Antidotes against HCI-induced chronic lung injury

摘要 接触盐酸(HCl)可导致严重的急性和慢性、潜在致命的肺损伤。 由于它的频繁和多次使用，接触盐酸的发生率一直在增加。此外， 氯化氢也牵涉到化学战中，既是一种引爆剂，更经常是一种有毒的 光气、光气酮、路易斯脱和氯气暴露。即使有相当数量的 关于盐酸的急性影响的数据，关于更严重的、可能致命的慢性后遗症的了解要少得多 而对于其中最危险的、不可逆转的和可能致命的 影响，即肺纤维化(PF)。普遍存在的促炎伴侣--热休克蛋白90 热休克蛋白90(HSP90)调节几种促纤维化因子的激活，在PF中上调。因此，我们 假设HSP90抑制剂，已经作为抗癌药物在临床试验中，可能被证明是有用的 防治盐酸慢性肺损伤和肺纤维化的对策。在初步研究中， 我们已经描述了在盐酸诱导的小鼠PF中的关键信号事件，并证明了治疗后 (从给药24小时后开始)使用HSP90抑制剂，AUY-922有效地阻断 重要的促纤维化信号上调，以及肺纤维化和肺纤维化的发展 慢性肺功能障碍。在目前的申请中，我们建议在三个方面扩展我们的初步调查结果： 1)确定临床上使用的HSP90抑制剂对盐酸诱导的小鼠肺功能最有效的解毒剂；2) 研究HSP70在HSP90抑制剂解毒作用中的潜在治疗作用 在另一种盐酸动物模型中证明HSP90抑制剂具有类似地抑制盐酸诱导的PF的能力。 诱发兔肺间质纤维化。这些研究的结果将为进一步的发展提供必要的信息 一种特定的HSP90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。

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.