCR2 is a key pathway mediating monocyte migration. In applicant's previous experiments, we found that the expression of chemokine CXCL1, CXCR2 and CXCR2+ macrophages increased significantly in Ang II perfusion retina. On the contrary, in the retinas of CXCR2 knockout and inhibitor treatment mice , the infiltration of macrophages, inflammatory cytokines, oxidative stress and vascular damage induced by Ang II were significantly reduced. However, the mechanism of CXCR2-mediated macrophage migration and its role in retinal vascular injury is unclear. This study intends to establish retinal vascular injury and fundus lesions models by Ang II perfusion. Explore the molecular mechanism of Ang II promoting the expression of CXCR2 in CXCR2 knockout, inhibitor treatment, bone marrow transplant mice and in vitro cell co-culture system; Elucidate the role and pathophysiological mechanism of bone-marine-derived CXCR2+ monocytes in retinal inflammation, vascular injury and fundus lesions. This study provides experimental basis for clarifying the molecular mechanism of CXCR2 promoting retinal vascular injury and looking for new drug targets to intervene in retinopathy.

视网膜血管损伤是眼底病变的主要病理特征。巨噬细胞聚集及炎症反应在高血压性视网膜血管损伤中起着重要作用，趋化因子受体CXCR2是介导单核细胞迁移的关键通路。申请人前期实验发现在AngII灌注的视网膜中，趋化因子CXCL1、CXCR2及CXCR2+巨噬细胞显著增加。相反，在CXCR2敲除和抑制剂处理的小鼠视网膜中，AngII引起的巨噬细胞浸润、炎症因子、氧化应激和血管损伤显著减少。但是，CXCR2介导巨噬细胞迁移及在视网膜血管损伤中的作用机制不清楚。本课题拟采用AngII灌注建立视网膜血管损伤和眼底病变模型。应用CXCR2敲除、抑制剂处理和骨髓移植小鼠及体外细胞共培养体系，探讨AngII促进CXCR2表达的分子机制；阐明骨髓来源的CXCR2+单核细胞在视网膜炎症反应、血管损伤及眼底病变中的作用及机制。为明确CXCR2促进视网膜血管损伤的分子机制和寻找干预眼底病变的新药物靶点提供实验依据。

视网膜血管损伤是眼底病变的主要病理特征。巨噬细胞聚集及炎症反应在高血压性视网膜血管损伤中起着重要作用，趋化因子受体CXCR2是介导单核细胞迁移的关键通路。本项目前期实验发现在AngII灌注的视网膜中，趋化因子CXCL1、CXCR2及CXCR2+巨噬细胞显著增加。相反，在CXCR2敲除和抑制剂处理的小鼠视网膜中，AngII引起的巨噬细胞浸润、炎症因子、氧化应激和血管损伤显著减少。但是，CXCR2介导巨噬细胞迁移及在视网膜血管损伤中的作用机制不清楚。本课题采用AngII灌注建立视网膜血管损伤和眼底病变模型。应用CXCR2敲除、抑制剂处理小鼠，探讨AngII促进CXCR2表达的分子机制；阐明骨髓来源的CXCR2+单核细胞在视网膜炎症反应、血管损伤及眼底病变中的作用及机制。为明确CXCR2促进视网膜血管损伤的分子机制和寻找干预眼底病变的新药物靶点提供实验依据。