Antidotes against HCI-induced chronic lung injury

针对 HCI 引起的慢性肺损伤的解毒剂

基本信息

批准号：
10015581
负责人：
John D Catravas
金额：
$ 45.88万
依托单位：
OLD DOMINION UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10015581
关键词：
Acute Aftercare Animal Model Animals Anti-Inflammatory Agents Antidotes Antineoplastic Agents Area Cessation of life Chemical Warfare Chlorine Chronic Clinical Clinical Trials Dangerousness Data Development Disease Progression Dose Effectiveness Event Exhibits Exposure to Functional disorder Gases Heat-Shock Proteins 70 Heat-Shock Proteins 90 Hour Human Hydrochloric Acid Illicit Drugs Incidence Inflammatory Injury Knockout Mice Laboratories Lead Lung Lung diseases Modeling Molecular Chaperones Mus Oils Oryctolagus cuniculus Oximes Pharmaceutical Preparations Phosgene Pirfenidone Plants Pulmonary Fibrosis Role Signal Transduction Site Swimming Pools Therapeutic Up-Regulation clinical investigation human model idiopathic pulmonary fibrosis indium-bleomycin inhibitor/antagonist irritation lewisite lung injury side effect treatment optimization

项目摘要

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.

概括接触盐酸 (HCl) 可导致严重的急性和慢性肺损伤，可能致命。由于其频繁和多次使用，接触 HCl 的发生率一直在增加。此外， HCl 也与化学战有关，既作为引发剂，更常见的是作为化学战的有毒产物。光气、光气肟、路易氏剂和氯暴露。尽管有相当数量关于 HCl 急性影响的数据，对更严重、可能致命的慢性后遗症知之甚少接触 HCl 的危险，并且对于其中最危险、不可逆转且可能致命的危险没有解毒剂效应，即肺纤维化（PF）。普遍存在的促炎分子伴侣，热休克蛋白 90 (HSP90) 调节多种促纤维化因子的激活，并在 PF 中表达上调。我们因此假设 HSP90 抑制剂已经作为抗癌药物进入临床试验，可能被证明是有用的针对 HCl 引起的慢性肺损伤和肺纤维化 (PF) 的对策。在初步研究中，我们描述了 HCl 诱导小鼠 PF 的关键信号转导事件，并证明治疗后（HCl 给药后 24 小时开始）与 HSP90 抑制剂一起，AUY-922 可有效阻断重要的促纤维化信号的上调，以及肺纤维化和肺纤维化的发展慢性肺功能障碍。在当前的应用中，我们建议在三个领域扩展我们的初步发现： 1) 确定临床上使用的 HSP90 抑制剂，该抑制剂作为 HCl 诱导的小鼠 PF 的解毒剂最有效，2) 研究 HSP70 在 HSP90 抑制剂的解毒作用中的潜在治疗作用以及 3) 证明 HSP90 抑制剂能够在另一种 HCl 动物模型中类似地抑制 HCl 诱导的 PF 诱发PF，兔子。这些研究的结果将为进一步开发提供所需的信息一种特定的 HSP90 抑制剂作为针对 HCl 诱导的肺纤维化和慢性肺功能障碍的解毒剂。