Exposure to hydrochloric acid (HCl) can cause severe acute and chronic, potentially lethal, pulmonary injury. Because of its frequent and multiple uses, the incidence of exposure to HCl has been increasing. Even though there is considerable amount of data on the acute effects of HCl, much less is known about the more severe, potentially lethal chronic sequels of exposure to HCl and no antidotes exist to the most dangerous, irreversible and potentially lethal of these effects, namely pulmonary fibrosis. Following initial, reversible inflammation, activation of pro-fibrotic pathways (e.g., ERK1/2., AKT) lead to fibroblast activation, extracellular matrix deposition and pulmonary fibrosis. Recently, it was reported that heat shock protein 90 (HSP90) is also upregulated in pulmonary fibrosis. We therefore hypothesized that HSP90 inhibitors may prove useful as countermeasures against HCl-induced chronic lung injury and pulmonary fibrosis. Our preliminary studies demonstrate that a single intra-tracheal instillation of HCl causes time-dependent collagen deposition, ERK1/2 phosphorylation, HSP90 upregulation and consequent airway dysfunction. More importantly, post-treatment (beginning 24 hours after HCl administration) with the HSP90 inhibitor, AUY-922 effectively blocks the development of both pulmonary fibrosis and chronic lung dysfunction. In this R21 application, we propose to expand on our initial findings through the following two specific aims:
Specific Aim 1 : Will establish the mouse model of HCl-induced chronic lung injury and pulmonary fibrosis, with specific quantifiable and reproducible biomarkers, demonstrate dose-response relationships and identify key pathologic signaling pathways.
Specific Aim 2 : Will investigate the effectiveness of the HSP90 inhibitor, AUY-922, in blocking HCl-induced pulmonary fibrosis, lung dysfunction and the upregulation of key pro-fibrotic pathways, in mice. Results from these studies will provide proof of concept for the further development of HSP90 inhibitors as antidotes against HCl-induced lung fibrosis and chronic lung dysfunction.
Exposure to hydrochloric acid (HCl) from accidental spills or in warfare can cause severe chronic, potentially lethal, pulmonary injury. Utilizing a mouse model of HCl-induced chronic lung injury (pulmonary fibrosis), we will investigate the potential antidotal activity of a class of drugs (heat shock protein 90 inhibitors) that are already in clinical investigation as anti-cancer agents and have been demonstrated to be well tolerated by humans and with relatively few and moderate side effects.
