Neutral endopeptidase determines the severity of pancreatitis-associated lung injury.
BACKGROUND
Neutral endopeptidase (NEP) is a cell-surface metalloprotease that degrades proinflammatory peptides such as substance P, neurokinin A, and bradykinin. Inhibition of NEP exacerbates both experimental pancreatitis and the associated lung injury. It is unclear if worsened lung injury is the indirect result of more severe pancreatitis or if it is a direct effect of NEP inhibition in the lung.


METHODS
We used a model of pancreatitis-associated lung injury (PALI) to test the hypothesis that antagonism or genetic deletion of NEP augments PALI inflammation and pulmonary damage irregardless of the degree of pancreatitic inflammation.


RESULTS
In NEP(+/+) mice, intraperitoneal injection of porcine pancreatic elastase (elastase, 0.085 U/g at t = 0 h and t = 1 h) caused a 7-fold increase in lung myeloperoxidase (MPO) activity and marked pulmonary edema, neutrophil infiltration, and hemorrhage at 4 h as compared to control animals. The pattern of lung injury induced by elastase mimicked that observed among a separate group of animals with PALI induced by cerulein but was not associated with pancreatitis. Both NEP(-/-) mice and NEP(+/+) mice pretreated with the NEP antagonist phosphoramidon (10 mg/kg s.c.) had significant elevations of lung MPO and worsened lung histology compared to NEP(+/+) mice given elastase alone. Antagonism of either the vanilloid receptor transient receptor vanilloid 1 or the substance P receptor NK1-R had no effect on elastase-mediated lung injury in NEP-deficient mice.


CONCLUSIONS
NEP is an inhibitor of pancreatic elastase-induced lung injury, presumably via degradation of proinflammatory mediators.
Department of Surgery, University of California, San Francisco, California 94143-0790, USA.
Amy Lightner
AL
Day
Elizabeth
E
Wick
Thomas H
TH
Jordan
Colleen E
CE
Jaffray
Nigel W
NW
Bunnett
Eileen F
EF
Grady
Kimberly S
KS
Kirkwood
D000818:Animals; D005260:Female; D007473:Ion Channels / Q000037:antagonists & inhibitors; D008171:Lung Diseases / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D015260:Neprilysin / Q000502:physiology*; D064729:Neurokinin-1 Receptor Antagonists; D010196:Pancreatic Elastase / Q000009:adverse effects*; D010195:Pancreatitis / Q000150:complications / Q000276:immunology*; D050916:TRPV Cation Channels
D007473:Ion Channels; D064729:Neurokinin-1 Receptor Antagonists; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D010196:Pancreatic Elastase; D015260:Neprilysin