Abstract
Background: Thyroid hormone (TH) is critical for maintenance of mitochondrial homeostasis during stress responses, but its role in lung fibrosis is unknown.
Methods and Results: Microarray data analysis revealed that DIO2 was significantly increased in IPF lungs compared to controls (9 fold). DIO2 mRNA and protein were significantly increased, 8- and 3-fold respectively in IPF lungs compared to controls. Genetic ablation of DIO2 or inhibition of TH synthesis by propylthiouracil enhanced bleomycin-induced lung fibrosis as assessed by significant increases in hydroxyproline (1.35-fold) and Masson Trichrome. Aerosolized TH delivery reversed bleomycin-induced fibrosis, as assessed by significant reductions in hydroxyproline (1.4 fold) and Masson Trichrome. Bleomycin injury caused mitochondrial dysfunction in primary murine alveolar type II epithelial cells (AECIIs) while TH therapy reversed these abnormalities as assessed by seahorse extracellular flux and electron microscopy technology. Aerosolized TH therapy induced lung mRNA levels of regulators of mitochondrial function, PPARGC1A and PINK1 (1.5- and 1.8-fold,respectively). TH treatment did not blunt fibrosis in PPARGC1A or PINK1 knockout mice.
Conclusions: We conclude that TH treatment is protective against fibrotic lung injury through restoration of AECIIs mitochondrial homeostasis and may represent an effective therapy for IPF.
- Copyright ©the authors 2016