Abstract
Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and very few available treatment options. The involvement of the purinergic receptor subtypes P2Y2 and P2X7 in fibrotic lung disease has been demonstrated recently. In this study, we investigated the role of P2Y6 receptors in the pathogenesis of IPF in humans and in the animal model of bleomycin-induced lung injury. P2Y6R 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 P2Y6R agonist uridine-5′-diphosphate were elevated in animals with bleomycin-induced pulmonary fibrosis. Inflammation and fibrosis following bleomycin administration were reduced in P2Y6R-deficient compared to wild-type animals confirming the pathophysiological relevance of P2Y6R subtypes for fibrotic lung diseases. Experiments with bone marrow chimeras revealed the importance of P2Y6R expression on lung structural cells for pulmonary inflammation and fibrosis. Similar effects were obtained when animals were treated with the P2Y6R antagonist MRS2578. In vitro studies demonstrated that proliferation and secretion of the pro-inflammatory/pro-fibrotic cytokine IL-6 by lung fibroblasts are P2Y6R-mediated processes. In summary, our results clearly demonstrate the involvement of P2Y6R subtypes in the pathogenesis of pulmonary fibrosis. Thus, blocking pulmonary P2Y6 receptors might be a new target for the treatment of IPF.
Highlights
Idiopathic pulmonary fibrosis (IPF) is deadly lung disease, which is believed to arise from aberrant proliferation of fibrous tissue following tissue injury
Increased extracellular ATP levels have been measured in the bronchoalveolar lavage (BAL) fluid derived from IPF patients or animals with bleomycin-induced pulmonary fibrosis, whereas deficiency in distinct P2R subtypes such as P2X7R or P2Y2R was associated with reduced inflammation and fibrosis following bleomycin administration [12,13,14]
Signaling via purinergic receptors has been demonstrated to be crucial for the pathophysiology of various lung disorders including pulmonary fibrosis [8, 14]
Summary
Idiopathic pulmonary fibrosis (IPF) is deadly lung disease, which is believed to arise from aberrant proliferation of fibrous tissue following tissue injury. Different cell types including inflammatory cells, lung fibroblasts, and abnormally activated alveolar epithelial cells have been shown to play a prominent role in IPF pathophysiology. Though some progress has been made, very few treatment options are available for IPF, at least partly due to the lack of knowledge about the processes regulating the progression of tissue injury to tissue fibrosis [1,2,3] Nucleotides such as adenosine-5′-triphosphate (ATP), adenosine-5′-diphosphate, uridine-5′-triphosphate, or uridine5′-diphosphate (UDP) are released into the extracellular space under various conditions, including inflammation or hypoxia [4,5,6,7]. As the expression of purinergic receptors is widespread, the involvement of more than one P2R subtype is likely
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