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Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function

Abstract

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.

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Figure 1: DIO2 levels and activity are higher in the lungs of patients with IPF than in normal-histology controls and its inhibition enhances bleomycin-induced lung fibrosis.
Figure 2: Aerosolized T3 blunts established fibrosis in two mouse models of lung fibrosis.
Figure 3: Thyroid hormone treatment reverses bleomycin-induced mitochondrial abnormalities in alveolar epithelial cells.
Figure 4: Thyroid hormone attenuates mitochondria-regulated apoptosis in lung epithelial cells.
Figure 5: The antifibrotic effects of thyroid hormone are mediated through PGC-1α.
Figure 6: PINK1 is required for the antifibrotic effects of thyroid hormone.

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Acknowledgements

The work was in part supported by US National Institutes of Health (NIH) grants R01HL095397, R01HL127349 (N.K.), R01HL1109233, R01HL125250 (E.L.H.), RO1DK65055 (A.C.B.) and RO1DK52798 (T.S.S.), the Flight Attendant Medical Research Institute (P.J.L.), American Lung Association Award RT 350419, Marie Sklodowska/Curie ERS/EU-RESPIRE 2-8860-2015 grant (A.T.), American Lung Association Award RG-415350 (A.S.) and Pulmonary Fibrosis Foundation (PPF) Albert Rose Established Investigator Award 415245 (G.Y.).

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G.Y. and A.T. performed most of the experiments with the assistance of R.W., J.D.H.-M., J.P.W.d.C., R.A.e.D., F.A., G.D., N.A., T.W., J.D., Y.G., R.D., G.H.I. and A.C.B. A.S. and P.M. performed the mitochondrial function experiments. M.G. and X.L. performed the electron microscopy experiments and analysis. G.Y., A.T. and N.K. performed the histological analyses with R.J.H. T.S.S. and G.H.I. assisted on the GC-1 animal experiments. G.Y., A.T. and N.K. conceived the project, designed the experiments, and analyzed and interpreted the results. A.T., G.Y. and N.K. drafted and revised the manuscript. E.L.H., P.J.L. and A.C.B. interpreted results and revised the manuscript.

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Competing interests

A.T., G.Y. and N.K. are inventors on a pending patent with the US Patent and Trademark Office on use of thyroid hormone as an antifibrotic agent entitled “Novel methods of treating or preventing fibrotic lung diseases,” OCR 6368-047162-7029P1 (00219). N.K. consulted for Biogen Idec, Boehringer Ingelheim, Numedii, MMI and Pliant and has an ongoing collaboration with MiRagen, all outside the subject matter of the submitted work. E.L.H. consulted for Boehringer Ingelheim and held grant funding from Sanofi and Promedior, all outside the subject matter of the submitted work. All other authors declare no competing interests.

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Yu, G., Tzouvelekis, A., Wang, R. et al. Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat Med 24, 39–49 (2018). https://doi.org/10.1038/nm.4447

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