Purinergic receptor remodelling in circulating and airway cells of patients with progressive fibrotic lung disease

Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are characterised by relentless fibrotic progression resistant to standard therapy. Purinergic signalling is poorly defined in IPF and PPF, and in this study we performed gene and protein expression analysis of immune and epithelial cells to better characterize P2X and P2Y receptor subtypes in patients with progressive fibrotic interstitial lung diseases (ILD). Patients with ILD ( n = 11), bronchoscopy patient controls ( n = 6) or healthy control subjects ( n = 11) were recruited. ILD nasal epithelial cells and bronchoalveolar lavage (BAL) immune cells showed significantly elevated protein expression levels of P2X7 ( P = 0.0064) and P2Y4 receptors ( P = 0.004 and P = 0.0145), with ILD monocytes additionally demonstrating increased P2X4 ( P = 0.0022). Levels of the receptor agonist, extracellular ATP (eATP), were 13-fold higher in ILD compared to controls ( P < 0.0001). eATP inversely correlated with lung function ( P = 0.001), and associated with increased receptor expression in vitro ( P = 0.0313). In addition, cytokines downstream of ATP purinergic receptor signalling including IL-β ( P < 0.0001), TNFR1 ( P = 0.0002), TGF-β ( P = 0.002) and VEGF ( P = 0.0048), were higher in BAL or plasma of ILD patient samples. These findings suggest eATP–P2 receptor signalling as a potential contributor to inflammation and fibrosis across IPF and PPF, highlighting this pathway as a promising therapeutic target.