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

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, was higher in lungs of patients with idiopathic pulmonary fibrosis compared to control individuals and 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. Given 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 TH anti-fibrotic properties are associated with protection of alveolar epithelial cells and restoration of mitochondrial function and thus may represent an effective therapy for pulmonary fibrosis.