The purinergic receptor subtype P2Y(2) mediates chemotaxis of neutrophils and fibroblasts in fibrotic lung disease

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with few available treatment options. Recently, the involvement of purinergic receptor subtypes in the pathogenesis of different lung diseases has been demonstrated. Here we investigated the role of the purinergic receptor subtype P2Y(2) in the context of fibrotic lung diseases. The concentration of different nucleotides was measured in the broncho-alveolar lavage (BAL) fluid derived from IPF patients and animals with bleomycin-induced pulmonary fibrosis. In addition expression of P2Y(2) receptors by different cell types was determined. To investigate the functional relevance of P2Y(2) receptors for the pathogenesis of the disease the bleomycin model of pulmonary fibrosis was used. Finally, experiments were performed in pursuit of the involved mechanisms. Compared to healthy individuals or vehicle treated animals, extracellular nucleotide levels in the BAL fluid were increased in patients with IPF and in mice after bleomycin administration, paralleled by a functional up-regulation of P2Y(2)R expression. Both bleomycin-induced inflammation and fibrosis were reduced in P2Y(2)R-deficient compared to wild type animals. Mechanistic studies demonstrated that recruitment of neutrophils into the lungs, proliferation and migration of lung fibroblasts as well as IL6 production are key P2Y(2)R mediated processes. Our results clearly demonstrate the involvement of P2Y(2)R subtypes in the pathogenesis of fibrotic lung diseases in humans and mice and hence support the development of selective P2Y(2)R antagonists for the treatment of IPF.