Substance P is a determinant of lethality in diet-induced hemorrhagic pancreatitis in mice.
BACKGROUND
The neuropeptide substance P (SP) induces plasma extravasation and neutrophil infiltration by activating the neurokinin 1-receptor (NK1-R). SP-induced neurogenic inflammation is terminated by the cell surface enzyme neutral endopeptidase (NEP), which degrades SP. We determined whether genetic deletion of the NK1-R reduces mortality and, conversely, whether genetic deletion of NEP increases mortality in a lethal model of hemorrhagic pancreatitis.


METHODS
Necrotizing pancreatitis was induced by feeding mice a diet deficient in choline and supplemented with ethionine. We determined the length of survival, the severity of pancreatitis (by measuring the neutrophil enzyme myeloperoxidase [MPO] and by histologic evaluation), and the severity of pancreatitis-associated lung injury (lung MPO and histology) in NK1-R (+/+)/(-/-) and NEP (+/+)/(-/-) mice.


RESULTS
Genetic deletion of the NK1-R significantly improved survival (100% vs 8% at 120 hours, P <.001) and reduced pancreatic MPO and acinar cell necrosis. Conversely, genetic deletion of NEP significantly worsened survival (0% vs 90% at 120 hours, P <.001) and exacerbated pancreatic MPO and pancreatitis-associated lung injury.


CONCLUSIONS
Substance P is an important determinant of lethality in this model of necrotizing pancreatitis. Defects in NEP expression could lead to uncontrolled inflammation.
Departments of Surgery and Physiology, University of California School of Medicine, San Francisco 94143-0790, USA.
J
J
Maa
E F
EF
Grady
S K
SK
Yoshimi
T E
TE
Drasin
E H
EH
Kim
M M
MM
Hutter
N W
NW
Bunnett
K S
KS
Kirkwood
D000208:Acute Disease; D000818:Animals; D002796:Choline Deficiency / Q000503:physiopathology*; D003643:Death; D004032:Diet; D005001:Ethionine / Q000494:pharmacology; D006470:Hemorrhage; D007249:Inflammation; D008168:Lung / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D015260:Neprilysin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology; D010195:Pancreatitis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D009195:Peroxidase / Q000097:blood; D018040:Receptors, Neurokinin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013373:Substance P / Q000502:physiology*
D018040:Receptors, Neurokinin-1; D013373:Substance P; D009195:Peroxidase; D015260:Neprilysin; D005001:Ethionine