Document Type

Article

Publication Date

2022

Publication Title

Frontiers in Pharmacology

Volume

13

Pages

1034464 (1-14)

DOI

10.3389/fphar.2022.1034464

Abstract

Exposure to high concentrations of hydrochloric acid (HCl) can lead to severe acute and chronic lung injury. In the aftermath of accidental spills, victims may be treated for the acute symptoms, but the chronic injury is often overlooked. We have developed a mouse model of acute and chronic lung injury, in which the peak of acute lung injury occurs on the day 4 after HCl exposure. We have also demonstrated that HSP90 inhibitors are effective antidotes when administered starting 24 h after HCl. In this study we examined the hypothesis that the novel oral HSP90 inhibitor TAS-116 can effectively ameliorate HCl-induced lung injury even when treatment starts at the peak of the acute injury, as late as 96 h after HCl. C57BI/6J mice were intratracheally instilled with 0.1N HCl. After 24 or 96 h, TAS-116 treatment began (3.5, 7 or 14 mg/kg, 5 times per week, p. o.) for either 2,3 or 4 or weeks. TAS-116 moderated the HCl-induced alveolar inflammation, as reflected in the reduction of white blood cells and total protein content in bronchoalveolar lavage fluid (BALF), overexpression of NLRP3 inflammasome, and inhibited the activation of pro-fibrotic pathways. Furthermore, TAS-116 normalized lung mechanics and decreased the deposition of extracellular matrix proteins in the lungs of mice exposed to HCl. Delayed and shortened treatment with TAS-116, successfully blocked the adverse chronic effects associated with acute exposure to HCl.

Rights

© 2022 Solopov, Colunga Biancatelli, Dimitropolou, Day and Catravas.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Data Availability

Article States: The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Original Publication Citation

Solopov, P. A., Colunga Biancatelli, R. M. L., Dimitropolou, C., Day, T., & Catravas, J. D. (2022). Optimizing antidotal treatment with the oral HSP90 inhibitor TAS-116 against hydrochloric acid-induced pulmonary fibrosis in mice. Frontiers in Pharmacology, 13, 1-14, Article 1034464. https://doi.org/10.3389/fphar.2022.1034464

ORCID

0000-0002-1705-027X (Solopov), 0000-0002-1174-3876 (Biancatelli), 0000-0002-5098-295X (Catravas)

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