Vascular endothelial growth factor induced lung edema

血管内皮生长因子诱导的肺水肿

• 批准号: 6638522
• 负责人: Robert J Kaner
• 金额: $ 33.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6638522
• 关键词: adult respiratory distress syndrome; biological signal transduction; electron microscopy; genetically modified animals; growth factor receptors; human subject; intensive care; laboratory mouse; leukocyte activation /transformation; molecular pathology; neutrophil; patient oriented research; protein isoforms; protein structure function; pulmonary edema; receptor binding; respiratory pharmacology; vascular endothelial growth factors; vascular endothelium permeability

DESCRIPTION (provided by applicant): Adult respiratory distress syndrome (ARDS) affects 150,000 individuals in the US annually with a mortality of 40 percent. Current treatment is supportive only. New therapies will require a detailed understanding of the molecular basis for this disorder. One of the earliest manifestations of ARDS is the development of noncardiogenic pulmonary edema. We have made the novel observation that pulmonary edema is induced by overexpression of the vascular endothelial growth factor (VEGF) gene in lung using a modified adenovirus vector approach. Gene transfer and overexpression of VEGF were confirmed by Northern analysis of mouse lung extracts and ELISA. Edema was observed in lung histology and quantified by lung wet-to-dry weight ratio and pulmonary capillary permeability to macromolecules by the Evan's blue dye assay and 131 l-albumin lung leak. This proposal will fully characterize the mechanism of VEGF-induced pulmonary edema with regard to endothelial permeability, alveolar dysfunction, VEGF receptor(s) specificity, signal transduction pathways and downstream effectors that mediate the edema. Ultrastructual information will be obtained by electron microscopy of VEGF-overexpressing lungs. Structure-function relationships of VEGF isoforms to the development of pulmonary edema will be defined using Ad vectors containing the genes for the various VEGF isoforms as well as mutant VEGFs which have specificity for binding to a particular VEGF receptor. Overexpression, immunoinhibition and pharmacologic inhibitor studies will define the roles of potential mediators downstream from VEGF such as endothelial nitric oxide synthase and nitric oxide and the intracellular signaling pathways that are activated during VEGF-induced edema. Studies to assess the potential role of activated neutrophils as a source of VEGF in vivo during acute lung injury will be developed. Bronchoalveolar lavage and plasma levels of VEGF will be measured in patients with acute lung injury to develop the hypothesis that overexpression of VEGF in lung may be one mechanism favoring increased permeability.

描述（由申请人提供）：成人呼吸窘迫综合征（ARDS） 美国每年有15万人感染，死亡率为40%。 目前的治疗只是支持性的。新疗法需要详细的 了解这种疾病的分子基础。最早的一 急性呼吸窘迫综合征的主要表现是非心源性肺水肿的发展。我们 已经做出了新的观察，即肺水肿是由 血管内皮生长因子（VEGF）基因在肺组织中的过度表达 使用改良的腺病毒载体方法。基因转移和过表达 通过小鼠肺提取物的北方分析和ELISA证实VEGF的表达。 在肺组织学中观察到水肿，并通过肺湿干重进行定量 伊文思蓝法测定肺毛细血管通透性 染料测定和131 L-白蛋白肺渗漏。该提案将充分体现 VEGF诱导肺水肿的内皮细胞损伤机制 通透性，肺泡功能障碍，VEGF受体特异性，信号 介导水肿的转导途径和下游效应物。 超微结构信息将通过电子显微镜获得， VEGF过度表达的肺。VEGF异构体的结构-功能关系 肺水肿的发展将使用Ad载体来定义， 各种VEGF同种型以及突变型VEGF的基因， 在一些实施方案中，所述抗体具有与特定VEGF受体结合的特异性。过度表达， 免疫抑制和药理学抑制剂研究将确定 VEGF下游的潜在介质，如内皮一氧化氮 合成酶和一氧化氮和细胞内信号通路， 在VEGF诱导的水肿中被激活。研究以评估 在急性肺损伤期间，活化的中性粒细胞作为体内VEGF的来源， 发展。将测量支气管肺泡灌洗和VEGF的血浆水平 在急性肺损伤患者中， VEGF在肺中的过度表达可能是一种有利于增加 磁导率