ROLE OF SUBSTANCE-P AND THE NEUROKININ-1 RECEPTOR IN ACUTE-PANCREATITIS AND PANCREATITIS-ASSOCIATED LUNG INJURY

Substance P, acting via the neurokinin 1 receptor (NK1R), plays an imp ortant role in mediating a variety of inflammatory processes. However, its role in acute pancreatitis has not been previously described. We have found that, in normal mice, substance P levels in the pancreas an d pancreatic acinar cell expression of NK1R are both increased during secretagogue-induced experimental pancreatitis. To evaluate the role o f substance P, pancreatitis was induced in mice that genetically lack NK1R by administration of 12 hourly injections of a supramaximally sti mulating dose of the secretagogue caerulein, During pancreatitis, the magnitude of hyperamylasemia, hyperlipasemia, neutrophil sequestration in the pancreas, and pancreatic acinar cell necrosis were significant ly reduced in NK1R-/-mice when compared with wild-type NK1R+/+ animals . Similarly, pancreatitis-associated lung injury, as characterized by intrapulmonary sequestration of neutrophils and increased pulmonary mi crovascular permeability, was reduced in NK1R-/-animals. These effects of NK1R deletion indicate that substance P, acting via NK1R, plays an important proinflammatory role in regulating the severity of acute pa ncreatitis and pancreatitis-associated lung injury.