TIE2 Activation for the Treatment of Chemical-Induced Acute Lung Injury

光气(COCl2)是一种有毒的工业化学品，会导致肺泡损伤，导致急性 肺水肿和致命性急性呼吸窘迫综合征。目前还没有有效的治疗方法 光气诱导的急性肺损伤(ALI)，被认为是一种重大的化学威胁。肺水肿 肺泡毛细血管内皮细胞屏障功能受损所致。这一障碍的关键调节者 功能是内皮受体酪氨酸激酶Tie2。Tie2的激动剂配体血管生成素-1激活Tie2 (Ang-1)，促进血管完整性，从而防止因炎症和其他原因导致的血管泄漏 各种因素。相反，主要作为Tie2拮抗剂的Ang-2促进多种血管渗漏。 病理情况。重要的是，Ang-2在光气诱导的ALI中表达增加，提示 Tie2活性降低是光气性肺水肿的重要因素。除了血管紧张素-2， Tie2受血管内皮细胞酪氨酸磷酸酶(VE-PTP)负调控。我们的团队已经 开发了高选择性的VE-PTP小分子抑制剂，显著提高了Tie2的活性和 在多种临床前模型中促进内皮屏障功能。我们的初步研究表明 一种这样的VE-PTP抑制剂AKB-9785显著降低了小鼠的血管通透性和死亡率 光气诱导的ALI模型，提示这类新化合物可能是有效的治疗方法 用于吸入光气和其他以肺泡为靶标的有毒工业气体而导致的继发性肺水肿。在……里面 根据我们最近的反R21奖所做的工作，我们在确定 治疗上述临床症状。具体地说，我们已经：1)开发了一种只有鼻子的老鼠 光气性ALI暴露模型的建立及光气呼吸效应的研究 吸入；2)通过体外筛选确定有效的、选择性的VE-PTP抑制剂/Tie2激活剂；3) 证实VE-PTP抑制是减少光气后肺血管漏的有效治疗方法 4)显示VE-PTP抑制光气减少的初步效果 吸入性死亡。这一提议的中心假设是，药物激活 Tie2使用高选择性和强大的VE-PTP小分子抑制剂将阻止光气- 导致血管渗漏、肺水肿和死亡。因此，这项提案的具体目标是 目的是：1)确定体外和体内效果最好的VE-PTP抑制剂；2) 证明VE-PTP抑制剂可预防光气引起的肺血管渗漏并减少标志物 3)确定成功抑制光气诱导的最佳VE-PTP抑制剂 死亡率。实现这些具体目标有望导致识别出可以 迅速转化为治疗光气性和其他肺泡性ALI的有效疗法。 瞄准有毒工业气体。

Phosgene (carbonyl chloride, COCl2) is a toxic industrial chemical that causes alveolar injury, resulting in acute pulmonary edema and fatal acute respiratory distress syndrome. No effective therapy currently exists to treat phosgene-induced acute lung injury (ALI), and it is considered a significant chemical threat. Pulmonary edema results from a disruption of alveolar capillary endothelial barrier function. A critical regulator of such barrier function is the endothelial receptor tyrosine kinase Tie2. Tie2 activation by its agonist ligand, angiopoietin-1 (ANG-1), promotes vascular integrity, thereby preventing vascular leak induced by inflammation and other factors. In contrast, ANG-2, which acts primarily as a Tie2 antagonist, promotes vascular leak in a variety of pathological conditions. Importantly, ANG-2 expression is increased in phosgene-induced ALI, suggesting that decreased Tie2 activity is an important factor in phosgene-induced pulmonary edema. In addition to ANG-2, Tie2 is negatively regulated by vascular endothelial-protein tyrosine phosphatase (VE-PTP). Our group has developed highly selective small molecule inhibitors of VE-PTP, which dramatically increase Tie2 activity and promote endothelial barrier function in multiple preclinical models. Our preliminary studies demonstrate that one such VE-PTP inhibitor, AKB-9785, significantly reduces vascular permeability and mortality in a mouse model of phosgene-induced ALI, suggesting that this novel class of compounds could be effective treatments for pulmonary edema secondary to inhalation of phosgene and other alveolar-targeted toxic industrial gases. In work performed under our recent CounterACT R21 award, we have made significant progress in identifying therapeutics for the above clinical syndromes. Specifically, we have: 1) developed a nose-only mouse exposure model of phosgene-induced ALI that allows us to study and treat the respiratory effects of phosgene inhalation; 2) identified potent, selective VE-PTP inhibitors/Tie2 activators through in vitro screening; 3) validated VE-PTP inhibition as an effective therapeutic for reducing pulmonary vascular leak after phosgene inhalation; and 4) demonstrated preliminary efficacy of VE-PTP inhibition in the reduction of phosgene inhalation-induced mortality. The central hypothesis of this proposal is that pharmacological activation of Tie2 using highly selective and potent small molecule inhibitors of VE-PTP will prevent phosgene- induced vascular leak, pulmonary edema, and mortality. Accordingly, the Specific Aims of this proposal are to: 1) Identify the most potent VE-PTP inhibitors with the greatest efficacy in vitro and in vivo; 2) Demonstrate that VE-PTP inhibitors prevent phosgene-induced pulmonary vascular leak and reduce markers of acute lung injury; and 3) Identify the best VE-PTP inhibitor that successfully inhibits phosgene-induced mortality. Accomplishing these Specific Aims is expected to lead to the identification of drugs that can be rapidly translated into effective therapies for the treatment of ALI induced by phosgene and other alveolar- targeted toxic industrial gases.