The journal of medical investigation : JMI · 2025
Analysis of the anti-fibrotic potential of a JAK inhibitor in a bleomycin-induced pulmonary fibrosis model.
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Nishimura Haruka, Kawano Hiroshi, Sato Seidai, Imakura Takeshi, Yamashita Yuya, Murakami Kojin, Haji Keiko, Bando Hiroki, Naito Nobuhito, Kagawa Kozo, Isomura Yuta, Koyama Kazuya, Ogawa Hirohisa, Nishimura Yoshihiro, Nishioka Yasuhiko
Аннотация
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.
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.