Hypoxia decreases lung neprilysin expression and increases pulmonary vascular leak

Although prior studies suggest that hypoxia may increase pulmonary vascular permeability, the mechanisms responsible for that effect remain uncertain. Neprilysin (neutral endopeptidase) is a cell surface metallopeptidase that degrades several vasoactive peptides including substance P and bradykinin. We hypothesized that hypoxia could reduce lung neprilysin expression, lead ing to increased vascular leak. Weanling rats were exposed to normobaric hy poxia (inspired O-2 fraction = 0.1). Lung neprilysin activity was significa ntly decreased after 24 and 48 h of hypoxia (P<0.006). The decrease in enzy me activity was associated with decreased lung neprilysin protein content a nd decreased lung neprilysin mRNA expression. Immunohistochemistry showed a predominantly perivascular distribution of neprilysin, with dear reduction s in neprilysin immunoreactivity after exposure to hypoxia. Exposure to hyp oxia for 24 h also caused marked increases in vascular leak (P=0.008), whic h were reversed by the administration of recombinant neprilysin. The hypoxi a-induced increase in leak was also reversed by substance P and bradykinin receptor antagonists. We conclude that in young rats hypoxia decreases lung neprilysin expression, which contributes to increased pulmonary vascular l eak via substance P and bradykinin receptors.