Pirfenidone exerts anti-inflammatory effects by inhibiting CXCL6 to alleviate idiopathic pulmonary fibrosis.

Abstract

Idiopathic pulmonary fibrosis (IPF) poses a health challenge with the destruction of lung architecture. It is featured by limited effective therapeutic options and a complex pathological mechanism. The molecular mechanism underlying the antifibrotic agent pirfenidone (PFD) remains to be fully determined. This study investigated the anti-inflammatory effects of pirfenidone in the treatment of IPF and explored its regulation of the C-X-C motif chemokine ligand 6 (CXCL6), a potent neutrophil chemoattractant. Using the murine model, pirfenidone has been identified to limit lung inflammation and neutrophil infiltration. Mice with pirfenidone administration expressed less CXCL6 than controls. Exogenous CXCL6 administration counteracted the anti-pulmonary fibrosis effect of pirfenidone in mice. Mechanistically, pirfenidone inhibited phosphorylation of NF-κB/p65, p38 MAPK, and Akt in IL-1β-stimulated macrophages, suggesting that pirfenidone modulated the inflammatory signaling pathways. Clinical analysis indicated that CXCL6 was upregulated in patients and decreased after pirfenidone treatment. Each unit increase in plasma CXCL6 concentration was linked to a 24% higher risk of death. This study identified the anti-inflammatory effects of pirfenidone and elucidated its novel mechanism by inhibiting CXCL6 secretion and neutrophil migration. Moreover, the identification of CXCL6 as a critical mediator of IPF may highlight a potential therapeutic target.