Substance P mediates inflammatory oedema in acute pancreatitis via activation of the neurokinin-1 receptor in rats and mice

1 Pancreatic oedema occurs early in the development of acute pancreatitis, and the overall extent of fluid loss correlates with disease severity. The tachykinin substance P (SP) is released from sensory nerves, binds to the n eurokinin-1 receptor (NK1-R) on endothelial cells and induces plasma extrav asation, oedema, and neutrophil infiltration, a process termed neurogenic i nflammation. We sought to determine the importance of neurogenic mechanisms in acute pancreatitis. 2 Pancreatic plasma extravasation was measured using the intravascular trac ers Evans blue and Monastral blue after administration of specific NK1-R ag onists/antagonists in rats and NK1-R(+/ +)/(-/-) mice. The effects of NK1-R genetic deletion/antagonism on pancreatic plasma extravasation, amylase, m yeloperoxidase (MPO), and histology in cerulein-induced pancreatitis were c haracterized. 3 In rats, both SP and the NK1-R selective agonist [Sar(9) Met(O-2)(11)]SP stimulated pancreatic plasma extravasation, and this response was blocked b y the NK1-R antagonist CP 96,345. Selective agonists of the NK-3 or NK-3 re ceptors had no effect. 4 In rats, cerulein stimulated pancreatic plasma extravasation and serum am ylase. These responses were blocked by the NK1-R antagonist CP 96,345. 5 In wildtype mice, SP induced plasma extravasation while SP had no effect in NK1-R knockout mice. 6 In NK1-R knockout mice, the effects of cerulein on pancreatic plasma extr avasation and hyperamylasemia were reduced by 60%, and pancreatic MPO by 75 %, as compared to wildtype animals. 7 Neurogenic mechanisms of inflammation are important in the development of inflammatory oedema in acute interstitial pancreatitis.