Document Type

Article

Publication Date

2024

Publication Title

International Journal of Molecular Sciences

Volume

25

Issue

3

Pages

1920 (1-15)

DOI

10.3390/ijms25031920

Abstract

Exposure to hydrochloric acid (HCl) can provoke acute and chronic lung injury. Because of its extensive production for industrial use, frequent accidental exposures occur, making HCl one of the top five chemicals causing inhalation injuries. There are no Food and Drug Administration (FDA)-approved treatments for HCl exposure. Heat shock protein 90 (HSP90) inhibitors modulate transforming growth factor-β (TGF-β) signaling and the development of chemical-induced pulmonary fibrosis. However, little is known on the role of Heat Shock Protein 70 (HSP70) during injury and treatment with HSP90 inhibitors. We hypothesized that administration of geranylgeranyl-acetone (GGA), an HSP70 inducer, or gefitinib (GFT), an HSP70 suppressant, alone or in combination with the HSP90 inhibitor, TAS-116, would improve or worsen, respectively, HCl-induced chronic lung injury in vivo and endothelial barrier dysfunction in vitro. GGA, alone, improved HCl-induced human lung microvascular endothelial cells (HLMVEC) barrier dysfunction and, in combination with TAS-116, improved the protective effect of TAS-116. In mice, GGA reduced HCl toxicity and while TAS-116 alone blocked HCl-induced chronic lung injury, co-administration with GGA, resulted in further improvement. Conversely, GFT potentiated HCl-induced barrier dysfunction and impaired the antidotal effects of TAS-116. We conclude that combined treatments with HSP90 inhibitors and HSP70 inducers may represent a novel therapeutic approach to manage HCl-induced chronic lung injury and pulmonary fibrosis.

Rights

© 2024 by the authors.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) license.

Data Availability

Article states: "The data presented in this study are available on request from the corresponding author."

Original Publication Citation

Colunga Biancatelli, R. M. L., Solopov, P. A., Day, T., Gregory, B., Osei-Nkansah, M., Dimitropoulou, C., & Catravas, J. D. (2024). HSP70 is a critical regulator of HSP90 inhibitor's effectiveness in preventing HCL-induced chronic lung injury and pulmonary fibrosis. International Journal of Molecular Sciences, 25(3), 1-15, Article 1920. https://doi.org/10.3390/ijms25031920

ORCID

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

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