Involvement of P2R signalling in the pathogenesis of fibrotic lung diseases

特发性肺纤维化(IPF)是一种进行性疾病，预后差。目前，还没有有效的治疗方法。这种毁灭性疾病的发病机制尚不完全清楚。在过去，细胞外核苷酸，如腺苷-5‘-三磷酸(ATP)，作为炎症和免疫调节的介质，通过嘌呤能受体(P2R)信号转导而受到关注。初步结果表明，在IPF患者或在诱导小鼠实验性肺纤维化后，细胞外ATP水平升高。此外，用非选择性的P2R拮抗剂治疗这些动物可以减少炎症和纤维化。该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肺间质纤维化发病机制的P2R亚型。因此，将使用P2R缺陷小鼠以及特异性的P2R拮抗剂。此外，还将研究成纤维细胞迁移和细胞内信号对不同核苷酸的反应。为了确认动物实验结果与人类情况的相关性，将IPF患者的支气管肺泡灌洗液和血细胞上的P2R表达与健康人进行比较。这些研究将为肺纤维化的病理生理机制提供重要的信息，并可能为治疗肺纤维化疾病开辟新的治疗途径。

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.