Pathogenesis of high altitude pulmonary edema: Does alveolar epithelial lining fluid vascular endothelial growth factor exacerbate capillary leak?

Vascular endothelial growth factor (VEGF) is a potent mediator of capillary leak if it gains access to its receptors on the capillary endothelium. We have observed that there are high levels of VEGF compartmentalized in the alveolar epithelial lining fluid of normal humans at levels 500-fold greater than plasma. The potential for high altitude to result in compromise of alveolar epithelial tight junctions and experimental animal studies in which pulmonary edema is induced when VEGF is overexpressed in the alveolar epithelium, suggest a mechanism. We hypothesize that when the epithelial barrier is compromised at high altitude the normally high level of VEGF in the alveolar epithelial fluid has access to the pulmonary endothelium, where it acutely alters permeability, markedly exacerbating the high permeability pulmonary edema that characterizes high altitude pulmonary edema. If correct, this paradigm opens the possibility of testing available anti-VEGF therapies to treat this potentially fatal disorder.