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）是一种进行性疾病，预后不良。目前，尚无有效的疗法。这种毁灭性疾病的发病机理尚不完全了解。过去，细胞外核苷酸，例如腺苷5’-三磷酸（ATP）通过嘌呤能受体（P2R）信号传导作为炎症和免疫调节的介体引起了人们的注意。初步结果表明，患有IPF的患者或诱导小鼠实验性肺纤维化后的细胞外ATP水平升高。此外，用非选择性P2R拮抗剂对这些动物进行处理导致注射量减少和纤维化。该项目的目的是确定与人类中小鼠和IPF的两种博来霉素诱导的肺纤维化的发病机理有关的P2R亚型。因此，将使用P2R缺乏的小鼠以及特定的P2R拮抗剂。另外，将研究成纤维细胞迁移和对不同核局部的细胞内信号传导。为了确认在动物实验中对人类情况获得的结果的相关性，将将P2R表达在支气管 - 肺泡灌洗和IPF患者的血液细胞上的表达与健康的个体。这些研究将提供有关肺纤维化病理生理学的重要信息，并可以为治疗纤维化肺部疾病的新治疗方法开放。