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

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.