Subtance P is a determinant of lethality in diet-induced hemorrhagic pancreatitis in mice

John Maa, Eileen F. Grady, Shandra K. Yoshimi, Todd E. Drasin, Edward H. Kim, Matthew M. Hutter, Nigel W. Bunnett, Kimberly S. Kirkwood

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)232-239
Number of pages8
JournalSurgery
Volume128
Issue number2
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Surgery

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