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: 9753248
• 负责人: Christopher D Kontos
• 金额: $ 44.67万
• 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 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753248
• 关键词: ANGPT1 gene; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Agonist; Albumins; Alveolar; Angiopoietin-2; Biological Assay; Blood Vessels; Blood capillaries; Bronchoalveolar Lavage Fluid; Cell Count; Cessation of life; Chemicals; Chlorides; Clinical; Development; Dose; Endothelial Cells; Endothelium; 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; Inhalation; Injury; Lead; Ligands; Liquid substance; Lung; 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; Structure; Syndrome; TEK gene; TIE-2 Receptor; Testing; Therapeutic; Time; Translating; Treatment Efficacy; Vascular Endothelial Growth Factors; Vascular Permeabilities; Work; chemical threat; cohort; effective therapy; in vivo; inhibitor/antagonist; medical countermeasure; 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（羰基氯，COCl2）是一种有毒的工业化学品，可引起肺泡损伤，导致急性肺泡损伤