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One or more keywords matched the following properties of VEGF--PULMONARY VASCULAR LEAK IN ACUTE LUNG INJURY

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abstract Acute lung injury is a frequent cause of morbidity and mortality in critically-ill patients and is the most important illness associated with noncardiogenic pulmonary edema. At its onset, a characteristically abrupt increase in endothelial permeability heralds a cascade of progressive lung dysfunction. While varied acute illnesses such as sepsis and trauma predispose to this disorder, all generate a common milieu characterized by a state of circulating oxidant stress, proinflammatory and proteolytic activity, intravascular coagulation and activation/intrapulmonary sequestration of neutrophils and platelets. Endothelial leak has been attributed to direct and indirect effects of these factors, yet acute lung injury can clearly occur independent of any mediator or cell. The propensity of the lung toward abrupt leak suggested to us the possible existence in the alveoli of a constitutive, direct-acting permeability factor releasable by certain triggers. We propose that vascular endothelial growth factor (VEGF) is an ideal candidate for such an agent. VEGF is one of the most potent, immediate-acting endothelial permeability factors known, its gene expression is most prominent in the lung, it is produced by alveolar epithelium, thereafter intercalates into the matrix of the alveolar wall, and is released in active form from matrix sites by proteolysis. In addition, our experiments show that VEGF causes pulmonary vascular leak and is overexpressed in alveolar epithelium in a model of lung injury. We have also found that VEGF is secreted by aggregating platelets, that VEGF is contained within neutrophils, and that VEGF is increased in plasma and present in bronchoalveolar lavage of patients with acute lung injury. The specific aims of this proposal are to test the hypotheses that (1) VEGF mediates pulmonary endothelial leak by intercellular and transcellular mechanisms and is a principle mediator of noncardiogenic pulmonary edema during acute lung injury; (2) that initial alveolar leak occurs due to intrapulmonary VEGF-release from stimulated neutrophils and platelets: and (3) that initial leak is also related to proteolytic release of VEGF from matrix sites in alveolar walls and continues later via overexpression of VEGF protein and VEGF receptor within injured alveoli. This work may aid the development of a treatment for acute lung injury and is undertaken to further knowledge of endothelial permeability, lung epithelial biology, and matrix-growth factor interactions.
label VEGF--PULMONARY VASCULAR LEAK IN ACUTE LUNG INJURY

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  • Acute Lung Injury

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