PT - JOURNAL ARTICLE AU - Craig M. Flory AU - Beverly J. Norris AU - Nicole A Larson AU - Lia G Coicou AU - Brenda L Koniar AU - Margaret Mysz AU - Timothy P Rich AU - David H Ingbar AU - Robert J Schumacher TI - A Preclinical safety study of thyroid hormone instilled into the lungs of healthy rats - an investigational therapy for ARDS. AID - 10.1124/jpet.120.000060 DP - 2020 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - JPET-AR-2020-000060 4099 - http://jpet.aspetjournals.org/content/early/2020/10/29/jpet.120.000060.short 4100 - http://jpet.aspetjournals.org/content/early/2020/10/29/jpet.120.000060.full AB - Acute respiratory distress syndrome (ARDS) is a severe, life threatening form of respiratory failure characterized by pulmonary edema, inflammation, and hypoxemia due to reduced alveolar fluid clearance (AFC). Alveolar fluid clearance is required for recovery and effective gas exchange, and higher rates of AFC are associated with reduced mortality. Thyroid hormones play multiple roles in lung function, and L-3,5,3'-triiodothyronine (T3) has multiple effects on lung AT2 cells. T3 enhances AFC in normal adult rat lungs when administered intramuscularly and in normal or hypoxia-injured lungs when given intratracheally. The safety of a commercially available formulation of liothyronine sodium (synthetic T3) administered intratracheally was assessed in an IND-enabling toxicology study in healthy rats. Instillation of the commercial formulation of T3 without modification rapidly caused tracheal injury and often mortality. Intratracheal instillation of T3 that was reformulated and brought to a neutral pH at the maximum feasible dose of 2.73 µg T3 in 300 µL for five consecutive days had no clinically relevant T3-related adverse clinical, histopathologic or clinical pathology findings. There were no unscheduled deaths that could be attributed to the reformulated T3 or control articles, no differences in the lung weights, and no macroscopic or microscopic findings considered to be related to treatment with T3. This preclinical safety study has paved the way for a phase I/II study to determine the safety and tolerability of a T3 formulation delivered into the lungs of ARDS patients, including COVID-19-asssociated ARDS, and to measure the effect on extra-vascular lung water in these patients Significance Statement There is growing interest in treating lung disease with thyroid hormone (T3) in pulmonary edema and ARDS. However, there is not any published experience on the impact of direct administration of T3 into the lung. An essential step is to determine the and safety of multiple doses of T3 administered in a relevant animal species. This study enabled FDA approval of a phase I/II clinical trial of T3 instillation in patients with ARDS, including COVID-19-asssociated ARDS (T3-ARDS ClinicalTrials.gov Identifier NCT04115514).