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P2Y₆ Receptor Activation Promotes Inflammation and Tissue Remodeling in Pulmonary Fibrosis.

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.

SUBMITTER: Muller T

PROVIDER: S-EPMC5572280 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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P2Y6 Receptor Activation Promotes Inflammation and Tissue Remodeling in Pulmonary Fibrosis.

Müller Tobias T Fay Susanne S Vieira Rodolfo Paula RP Karmouty-Quintana Harry H Cicko Sanja S Ayata Cemil Korcan CK Zissel Gernot G Goldmann Torsten T Lungarella Giuseppe G Ferrari Davide D Di Virgilio Francesco F Robaye Bernard B Boeynaems Jean-Marie JM Lazarowski Eduardo R ER Blackburn Michael R MR Idzko Marco M

Frontiers in immunology 20170822

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 i ...[more]

PMID: 28878780

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Project description:Chronic wounds are a public health problem worldwide, especially those related to diabetes. Besides being an enormous burden to patients, it challenges wound care professionals and causes a great financial cost to health system. Considering the absence of effective treatments for chronic wounds, our aim was to better understand the pathophysiology of tissue repair in diabetes in order to find alternative strategies to accelerate wound healing. Nucleotides have been described as extracellular signaling molecules in different inflammatory processes, including tissue repair. Adenosine-5'-diphosphate (ADP) plays important roles in vascular and cellular response and is immediately released after tissue injury, mainly from platelets. However, despite the well described effect on platelet aggregation during inflammation and injury, little is known about the role of ADP on the multiple steps of tissue repair, particularly in skin wounds. Therefore, we used the full-thickness excisional wound model to evaluate the effect of local ADP application in wounds of diabetic mice. ADP accelerated cutaneous wound healing, improved new tissue formation, and increased both collagen deposition and transforming growth factor-β (TGF-β) production in the wound. These effects were mediated by P2Y12 receptor activation since they were inhibited by Clopidogrel (Clop) treatment, a P2Y12 receptor antagonist. Furthermore, P2Y1 receptor antagonist also blocked ADP-induced wound closure until day 7, suggesting its involvement early in repair process. Interestingly, ADP treatment increased the expression of P2Y12 and P2Y1 receptors in the wound. In parallel, ADP reduced reactive oxygen species (ROS) formation and tumor necrosis factor-α (TNF-α) levels, while increased IL-13 levels in the skin. Also, ADP increased the counts of neutrophils, eosinophils, mast cells, and gamma delta (γδ) T cells (Vγ4+ and Vγ5+ cells subtypes of γδ+ T cells), although reduced regulatory T (Tregs) cells in the lesion. In accordance, ADP increased fibroblast proliferation and migration, myofibroblast differentiation, and keratinocyte proliferation. In conclusion, we provide strong evidence that ADP acts as a pro-resolution mediator in diabetes-associated skin wounds and is a promising intervention target for this worldwide problem.

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P2Y₆ Receptor Activation Promotes Inflammation and Tissue Remodeling in Pulmonary Fibrosis.

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P2Y<sub>6</sub> Receptor Activation Promotes Inflammation and Tissue Remodeling in Pulmonary Fibrosis.

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