Antidotes against mustard-induced chronic lung injury

芥末引起的慢性肺损伤的解毒剂

基本信息

批准号：
9789315
负责人：
John D Catravas
金额：
$ 19.38万
依托单位：
OLD DOMINION UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789315
关键词：
Acute Aftercare Animal Model Anti-Inflammatory Agents Antidotes Antineoplastic Agents Area Biochemical Biological Markers Bleomycin Chemical Warfare Chemical Warfare Agents Chronic Clinical Clinical Trials Collagen Dangerousness Data Deposition Development Dose Effectiveness Event Exhibits Exposure to Extracellular Matrix Fibroblasts Fibrosis Functional disorder Heat-Shock Proteins 90 Histologic Hour Human Incidence Inflammatory Inflammatory Response Injury Iran Iraq Lead Lung Lung diseases Macrophage Activation Mechlorethamine Melphalan Molecular Chaperones Mus Mustard Mustard Gas Nitrogen Oxidative Stress Pathogenesis Pathologic Pathway interactions Pharmaceutical Preparations Property Pulmonary Fibrosis Reporting Reproducibility Risk Signal Pathway Signaling Molecule Smooth Muscle Actin Staining Method Sulfur Up-Regulation War World War I clinical candidate clinical investigation human model indium-bleomycin inhibitor/antagonist lung injury macrophage mouse model prevent response side effect symposium

项目摘要

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.

暴露于硫（SM）或氮（NM）芥末会导致急性和慢性，可能致命，可能是致命的肺部损伤是自20世纪初期使用的化学战剂世纪。最危险的，不可逆的和寒冷的作用，即肺纤维化。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导致成纤维细胞激活，细胞外基质沉积和肺纤维化的途径。据报道，促炎热激蛋白90（HSP90）的抑制剂阻止了博来霉素诱导的肺纤维化。药物可能被证明是针对芥末引起的慢性肺肺和肺的对策纤维化。我们在生化和组织学上产生以环节和肺炎为特征实质胶原蛋白沉积，HSP90和αSMA的上调以及随之而来的气道功能障碍在30 NM灌输后的几天（在NM管理后24小时开始） HSP90抑制剂AUY-922，有效阻止了胶原蛋白沉积，肺纤维化和 αSMA上调。 NM IID慢性肺肺肺肺肺和肺部膜膜薄膜泡沫的鼠模型为您提供了证明概念 HSP90抑制剂的解剖特性，AUY-922 目的：1）我们将建立NM诱导的慢性肺肺肺肺肺肺肺肺肺肺肺肺纤维化的小鼠模型，并具有特定的可量化和可重复的生物标志物，展示剂量反应关系并识别凯西病理信号通路； 2）我们将研究HSP90抑制剂的有效性阻止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从研究中提供了概念证明，以进一步发展HSP90 作为针对芥末引起的肺纤维化和慢性肺肺功能障碍的解毒剂。