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 I-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.