Vascular endothelial growth factor induced lung edema

血管内皮生长因子诱导的肺水肿

• 批准号: 6537540
• 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/6537540
• 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（申请人提供）：成人呼吸窘迫综合征（ARDS）