Antidotes against mustard-induced chronic lung injury

暴露于硫（SM）或氮（NM）芥子气可导致严重的急性和慢性，潜在的致命， 肺损伤NM和SM是自20世纪初以来反复使用的化学战剂 世纪。到目前为止，没有临床解毒剂可用于治疗暴露于SM或NM的慢性后遗症， 这些影响中最危险、不可逆和潜在致命的，即肺纤维化。SM暴露 或NM触发氧化应激、富含巨噬细胞的炎症反应和促纤维化的刺激。 这些途径导致成纤维细胞活化、细胞外基质沉积和肺纤维化。近日 据报道，促炎性热休克蛋白90（HSP 90）的抑制剂可预防博来霉素诱导的 肺纤维化因此，我们假设已经在临床试验中作为抗癌药物的HSP90抑制剂， 药物，可能被证明是有用的对策，对芥末诱导的慢性肺损伤和肺 纤维化我们的初步研究表明，单次气管内滴注NM，美法仑， 产生生化和组织学上明显的肺纤维化，其特征在于支气管周围和 30岁时实质胶原沉积、HSP 90和α SMA上调以及随后的气道功能障碍 NM滴注后24天。治疗后（NM给药后24小时开始），使用临床使用的 HSP90抑制剂AUY-922有效地阻断胶原沉积、肺纤维化和肺纤维化的发展。 α SMA上调。在这个R21应用程序中，我们建议在两个方面扩展我们的初步发现： NM诱导的慢性肺损伤和肺纤维化的小鼠模型，并为NM诱导的慢性肺损伤和肺纤维化的概念提供证据。 HSP90抑制剂AUY-922的解毒特性。我们将通过以下两项具体措施实现这一目标： 目的：1）建立NM诱导的慢性肺损伤和肺纤维化小鼠模型， 特异性可定量和可重复的生物标志物，证明剂量-反应关系，并确定关键 病理信号通路; 2）我们将研究HSP90抑制剂AUY-922的有效性， 阻断NM诱导的肺纤维化、肺功能障碍和关键促纤维化途径的上调， 小鼠这些研究结果将为进一步开发HSP90抑制剂提供概念依据 作为对抗芥子气引起的肺纤维化和慢性肺功能障碍的解毒剂。

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 αSMA 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 αSMA 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.