Thyroid hormone (TH) is critical for the maintenance of cellular homeostasis during stress responses, but its role in lung fibrosis is unknown. Here we found that the activity and expression of iodothyronine deiodinase 2 (DIO2), an enzyme that activates TH, were higher in lungs from patients with idiopathic pulmonary fibrosis than in control individuals and were correlated with disease severity. We also found that Dio2-knockout mice exhibited enhanced bleomycin-induced lung fibrosis. Aerosolized TH delivery increased survival and resolved fibrosis in two models of pulmonary fibrosis in mice (intratracheal bleomycin and inducible TGF-β1). Sobetirome, a TH mimetic, also blunted bleomycin-induced lung fibrosis. After bleomycin-induced injury, TH promoted mitochondrial biogenesis, improved mitochondrial bioenergetics and attenuated mitochondria-regulated apoptosis in alveolar epithelial cells both in vivo and in vitro. TH did not blunt fibrosis in Ppargc1a- or Pink1-knockout mice, suggesting dependence on these pathways. We conclude that the antifibrotic properties of TH are associated with protection of alveolar epithelial cells and restoration of mitochondrial function and that TH may thus represent a potential therapy for pulmonary fibrosis.

中文翻译：

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甲状腺激素通过改善上皮线粒体功能来抑制小鼠肺纤维化。


甲状腺激素（TH）对于应激反应期间维持细胞稳态至关重要，但其在肺纤维化中的作用尚不清楚。在这里，我们发现特发性肺纤维化患者肺部的碘甲状腺原氨酸脱碘酶 2 (DIO2)（一种激活 TH 的酶）的活性和表达高于对照个体，并且与疾病严重程度相关。我们还发现 Dio2 敲除小鼠表现出博来霉素诱导的肺纤维化增强。在两种小鼠肺纤维化模型（气管内博莱霉素和诱导型 TGF-β1）中，雾化 TH 递送可提高存活率并解决纤维化问题。 Sobetirome 是一种 TH 模拟物，也能减弱博莱霉素诱导的肺纤维化。博来霉素诱导的损伤后，TH 在体内和体外促进肺泡上皮细胞中线粒体生物合成，改善线粒体生物能并减弱线粒体调节的细胞凋亡。 TH 并没有减弱 Ppargc1a 或 Pink1 敲除小鼠的纤维化，表明对这些途径的依赖性。我们的结论是，TH 的抗纤维化特性与肺泡上皮细胞的保护和线粒体功能的恢复有关，因此 TH 可能代表肺纤维化的潜在治疗方法。