| Summary: | Chronic obstructive pulmonary disease (COPD) is a complex pulmonary condition characterized by bronchitis, emphysema, and mucus stasis. Due to the variability in symptoms among patients, traditional approaches to treating COPD as a singular disease are limited. This led us to focus on phenotype/endotype classifications. In this study, we explore the potential therapeutic role of thyroid hormone (T<sub>3</sub>) by using mouse models: emphysema-dominant elastase-induced COPD and airway-dominant C57BL/6-βENaC-Tg to represent different types of the disease. Here, we showed that intratracheal T<sub>3</sub> treatment (40, 80 μg/kg, <i>i.t.</i>, every other day) resulted in significant improvements regarding emphysema and the enhancement of respiratory function in the elastase-induced COPD model. T<sub>3</sub>-dependent improvement is likely linked to the up-regulation of <i>Ppargc1a</i>, a master regulator of mitochondrial biogenesis, and <i>Gclm</i>, a factor associated with oxidative stress. Conversely, neither short- nor long-term T<sub>3</sub> treatments improved COPD pathology in the C57BL/6-βENaC-Tg mice. Because the up-regulation of extrathyroidal T<sub>3</sub>-producing enzyme <i>Dio2</i>, which is also considered a marker of T<sub>3</sub> requirement, was specifically observed in elastase-induced COPD lungs, these results demonstrate that exogenous T<sub>3</sub> supplementation may have therapeutic potential for acute but not chronic COPD exacerbation. Moreover, this study highlights the relevance of considering not only COPD phenotypes but also COPD endotypes (expression levels of <i>Ppargc1a</i> and/or <i>Dio2</i>) in the research and development of better treatment approaches for COPD.
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