205
Views
24
CrossRef citations to date
0
Altmetric
Articles

Post-treatment with a heat shock protein 90 inhibitor prevents chronic lung injury and pulmonary fibrosis, following acute exposure of mice to HCl

, , , & ORCID Icon
Pages 203-216 | Received 03 Dec 2019, Accepted 29 Apr 2020, Published online: 13 May 2020
 

Abstract

Aim/Purpose: Exposure to high levels of hydrochloric acid (HCl) is associated with severe lung injury including both acute inflammation and chronic lung disease, which leads to the development of pulmonary fibrosis. Currently, there are no specific therapeutic agents for HCl-induced lung injury. Heat shock protein 90 (HSP90) has been implicated in the pathogenesis of pulmonary fibrosis. Thus, we have used a murine model of intra-tracheal acid instillation to investigate the antidotal effects of AUY-922, a small molecule HSP90 inhibitor, already in clinical trials for various types of cancer, against HCl-induced chronic lung injury and pulmonary fibrosis.

Methods: HCl (0.1 N, 2 μl/g body weight) was instilled into male C57Bl/6J mice at day 0. After 24 h, mice began receiving 1 mg/kg AUY-922, 2x/week for 15 or 30 days.

Results: AUY-922 suppressed the HCl-induced sustained inflammation, as reflected in the reduction of leukocyte and protein concentrations in bronchoalveolar lavage fluid, and inhibited the activation of pro-fibrotic biomarkers, ERK and HSP90. Furthermore, AUY-922 improved lung function, decreased the overexpression and accumulation of extracellular matrix proteins and dramatically reduced histologic evidence of fibrosis in the lungs of mice exposed to HCl.

Conclusions: We conclude that AUY-922, and possibly other HSP90 inhibitors, successfully block the adverse effects associated with acute exposures to HCl and may represent an effective antidote against HCl-induced chronic lung injury and fibrosis.

Acknowledgments

We thank the Eastern Virginia Medical School Department of Anatomy and Pathology Histology Laboratory for lung tissue processing and staining. We thank Betsy Gregory for her outstanding technical assistance.

Disclosure statement

The authors have no financial conflicts of interest.

Additional information

Funding

This study is supported by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD) and the National Institute of Environmental Health Sciences (NIEHS) (grant number R21ES029309).

Log in via your institution

Log in to Taylor & Francis Online

PDF download + Online access
  • 48 hours access to article PDF & online version
  • Article PDF can be downloaded
  • Article PDF can be printed
USD 65.00 Add to cart
* Local tax will be added as applicable

Related Research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.