Analysis of the anti-fibrotic potential of a JAK inhibitor in a bleomycin-induced pulmonary fibrosis model

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Background:Interstitial lung disease (ILD) associated with connective tissue diseases (CTD-ILD) remains to be a major cause of mortality. Different from idiopathic form, CTD-ILD involves more immune dysregulation along with aberrant fibroblast activation. Therefore, therapy targeting both profibrotic and proinflammatory molecules could be ideal for CTD-ILD. Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals. The purpose of this study is to reveal the anti-fibrotic potential of JAK inhibitors (JAKis). Methods:The anti-fibrotic effect of a JAKi with a particular focus on baricitinib was examined using a human lung fibroblast cell line and a bleomycin (BLM)-induced pulmonary fibrosis model in mice. Results:Baricitinib, a selective JAK1, 2 inhibitor suppressed transforming growth factor-β (TGF-β)-induced phosphorylation of JAK2 in human lung fibroblasts. Baricitinib also strongly suppressed the TGF-β-induced collagen1 and α-smooth muscle actin (α-SMA) expression in fibroblasts. Moreover, baricitinib ameliorated lung fibrosis in BLM-treated mice, particularly when administered in the late phase. The number of α-SMA or collagen triple helix repeat containing 1 (CTHRC1) positive fibroblasts in BLM-treated lungs was reduced by administration of baricitinib. Conclusions:Our data suggest that baricitinib may improve pulmonary fibrosis by directly inhibiting fibroblast activation via JAK2 blockade. J. Med. Invest. 72 : 298-307, August, 2025