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

基本信息

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
项目类别：
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

项目摘要

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.

Phosgene（碳氯化物，COCL2）是一种有毒的工业化学化学物质，会导致肺泡损伤，导致急性肺水肿和致命的急性呼吸窘迫综合征。目前没有有效的治疗方法来治疗 Phosgene引起的急性肺损伤（ALI）被认为是重大的化学威胁。肺水肿肺泡毛细管内皮屏障功能的破坏结果。这种障碍的关键调节器功能是内皮受体酪氨酸激酶TIE2。 TIE2激动剂配体激活Angiopoietin-1 （Ang-1），促进血管完整性，从而防止炎症和其他因素。相比之下，主要充当TIE2拮抗剂的Ang-2促进了各种血管泄漏病理状况。重要的是，在磷酸化诱导的ALI中，Ang-2表达增加，表明 TIE2活性的降低是磷酸诱导的肺水肿的重要因素。除了ang-2， TIE2受血管内皮蛋白酪氨酸磷酸酶（VE-PTP）负调节。我们的小组有开发了高度选择性的小分子抑制剂的VE-PTP，该抑制剂显着增加了TIE2活性和在多个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可显着降低小鼠的血管渗透性和死亡率 Phosgene诱导的Ali的模型，表明这种新型化合物可能是有效的治疗方法用于继发于吸入磷酸盐和其他牙槽靶向有毒工业气体的肺水肿。在根据我们最近的Counteract R21奖，我们在确定方面取得了重大进展上述临床综合征的治疗剂。具体来说，我们有：1）开发了只有鼻子的鼠标 Phosgene引起的ALI的暴露模型，使我们能够研究和治疗磷酸的呼吸作用吸入； 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）经过验证的VE-PTP抑制作用是减少肺血管泄漏的有效治疗方法吸入； 4）证明了VE-PTP抑制在减少磷酸的初步疗效吸入引起的死亡率。该提议的中心假设是使用高度选择性和有效的小分子抑制剂的TIE2将防止斑态 - 诱导血管泄漏，肺水肿和死亡率。因此，该提议的具体目的为：1）鉴定体外和体内功效最大的最有效的VE-PTP抑制剂； 2）证明VE-PTP抑制剂可防止磷酸诱导的肺血管泄漏并减少标记急性肺损伤； 3）确定成功抑制Phosgene诱导的最佳VE-PTP抑制剂死亡。预计完成这些具体目标将导致对可能是的药物的识别迅速转化为有效的疗法，用于治疗富香烯和其他肺泡诱导的ALI 有针对性的有毒工业气体。