title: Hypoxia decreases lung neprilysin expression and increases pulmonary vascular leak.
abstract: 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, leading to increased vascular leak. Weanling rats were exposed to normobaric hypoxia (inspired O(2) fraction = 0.1). Lung neprilysin activity was significantly decreased after 24 and 48 h of hypoxia (P < 0.006). The decrease in enzyme activity was associated with decreased lung neprilysin protein content and decreased lung neprilysin mRNA expression. Immunohistochemistry showed a predominantly perivascular distribution of neprilysin, with clear reductions in neprilysin immunoreactivity after exposure to hypoxia. Exposure to hypoxia for 24 h also caused marked increases in vascular leak (P = 0.008), which were reversed by the administration of recombinant neprilysin. The hypoxia-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 leak via substance P and bradykinin receptors.
authors.affiliation: Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. todd.carpenter@uchsc.edu
authors.forename: T C
authors.initials: TC
authors.lastname: Carpenter
authors.forename: K R
authors.initials: KR
authors.lastname: Stenmark
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply / Q000201:enzymology; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D008833:Microcirculation / Q000502:physiology; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D010100:Oxygen / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011654:Pulmonary Edema / Q000378:metabolism* / Q000503:physiopathology*; D011812:Quinuclidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013373:Substance P / Q000378:metabolism; D014867:Water / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011480:Protease Inhibitors; D011812:Quinuclidines; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D014867:Water; C069018:SCH 42495; C085215:SR 140333; D013373:Substance P; C065679:icatibant; D008715:Methionine; D015260:Neprilysin; D010100:Oxygen; D001920:Bradykinin