缺氧条件下纤维细胞向肺趋化时甲酰肽受体的作用

Cirulating fibrocytes are recruited to adventitia of pulmonary vasculars and are involved in the vascular remodeling. Our preliminary data showed that the formylpeptide receptors (FPRs) were expressed in the fibrocytes at high level, hypobaric hypoxia upregulated the level of FPRs agonists such as annexin A1, and the FPR antagonist reduced the chemotaxis of fibrocytes to pulmonary and attenuated hypoxia-induced pulmonary vascular remodeling. FPRs enable inflamatory cells of the prioritize chemotactic cues by preventing distraction during migration. Activation of the recepors can modulate oxygen sensing by regulating the expression and translocation of hypoxic inducible factor 1 which result in increased ability of glucose and oxygen uptaking to benefit for migrating under hypoxia exposure. The project was designed to study on the chemistry nature of hypoxia-induced FPR agonists and the change of FPRs and make clear how oxgen sensing pathways mediate hypoxia-induced expression of FPRs and its agonists. It is also planned to investigate how agonist-induced activation of FPRs induces cellular skeleton polymerization, distraction-preventing, modulation of oxygen sensing to optimize migration of fibrocytes to pulmonary under hypoxia. Finally, the roles of FPRs in remodeling of pulmonary vascular will be studied by comparing the thichness of vascular, right ventricular systolic pressure, number of fibrocytes and extracellular matrix in adventitia of pulmonary vascular in FPR-overexpressed /FPR-silenced fibrocyte transplanted mice, FPRs knockout / knockin mice, FPR agonist / antagonist treated mice. The project is to reveal a new mechansim of chemotaxis of fibrocytes to pulmonary to remodel pulmonary vascular under hypobaric hypoxia exposure, and provide a new strategy for prevention or treatment of hypoxic pulmonary hypertension.

循环"纤维细胞（FC）"在缺氧时募集于肺血管外膜层，参与肺血管改建。初步研究发现FC表达丰富的甲酰肽受体（FPR），缺氧引起肺组织表达大量甲酰肽受体激动剂Annexin A1，FPR拮抗剂明显改善缺氧肺血管改建。而且FPR信号具有强烈的趋化、抗干扰、低氧信号调制（通过HIF1、ROS）等重要而独特的功能,为此，本项目①弄清缺氧肺组织中FPR及其配体类别、分布与变化特点；②从细胞低氧信号感知途径研究缺氧时肺源性FPR配体产生增多以及循环纤维细胞FPRs表达变化的分子机制；③从细胞趋化过程中信号传导、抗干扰、低氧信号调制、抗缺氧等方面，研究FPRs被其激动剂激活后介导低氧条件下细胞趋化至肺的机制；④通过FPRs 拮抗剂、基因敲除等手段，明确FC趋化至肺参与肺血管改建过程中FPRs的作用。本项目旨在从FPRs揭示缺氧时FC趋化至肺参与肺血管改建的新机制，为防治缺氧性肺动脉高压提供新思路。

循环“纤维细胞”在缺氧时募集于肺血管外膜层，参与肺血管改建。在此基础之上，本项目研究发现纤维细胞表达丰富的甲酰肽受体（FPR），缺氧通过低氧感知信号途径等引起肺组织产生大量甲酰肽受体激动剂Annexin A1、CRAMP、Humanin等，同时引起纤维细胞等炎症细胞FPR的表达上调。FPR 被这些激动剂激活后，介导缺氧条件下细胞的趋化、抗干扰、抗缺氧、低氧信号调制（通过HIF1、ROS）等功能，进而影响缺氧肺血管改建、缺氧肺动脉高压的形成。本项目通过比较使用FPR拮抗剂、FPR1基因敲除后肺血管周围纤维细胞浸润、血管壁厚度、肺动脉压（间接指标）等，发现纤维细胞趋化至肺参与肺血管改建过程中FPRs发挥了十分重要的作用。本项目从FPRs 揭示了缺氧时纤维细胞趋化至肺参与肺血管改建的新机制，从控制纤维细胞及其FPRs这一靶点，为防治缺氧性肺动脉高压提供了新思路。