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 important 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 and pancreatic acinar cell expression of NK1R are both increased during secretagogue-induced experimental pancreatitis. To evaluate the role of substance P, pancreatitis was induced in mice that genetically lack NK1R by administration of 12 hourly injections of a supramaximally stimulating dose of the secretagogue caerulein. During pancreatitis, the magnitude of hyperamylasemia, hyperlipasemia, neutrophil sequestration in the pancreas, and pancreatic acinar cell necrosis were significantly 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 microvascular 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 pancreatitis and pancreatitis-associated lung injury.
Bhatia
M
M
Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Saluja
A K
AK
Hofbauer
B
B
Frossard
J L
JL
Lee
H S
HS
Castagliuolo
I
I
Wang
C C
CC
Gerard
N
N
Pothoulakis
C
C
Steer
M L
ML
D000208:Acute Disease; D000681:Amylases / Q000378:metabolism; D000818:Animals; D002108:Ceruletide; D017353:Gene Deletion; D008168:Lung / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000473:pathology*; D010195:Pancreatitis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D018040:Receptors, Neurokinin-1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives / Q000502:physiology*
D018040:Receptors, Neurokinin-1; D013373:Substance P; D002108:Ceruletide; D000681:Amylases