A preclinical safety study of thyroid hormone instilled into the lungs of healthy rats—an investigational therapy for ARDS

Craig M. Flory, Beverly J. Norris, Nicole A. Larson, Lia G. Coicou, Brenda L. Koniar, Margaret A. Mysz, Timothy P. Rich, David H. Ingbar, Robert J. Schumacher

Research output: Contribution to journalArticlepeer-review


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-3,5,39-triiodothyronine (T3) has multiple effects on lung alveolar type II 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 Investigational New Drug Application–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 mg T3 in 300 ml for 5 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 patients with ARDS, including coronavirus disease 2019–associated ARDS, and to measure the effect on extravascular lung water in these patients.

Original languageEnglish (US)
Pages (from-to)74-83
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - Jan 1 2021

Bibliographical note

Funding Information:
This study was funded by the University of Minnesota Center for Translational Medicine. Author Disclosure Statement: R.J.S., T.P.R. and D.H.I. are inventors on a pending patent related to this work. For C.M.F., B.J.N., N.A.L., L.G.C., B.L.K. and M.A.M., no competing financial interests exist. Primary laboratory of origin: (Center for Translational Medicine, University of Minnesota, Minneapolis, MN). https://doi.org/10.1124/jpet.120.000060. s This article has supplemental material available at jpet.aspetjournals.org.

Publisher Copyright:
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.

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