Antidotes against HCI-induced chronic lung injury

针对 HCI 引起的慢性肺损伤的解毒剂

• 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
• 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

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.

总结 暴露于盐酸（HCl）可导致严重的急性和慢性、潜在致命的肺损伤。 由于其频繁和多次使用，接触盐酸的发生率一直在增加。此外，委员会认为， HCl也牵涉到化学战中，既作为引发剂，也更经常地作为化学战的有毒产物。 光气、光气肟、路易氏剂和氯气暴露。尽管有大量的 关于盐酸急性效应的数据，对更严重的、潜在致命的慢性后遗症的了解要少得多。 暴露在HCl中，并且没有解毒剂存在于最危险的，不可逆的和潜在的致命的这些 肺纤维化（PF）。普遍存在的促炎分子伴侣热休克蛋白90 热休克蛋白90（HSP 90）调节几种促纤维化因子的活化，并在PF中上调。 假设HSP 90抑制剂，已经在临床试验中作为抗癌剂，可能被证明是有用的， 盐酸诱导的慢性肺损伤和肺纤维化（PF）的对策。在初步研究中， 我们已经描述了盐酸诱导的小鼠PF中的关键信号事件，并证明了治疗后 （HCl给药后24小时开始）与HSP 90抑制剂一起，AUY-922有效地阻断了HSP 90抑制剂的作用。 重要的促纤维化信号的上调，以及肺纤维化和 慢性肺功能障碍在当前的应用中，我们建议在三个方面扩展我们的初步发现： 1)确定临床上使用的HSP 90抑制剂，其在小鼠中作为HCl诱导的PF的解毒剂是最有效的，2） 研究HSP 70在HSP 90抑制剂的解毒作用中的潜在治疗作用; 3） 证明了HSP 90抑制剂在另一种HCl诱导的PF动物模型中类似地抑制HCl诱导的PF的能力。 诱导PF，兔子。这些研究结果将为进一步的发展提供所需的信息 HSP 90特异性抑制剂作为盐酸诱导的肺纤维化和慢性肺功能障碍的解毒剂。