Involvement of multiple purinergic receptor subtypes in the pathogenesis of pulmonary fibrosis

Excessive tissue injury leads to abnormal wound healing responses to promote tissue fibrosis. This is a particularly deadly process in the interstitial lung disease known as idiopathic pulmonary fibrosis (IPF). The factors involved in the progression of normal healing processes to tissue fibrosis are poorly defined; however, recent studies suggest that the local release of ATP and other nucleotides may impact tissue responses to injury mediated by P2 purinergic receptors. Here we show that ATP levels are elevated in patients with IPF. Furthermore, using a comprehensive approach, we systematically assessed the role of all P2 purinergic receptors in a murine model of pulmonary fibrosis. We demonstrate that genetic deletion of key P2 receptors or treatment with both broad and selective P2 receptor antagonists can attenuate pulmonary inflammation, fibrotic mediator production and tissue fibrosis.

In summary we were able to demonstrate that different purinergic receptor subtypes are involved in the pathogenesis of pulmonary fibrosis. Hence, targeting purinergic receptors might be a new approach for the treatment of fibrotic lung diseases.