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。 暴露于光气引起主要靶向肺泡的急性肺损伤（ALI），导致急性肺损伤。 肺水肿和致命的急性呼吸窘迫综合征。在这方面，它与其他代理商类似 比如氯化苦和全氟异丁烯。目前没有有效的治疗方法 它被认为是一种重要的化学威胁风险。血管生成素（Ang）-1/Tie2 信号通路是维持血管完整性和防止血管渗漏的最有效介质之一 由多种刺激诱导，包括炎症，血管内皮生长因子（a.k.a.，血管 渗透因子），血清素和组胺，表明该途径非特异性抑制血管内皮细胞的生长。 磁导率Ang-1/Tie2信号传导受天然存在的拮抗配体Ang-2负调控。 大量证据表明，Ang-2的上调在促进肺动脉高压中起关键作用。 血管渗漏在各种病理条件下，如败血症，和抑制Ang-2或激活 Ang-1/Tie2可降低脓毒症大鼠肺血管通透性，降低死亡率。最近，安- 已经显示在IFN-γ基因诱导的ALI中，Angiopoietin/Tie2表达增加，突出了Angiopoietin/Tie2的表达。 作为化学性肺损伤的潜在治疗靶点。除了Ang-2，Tie2是 由血管内皮蛋白酪氨酸磷酸酶（VE-PTP）负调控。初步研究， 我们的研究小组证明，用高选择性小分子化合物抑制VE-PTP导致 显著的Tie2活化和增强的内皮屏障功能。在小鼠肺血管模型中 泄漏导致休克和死亡的高发生率，给予VE-PTP的小分子抑制剂 完全阻断这些不良影响。基于这些结果，我们假设Tie2的激活 使用高选择性和有效的VE-PTP小分子抑制剂将防止β-内酰胺酶基因诱导的 血管渗漏肺水肿和死亡率为了验证这一假设，本研究的具体目的是 建议是：1）开发和表征β-内酰胺酶诱导的急性肺损伤的小鼠模型; 2）鉴定 在体外具有最大功效的最有效VE-PTP抑制剂;以及3）确定VE-PTP的功效 抑制剂在预防β-内酰胺酶诱导的肺血管渗漏、肺水肿、缺氧和死亡中的作用 在小鼠模型中。这些目标的完成将导致识别潜在的治疗小 这些分子可以推进到后续的药理学/毒理学测试和开发， 因吸入光气和类似有毒工业化学品而导致的急性肺损伤的治疗。

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.