What question did this study set out to answer?

The aim is to define purinergic signaling, particularly P2X and P2Y receptor subtypes, in patients with progressive fibrotic lung diseases.

July 26, 2026Open Access

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

LFLuke FordeBeaumont Hospital DGDebananda GogoiRoyal College of Surgeons in Ireland RBRory BairdBeaumont Hospital

Key Points

The aim is to define purinergic signaling, particularly P2X and P2Y receptor subtypes, in patients with progressive fibrotic lung diseases.
Gene and protein expression analysis performed on immune and epithelial cells.
Recruited 11 ILD patients, 6 bronchoscopy patient controls, and 11 healthy controls.
Measured protein levels of purinergic receptors and their agonist in circulating and airway cells.
Significantly elevated P2X7 and P2Y4 protein receptors in ILD nasal epithelial and BAL immune cells (P = 0.0064 and P = 0.004, respectively).
Extracellular ATP (eATP) was 13-fold higher in ILD samples compared to controls (P < 0.0001).
Cytokines associated with eATP-P2 signaling, such as IL-β, TNFR1, TGF-β, and VEGF, were higher in ILD samples.

Abstract

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.

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