Research Project
10015581
SUMMARY 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. Furthermore, HCl is also implicated in chemical warfare both as an initiating agent and more often as a toxic product of phosgene, phosgene oxime, Lewisite and chlorine exposure. 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 (PF). The ubiquitous pro-inflammatory chaperone, heat shock protein 90 (HSP90) regulates the activation of several pro-fibrotic factors and is upregulated in PF. We therefore hypothesized that HSP90 inhibitors, already in clinical trials as anti-cancer agents, may prove useful as countermeasures against HCl-induced chronic lung injury and pulmonary fibrosis (PF). In Preliminary Studies, we have described key signaling events in HCl-induced PF in mice and have demonstrated that post-treatment (beginning 24 hours after HCl administration) with the HSP90 inhibitor, AUY-922 effectively blocks the upregulation of important pro-fibrotic signals, as well as the development of both pulmonary fibrosis and chronic lung dysfunction. In the current application, we propose to expand on our initial findings in three areas: 1) identify the clinically used HSP90 inhibitor which is most effective as antidote in HCl-induced PF in mice, 2) investigate a potential therapeutic role of HSP70 in the antidotal effects of HSP90 inhibitors and 3) demonstrate the ability of HSP90 inhibitors to similarly inhibit HCl-induced PF in another animal model of HCl- induced PF, the rabbit. Results from these studies will provide needed information for the further development of a specific HSP90 inhibitor as antidote against HCl-induced lung fibrosis and chronic lung dysfunction.
