Thyroid hormone agonism in acute lung injury

Acute lung injury/acute respiratory distress syndrome (ARDS) is characterized by a sudden decline in lung function, leading to impaired gas exchange. This in term can ultimately lead to complications and death, despite oxygen treatment and the use of ventilators. This syndrome can be caused by a variety of insults, such as exposure to toxic agents, aspiration of gastric content or infection (as for example currently COVID-19). Up to no, there is no specific pharmacologic treatment available and mortality is high. Triiodothyronine (T3) and thyroxine (T4) are two hormones produced by the thyroid gland, with T3 being more potent. These mediators are most well known for their effects in promoting metabolism. However, recent evidence also unraveled a role for thyroid hormone as a potential therapeutic agent in idiopathic pulmonary fibrosis, a lung disease with dire outcomes. Most of this effect seems to be caused by protective actions on mitochondria, organelles which are predominantly involved in cellular energy metabolism. Interestingly, publications show that also in ARDS, mitochondrial integrity is affected in multiple cell types. This is reflected by the fact that mitochondrial DNA is increased in the blood of ARDS patients. The main hypothesis of this study is to unravel whether thyroid hormone administration might be beneficial in models of ARDS and which pathways might be responsible for these effects. To answer these questions, we will employ animal models, as well as cell culture and human tissue. To further study and understand the underlying signaling pathways, we will use both pharmacologic and molecular tools. The main strength of this project lies in the fact that thyroid hormone is already used as a therapeutic in humans and there is ample data on its tolerability in clinical settings (albeit for different indications, e.g. hypothyroidism). Taken together, the results of our work could contribute to both a better understanding and better treatment options for ARDS.