Müller Tobias, Fay Susanne, Vieira Rodolfo Paula, Karmouty-Quintana Harry, Cicko Sanja, Ayata Cemil Korcan, Zissel Gernot, Goldmann Torsten, Lungarella Giuseppe, Ferrari Davide, Di Virgilio Francesco, Robaye Bernard, Boeynaems Jean-Marie, Lazarowski Eduardo R, Blackburn Michael R, Idzko Marco
Department of Pneumology, University Medical Center Freiburg, Freiburg, Germany.
Division of Pneumology, University Hospital RWTH Aachen, Aachen, Germany.
Front Immunol. 2017 Aug 22;8:1028. doi: 10.3389/fimmu.2017.01028. eCollection 2017.
Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and very few available treatment options. The involvement of the purinergic receptor subtypes P2Y and P2X in fibrotic lung disease has been demonstrated recently. In this study, we investigated the role of P2Y receptors in the pathogenesis of IPF in humans and in the animal model of bleomycin-induced lung injury. P2YR expression was upregulated in lung structural cells but not in bronchoalveolar lavage (BAL) cells derived from IPF patients as well as in animals following bleomycin administration. Furthermore, BAL fluid levels of the P2YR agonist uridine-5'-diphosphate were elevated in animals with bleomycin-induced pulmonary fibrosis. Inflammation and fibrosis following bleomycin administration were reduced in P2YR-deficient compared to wild-type animals confirming the pathophysiological relevance of P2YR subtypes for fibrotic lung diseases. Experiments with bone marrow chimeras revealed the importance of P2YR expression on lung structural cells for pulmonary inflammation and fibrosis. Similar effects were obtained when animals were treated with the P2YR antagonist MRS2578. studies demonstrated that proliferation and secretion of the pro-inflammatory/pro-fibrotic cytokine IL-6 by lung fibroblasts are P2YR-mediated processes. In summary, our results clearly demonstrate the involvement of P2YR subtypes in the pathogenesis of pulmonary fibrosis. Thus, blocking pulmonary P2Y receptors might be a new target for the treatment of IPF.
特发性肺纤维化（IPF）是一种预后较差且治疗选择非常有限的疾病。嘌呤能受体亚型P2Y和P2X参与纤维化肺病的情况最近已得到证实。在本研究中，我们调查了P2Y受体在人类IPF发病机制以及博来霉素诱导的肺损伤动物模型中的作用。P2YR在肺结构细胞中表达上调，但在IPF患者来源的支气管肺泡灌洗（BAL）细胞以及博来霉素给药后的动物中未上调。此外，博来霉素诱导的肺纤维化动物的BAL液中P2YR激动剂尿苷-5'-二磷酸水平升高。与野生型动物相比，P2YR缺陷型动物博来霉素给药后的炎症和纤维化减轻，证实了P2YR亚型与纤维化肺病的病理生理相关性。骨髓嵌合体实验揭示了肺结构细胞上P2YR表达对肺部炎症和纤维化的重要性。当用P2YR拮抗剂MRS2578治疗动物时也获得了类似的效果。研究表明，肺成纤维细胞促炎/促纤维化细胞因子IL-6的增殖和分泌是P2YR介导的过程。总之，我们的结果清楚地证明了P2YR亚型参与肺纤维化的发病机制。因此，阻断肺P2Y受体可能是治疗IPF的新靶点。
