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.
Maa
J
J
Departments of Surgery and Physiology, University of California School of Medicine, San Francisco 94143-0790, USA.
Grady
E F
EF
Yoshimi
S K
SK
Drasin
T E
TE
Kim
E H
EH
Hutter
M M
MM
Bunnett
N W
NW
Kirkwood
K S
KS
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