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, 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.
Carpenter
T C
TC
Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. todd.carpenter@uchsc.edu
Stenmark
K R
KR
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
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