Filgotinib Improves Experimental Pulmonary Fibrosis by Modulating JAK1/STAT3/SOCS3/IL-17A Signalling

Regulatory agencies in Europe and Japan have approved filgotinib, a selective JAK1 inhibitor, for use in treating rheumatoid arthritis, but its effect and mechanism of action in treating pulmonary fibrosis remain unclear.

We performed an in vivo investigation in rats on filgotinib's effect on pulmonary fibrosis resulting from the intratracheal infusion of bleomycin (BLM). Then, we focused on the mechanisms by which filgotinib inhibits experimentally induced pulmonary fibrosis in vitro by determining its effect on TGF-β1-induced proliferation of mouse lung fibroblasts.

Continuous gavage of filgotinib at 20 mg/kg for 14 days elicited protective effects in the BLM-induced rat experimental pulmonary fibrosis model, as reflected in changes in Hounsfield units as an indicator of overall pulmonary function and in the lung coefficient and lung microscopic pathology scores as indicators of gross pulmonary pathology. Protein expression levels of IL-17A, phosphorylated tyrosine kinase (p-JAK1), p-STAT3 and cytokine signal transduction inhibitor 3 (SOCS3) were also changed. In in vitro studies, filgotinib at 1 μM reduced TGF-β1-induced fibroblast proliferation and produced lower levels of IL-17A, p-JAK1 and p-STAT3, but higher SOCS3.

Filgotinib appeared to alleviate experimental pulmonary fibrosis by reducing fibroblast proliferation via inhibition of the JAK1/STAT3/SOCS3/IL-17A pathway.