Idiopathic pulmonary fibrosis (IPF) poses significant challenges due to limited treatment options despite its complex pathogenesis involving cellular and molecular mechanisms. This study investigated the role of transient receptor potential ankyrin 1 (TRPA1) channels in regulating M2 macrophage polarization in IPF progression, potentially offering novel therapeutic targets. Using a bleomycin-induced pulmonary fibrosis model in C57BL/6J mice, we assessed the therapeutic potential of the TRPA1 inhibitor HC-030031. TRPA1 upregulation was observed in fibrotic lungs, correlating with worsened lung function and reduced survival. TRPA1 inhibition mitigated fibrosis severity, evidenced by decreased collagen deposition and restored lung tissue stiffness. Furthermore, TRPA1 blockade reversed aberrant M2 macrophage polarization induced by bleomycin, associated with reduced Smad2 phosphorylation in the TGF-β1-Smad2 pathway. In vitro studies with THP-1 cells treated with bleomycin and HC-030031 corroborated these findings, highlighting TRPA1's involvement in fibrotic modulation and macrophage polarization control. Overall, targeting TRPA1 channels presents promising therapeutic potential in managing pulmonary fibrosis by reducing pro-fibrotic marker expression, inhibiting M2 macrophage polarization, and diminishing collagen deposition. This study sheds light on a novel avenue for therapeutic intervention in IPF, addressing a critical need in the management of this challenging disease.

Graphical abstract

中文翻译：

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瞬时受体电位锚蛋白 1 在特发性肺纤维化中的作用：M2 巨噬细胞极化的调节

尽管特发性肺纤维化（IPF）的发病机制涉及细胞和分子机制，但由于治疗选择有限，因此带来了重大挑战。本研究调查了瞬时受体电位锚蛋白 1 (TRPA1) 通道在 IPF 进展中调节 M2 巨噬细胞极化的作用，可能提供新的治疗靶点。我们在 C57BL/6J 小鼠中使用博来霉素诱导的肺纤维化模型，评估了 TRPA1 抑制剂 HC-030031 的治疗潜力。在纤维化肺中观察到 TRPA1 上调，与肺功能恶化和生存率降低相关。 TRPA1 抑制可减轻纤维化的严重程度，胶原蛋白沉积减少并恢复肺组织硬度即可证明这一点。此外，TRPA1 阻断逆转了博来霉素诱导的异常 M2 巨噬细胞极化，这与 TGF-β1-Smad2 途径中 Smad2 磷酸化的减少有关。用博莱霉素和 HC-030031 处理的 THP-1 细胞进行的体外研究证实了这些发现，强调了 TRPA1 参与纤维化调节和巨噬细胞极化控制。总体而言，靶向 TRPA1 通道通过减少促纤维化标志物表达、抑制 M2 巨噬细胞极化和减少胶原沉积来控制肺纤维化，具有广阔的治疗潜力。这项研究揭示了 IPF 治疗干预的新途径，满足了管理这种具有挑战性的疾病的关键需求。

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