イグラチモドの線維芽細胞から筋線維芽細胞への移行を阻害することによる肺線維症に対する抗線維化効果

Anti-fibrotic effect of iguratimod on pulmonary fibrosis by inhibiting the fibroblast-to-myofibroblast transition.

• Haobo Lin
• Chaochen Wu
• Fu Zhu
• Guangfeng Zhang
• Yuesheng Xie
• Yang Cui
• Guangfu Dong
• Xiao Zhang

抄録

目的:

肺線維症（PF）は、重大な罹患率と死亡率を引き起こす重篤な肺疾患である。PFの病因は、Smad3依存性TGF-β1経路を活性化する最も強力なプロ線維芽細胞因子TGF-β1によって駆動される線維芽細胞から筋線維芽細胞への移行（FMT）に起因しています。イグラチモド（IGU）は、炎症性因子の分泌を抑制する一方で、多細胞の分化を修飾することができる新規抗リウマチ薬である。そこで本研究では、IGUのFMTに対する効果を調べることを目的とした。

PURPOSE: Pulmonary fibrosis (PF) is a severe lung disease causing significant morbidity and mortality. PF pathogenesis is attributed to the fibroblast-to-myofibroblast transition (FMT) driven by the most potent pro-fibrogenic factor TGF-β1 activating the Smad3-dependent TGF-β1 canonical pathway. Iguratimod (IGU) is a novel anti-rheumatic drug that suppresses the secretion of inflammatory factors, but is also able to modulate the differentiation of multiple cells. Therefore, the aim of this work was to investigate the effect of IGU on FMT.

材料・物質:

MATERIALS/METHODS: PF mouse model was induced in C57BL/6 male mice by bleomycin. The effect of IGU was assessed through the evaluation of lung morphology by H&E and through the collagen accumulation in the lung by Masson staining. Primary human lung fibroblasts (pHLFs) were also used to evaluate the effect of IGU in vitro on TGF-β1-stimulated cells, and proliferation, migration and invasion were measured, together with genes and proteins involved in FMT.

結果:

IGUはマウスのブレオマイシン誘発PFを減衰させ、肺の病理学的変化を改善した。また、TGF-β1刺激を受けたpHLFにおいて、IGUはアポトーシスを起こさずに増殖、遊走、浸潤を有意に抑制した。さらに、IGUはTGF-β1によるコラーゲンIとIIIのmRNA発現の増加を有意に減少させ、肺機能障害を減少させ、α-SMA、Smad2とSmad3のリン酸化、フィブロネクチン発現とF-アクチンマイクロフィラメント形成を減少させ、Smad3経路の阻害を通じてFMTを減衰させた。

RESULTS: IGU attenuated bleomycin-induced PF in mice and improved the pathological changes in their lungs. In addition, IGU significantly inhibited proliferation, migration and invasion in TGF-β1-stimulated pHLFs without causing apoptosis. Moreover, IGU significantly reduced TGF-β1-induced increase of collagen I and III mRNA expression, thus reducing lung function impairment, and α-SMA, Smad2 and Smad3 phosphorylation, fibronectin expression and F-actin microfilament formation, thus attenuating FMT through the inhibition of the Smad3 pathway.

結論:

その結果、IGUはFMTの抑制に有効であることが明らかになり、PFの進行予防に有効な抗線維化剤である可能性が示唆されました。

CONCLUSIONS: Our results collectively revealed the beneficial effect of IGU on the inhibition of FMT, thus suggesting that it might act as an effective anti-fibrotic agent in preventing the progression of PF.

Copyright © 2020. Published by Elsevier B.V.