Exposure to sulfur (SM) or nitrogen (NM) mustard can cause severe acute and chronic, potentially lethal, pulmonary injury. NM and SM are chemical warfare agents that have been used repeatedly since the early 20th century. To date no clinical antidote is available against the chronic sequels of exposure to SM or NM and to the most dangerous, irreversible and potentially lethal of these effects, namely pulmonary fibrosis. Exposure to SM or NM triggers oxidative stress, a macrophage-rich inflammatory response and stimulation of pro-fibrotic pathways that lead to fibroblast activation, extracellular matrix deposition and pulmonary fibrosis. Recently, it was reported that inhibitors of the pro-inflammatory heat shock protein 90 (HSP90) prevent bleomycin-induced pulmonary fibrosis. We therefore hypothesized that HSP90 inhibitors, already in clinical trials as anti-cancer agents, may prove useful as countermeasures against mustard-induced chronic lung injury and pulmonary fibrosis. Our preliminary studies demonstrate that a single intra-tracheal instillation of the NM, melphalan, produces biochemically and histologically evident pulmonary fibrosis characterized by peribronchial and parenchymal collagen deposition, upregulation of HSP90 and ?SMA and consequent airway dysfunction at 30 days after NM instillation. Post-treatment (beginning 24 hours after NM administration) with the clinically used HSP90 inhibitor, AUY-922, effectively blocks the development of collagen deposition, pulmonary fibrosis and ?SMA upregulation. In this R21 application, we propose to expand on our initial findings in two areas: establish the murine model of NM-induced chronic lung injury and pulmonary fibrosis and provide proof of concept for the antidotal properties of the HSP90 inhibitor, AUY-922. We will achieve this through the following two specific aims: 1) we will establish the mouse model of NM-induced chronic lung injury and pulmonary fibrosis, with specific quantifiable and reproducible biomarkers, demonstrate dose-response relationships and identify key pathologic signaling pathways; 2) we will investigate the effectiveness of the HSP90 inhibitor, AUY-922, in blocking NM-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 mustard-induced lung fibrosis and chronic lung dysfunction.
Exposure to nitrogen or sulfur mustards during warfare can cause severe chronic, potentially lethal, pulmonary injury. Utilizing a mouse model of mustard-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.
