Tie2 Activation for the Treatment of Chemical-Induced Acute Lung Injury

摘要 光气是一种常见的有毒工业化学品，用于制造塑料和工业材料。 暴露在光气中会导致急性肺损伤(ALI)，主要针对肺泡，导致急性 肺水肿和致命性急性呼吸窘迫综合征。在这方面，它与其他药剂相似 以氯苦参碱和全氟异丁烯等肺泡为靶标。目前还没有有效的治疗方法。 光气诱导的ALI，被认为是一个重大的化学威胁风险。血管生成素(Ang)-1/Tie2 信号通路是血管完整性和防止血管渗漏的最有效的介体之一 由多种刺激诱导，包括炎症、血管内皮生长因子(又名血管)、 通透性因子)、5-羟色胺和组胺，表明这一途径非特异性地抑制血管 渗透性。Ang-1/Tie2信号转导受天然产生的拮抗配体Ang-2的负调控。 大量证据表明，Ang-2的上调在促进肺损伤中起着关键作用。 血管渗漏在各种病理条件下，如脓毒症，以及Ang-2的抑制或激活 Ang-1/Tie2在脓毒症模型中可预防肺血管通透性，降低死亡率。最近，Ang- 在光气性ALI中，血管生成素/Tie2的表达增强。 通路是治疗化学性肺损伤的潜在靶点。除了Ang-2，Tie2还 受血管内皮细胞蛋白酪氨酸磷酸酶(VE-PTP)负调控。初步研究来自 我们的小组证明，用高度选择性的小分子化合物抑制VE-PTP会导致 戏剧性的Tie2激活和增强的内皮屏障功能。在小鼠肺血管模型中 导致休克和死亡的高发生率的泄漏，使用VE-PTP的小分子抑制剂 完全阻断这些不良影响。根据这些结果，我们假设Tie2的激活 使用高选择性和强效的VE-PTP小分子抑制剂将防止光气诱导 血管渗漏、肺水肿和死亡率。为了检验这一假设，这项研究的具体目的是 建议：1)建立和表征光气诱导的急性肺损伤的小鼠模型；2)鉴定 体外最有效的VE-PTP抑制剂；以及3)决定VE-PTP的疗效 预防光气所致肺血管渗漏、肺水肿、低氧和死亡的抑制剂 在小鼠模型中。完成这些目标将导致识别潜在的治疗性小分子 可进一步用于后续药理学/毒理学测试和开发的分子 治疗因吸入光气和类似有毒工业化学品而造成的急性肺损伤。

ABSTRACT Phosgene is a common toxic industrial chemical used in the manufacture of plastics and industrial materials. Exposure to phosgene gas causes acute lung injury (ALI) that primarily targets alveoli, resulting in acute pulmonary edema and fatal acute respiratory distress syndrome. In this respect, it is similar to other agents that target alveoli such as chloropicrin and perfluoroisobutylene. No effective therapies currently exist to treat phosgene-induced ALI, and it is considered a significant chemical threat risk. The Angiopoietin (Ang)-1/Tie2 signaling pathway is one of the most potent mediators of vascular integrity and prevention of vascular leak induced by a variety of stimuli, including inflammation, vascular endothelial growth factor (a.k.a., vascular permeability factor), serotonin, and histamine, suggesting that this pathway non-specifically inhibits vascular permeability. Ang-1/Tie2 signaling is negatively regulated by the naturally occurring antagonistic ligand, Ang-2. Substantial evidence now demonstrates that upregulation of Ang-2 plays a key role in promoting pulmonary vascular leak in a variety of pathological conditions, such as sepsis, and inhibition of Ang-2 or activation of Ang-1/Tie2 can prevent pulmonary vascular permeability and reduce mortality in sepsis models. Recently, Ang- 2 expression has been shown to be increased in phosgene-induced ALI, highlighting the Angiopoietin/Tie2 pathway as a potential therapeutic target in chemical-induced lung injury. In addition to Ang-2, Tie2 is negatively regulated by vascular endothelial protein tyrosine phosphatase (VE-PTP). Preliminary studies from our group demonstrate that inhibition of VE-PTP with highly selective small molecule compounds results in dramatic Tie2 activation and enhanced endothelial barrier function. In a mouse model of pulmonary vascular leak that causes a high incidence of shock and death, administration of a small molecule inhibitor of VE-PTP completely blocks these adverse effects. Based on these results, we hypothesize that activation of Tie2 using highly selective and potent small molecule inhibitors of VE-PTP will prevent phosgene-induced vascular leakage, pulmonary edema, and mortality. To test this hypothesis, the Specific Aims of this proposal are to: 1) Develop and characterize a mouse model of phosgene-induced acute lung injury; 2) Identify the most potent VE-PTP inhibitors with the greatest efficacy in vitro; and 3) Determine the efficacy of VE-PTP inhibitors in preventing phosgene-induced pulmonary vascular leak, pulmonary edema, hypoxia, and mortality in a mouse model. Completion of these Aims will lead to the identification of potentially therapeutic small molecules that can be advanced to subsequent pharmacology/toxicology testing and development as treatments for acute lung injury resulting from the inhalation of phosgene and similar toxic industrial chemicals.