Involvement of P2R signalling in the pathogenesis of fibrotic lung diseases

P2R 信号传导参与纤维化肺疾病的发病机制

• 批准号: 221560265
• 负责人: Dr. Tobias Müller
• 金额: --
• 依托单位: Klinik für Kardiologie, Angiologie und Internistische Intensivmedizin (Med. Klinik I)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/221560265?language=en
• 关键词: Involvement; P2R; signalling; pathogenesis; fibrotic

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Currently, there is no effective therapy available. The pathogenesis of this devastating disease is not fully understood. In the past, extracellular nucleotides, e. g. adenosine-5’-triphosphate (ATP) have gained attention as mediators of inflammation and immuno-regulation via purinergic receptor (P2R) signalling. Preliminary results showed that extracellular ATP levels are elevated in patients suffering from IPF or after the induction of experimental lung fibrosis in mice. Furthermore, treatment of these animals with non-selective P2R antagonists led to reduced inflammation and fibrosis. The aim of this project is to identify the P2R subtypes involved in the pathogenesis of both bleomycin-induced lung fibrosis in mice and IPF in humans. Therefore, P2R deficient mice as well as specific P2R antagonists will be used. Additionally, fibroblast migration and intracellular signalling in response to different nucleotides will be investigated. To confirm the relevance of the results obtained in animal experiments for the situation in humans, P2R expression on broncho-alveolar lavage and blood cells from IPF patients will be compared to healthy individuals. These studies will provide important information about the pathophysiology of pulmonary fibrosis and could open a new therapeutic approach for the treatment of fibrotic lung diseases.

特发性肺纤维化（IPF）是一种预后不良的进行性疾病。目前，尚无有效的治疗方法。这种毁灭性疾病的发病机制尚未完全清楚。过去，细胞外核苷酸，e。G.腺苷-5 ′-三磷酸（ATP）作为炎症介质和通过嘌呤能受体（P2 R）信号传导的免疫调节已经引起了人们的注意。初步结果显示，在患有IPF的患者中或在诱导小鼠实验性肺纤维化后，细胞外ATP水平升高。此外，用非选择性P2 R拮抗剂治疗这些动物可以减少炎症和纤维化。本项目的目的是确定参与博莱霉素诱导的小鼠肺纤维化和人类IPF发病机制的P2 R亚型。因此，将使用P2 R缺陷小鼠以及特异性P2 R拮抗剂。此外，将研究成纤维细胞迁移和细胞内信号传导对不同核苷酸的反应。为了证实动物实验中获得的结果与人类情况的相关性，将来自IPF患者的支气管肺泡灌洗液和血细胞上的P2 R表达与健康个体进行比较。这些研究将为肺纤维化的病理生理学提供重要信息，并可能为纤维化肺疾病的治疗开辟新的治疗途径。