Recombinant human neutral endopeptidase ameliorates pancreatic elastase-induced lung injury.
BACKGROUND
Genetic deletion of neutral endopeptidase (NEP), a cell-surface metalloprotease that degrades proinflammatory peptides, exacerbates lung injury induced by pancreatic elastase in a model of pancreatitis-associated lung injury. We tested 3 hypotheses: (1) genetic deletion of NEP prolongs lung recovery after elastase injections; (2) elastase-mediated lung injury is associated with down-regulation of NEP; and (3) pretreatment of NEP (-/-) and (+/+) animals with recombinant human NEP (rhNEP) reduces pulmonary damage in this model.


METHODS
NEP (+/+) or (-/-) mice were injected with pancreatic elastase (0.085 U/g/dose intraperitoneally) or saline carrier at t = 0 hours and t = 1 hour. Some mice were pretreated with rhNEP (3 mg/kg intraperitoneally). Serum elastase, lung histologic score, myeloperoxidase, and NEP activities were measured at 4, 8, or 12 hours.


RESULTS
NEP (-/-) mice had worse pulmonary inflammation at 4 and 8 hours versus (+/+) mice. Lung NEP activity was similar in elastase-treated and control (+/+) animals. Pretreatment with rhNEP reduced myeloperoxidase and improved histology at 4 hours in NEP (-/-) and (+/+) mice.


CONCLUSIONS
Pancreatic elastase induces lung injury that is worse and prolonged in NEP (-/-) mice. Pretreatment with rhNEP ameliorates this injury. Thus, upregulation of NEP is a potential therapeutic approach for pancreatitis-associated lung injury.
Lightner
Amy M
AM
Department of Surgery, University of California, San Francisco, USA.
Jordan
Thomas H
TH
Bunnett
Nigel W
NW
Grady
Eileen F
EF
Kirkwood
Kimberly S
KS
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D015260:Neprilysin / Q000378:metabolism / Q000494:pharmacology*; D009504:Neutrophils / Q000201:enzymology; D010196:Pancreatic Elastase / Q000378:metabolism / Q000494:pharmacology*; D010195:Pancreatitis / Q000150:complications / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology* / Q000209:etiology; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000201:enzymology
D011994:Recombinant Proteins; D009195:Peroxidase; D010196:Pancreatic Elastase; D015260:Neprilysin