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

TIE2 激活治疗化学引起的急性肺损伤

• 批准号: 9352549
• 负责人: Christopher D Kontos
• 金额: $ 46.2万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352549
• 关键词: ANGPT1 gene; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Agonist; Albumins; Alveolar; Angiopoietin-2; Biological Assay; Blood Vessels; Blood capillaries; Breathing; Bronchoalveolar Lavage Fluid; Cell Count; Cessation of life; Chemicals; Chlorides; Clinical; Development; Dose; Endothelial Cells; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Exposure to; Extravasation; Functional disorder; Gases; Goals; Histamine; Human; In Vitro; Inbred Mouse; Inbred Strains Mice; Inbreeding; Industrialization; Inflammation; Injury; Lead; Ligands; Liquid substance; Lung; Medical; Modeling; Mouse Strains; Mus; Nose; Pathologic; Pharmaceutical Preparations; Pharmacology; Phosgene; Population; Pre-Clinical Model; Prevention; Proteins; Pulmonary Edema; Receptor Protein-Tyrosine Kinases; Secondary to; Sepsis; Serotonin; Signal Transduction; Specificity; Syndrome; TEK gene; Testing; Therapeutic; Time; Translating; Treatment Efficacy; Vascular Endothelial Growth Factors; Vascular Permeabilities; Work; capillary; chemical threat; cohort; effective therapy; in vivo; inhibitor/antagonist; microCT; mortality; mouse model; novel; phosphatase inhibitor; prevent; respiratory; screening; sex; small molecule inhibitor; toxic industrial chemical; vascular endothelial protein tyrosine phosphatase

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.

光气（碳酰氯，COCl2）是一种有毒的工业化学品，会导致肺泡损伤，导致急性呼吸衰竭 肺水肿和致命的急性呼吸窘迫综合征。目前尚无有效疗法可以治疗 光气引起的急性肺损伤（ALI），它被认为是一种重大的化学威胁。肺水肿 肺泡毛细血管内皮屏障功能破坏的结果。这种屏障的关键调节器 功能是内皮受体酪氨酸激酶Tie2。 Tie2 由其激动剂配体血管生成素-1 激活 (ANG-1)，促进血管完整性，从而防止炎症和其他引起的血管渗漏 因素。相比之下，ANG-2 主要作为 Tie2 拮抗剂，促进多种血管渗漏。 病理状况。重要的是，ANG-2 表达在光气诱导的 ALI 中增加，表明 Tie2活性降低是光气引起的肺水肿的重要因素。除了ANG-2之外， Tie2 受到血管内皮蛋白酪氨酸磷酸酶 (VE-PTP) 的负向调节。我们组有 开发了 VE-PTP 的高选择性小分子抑制剂，可显着提高 Tie2 活性 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 其中一种 VE-PTP 抑制剂 AKB-9785 可显着降低小鼠的血管通透性和死亡率 光气诱导的 ALI 模型，表明此类新型化合物可能是有效的治疗方法 用于吸入光气和其他针对肺泡的有毒工业气体继发的肺水肿。在 根据我们最近的 CounterACT R21 奖项进行的工作，我们在确定 针对上述临床症状的治疗。具体来说，我们：1）开发了一种只有鼻子的小鼠 光气诱导的 ALI 暴露模型使我们能够研究和治疗光气对呼吸系统的影响 吸入； 2）通过体外筛选鉴定出有效的、选择性的VE-PTP抑制剂/Tie2激活剂； 3） 验证 VE-PTP 抑制是减少光气后肺血管渗漏的有效治疗方法 吸入； 4) 证明了 VE-PTP 抑制在减少光气方面的初步功效 吸入引起的死亡。该提案的中心假设是药理学激活 Tie2 使用高度选择性和有效的 VE-PTP 小分子抑制剂将防止光气- 诱发血管渗漏、肺水肿和死亡。因此，本提案的具体目标 目的是： 1) 鉴定在体外和体内具有最大功效的最有效的 VE-PTP 抑制剂； 2） 证明 VE-PTP 抑制剂可预防光气诱导的肺血管渗漏并减少标志物 急性肺损伤； 3) 确定能够成功抑制光气诱导的最佳 VE-PTP 抑制剂 死亡。实现这些具体目标预计将导致确定可用于 迅速转化为治疗光气和其他肺泡诱导的 ALI 的有效疗法 目标有毒工业气体。