Triiodothyronine activates THRβ to promote PGC1α expression alleviating PQ-induced pulmonary fibrosis.

Thyroid hormone (TH) and it most active form triiodothyronine (T3) are crucial in promoting mitochondrial biogenesis and maintaining cellular homeostasis during the stress response, but their role in paraquat (PQ)-induced pulmonary fibrosis isunclear. The aim of this study was to examine whether there was a deficiency of TH in mouse lung tissue after PQ administration, and to explore the effect of T3, and potential mechanisms of action, in alleviation of PQ-induced pulmonary fibrosis. We found that the activity and expression of iodothyronine deiodinase 2 (DIO2), an enzyme that activates TH, were higher in the lungs of patients with pulmonary fibrosis than in controls. The expression of DIO2 in lung tissue of PQ injured mice was significantly increased compared to controls (P < 0.001), while the serum T3 level was significantly reduced, compared to the control group (P < 0.001). T3 nebulization significantly improved PQ-induced pulmonary fibrosis in mice, possibly by activating thyroid hormone receptor beta (THRβ). T3 and sobetirome, a specific THRβ agonist significantly upregulated peroxlsome proliferator-activated receptor-γ coactlvator-1α (PGC1α) expression, and NH-3 (an antagonist of the thyroid hormone receptor), a THRβ-specific antagonist, significantly inhibited (P < 0.0001) the beneficial effects of T3 on the PQ-induced mitochondrial apoptotic pathway in an epithelial cell line, in vitro. T3 via the THRβ / PGC1α pathway protected against PQ induced pulmonary fibrosis, furnishing a scientific basis for further research on T3 and this pathway could offer a potential novel therapeutic strategy for treating PQ poisoning in humans.