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

被引:80
作者
Grady, EF
Yoshimi, SK
Maa, J
Valeroso, D
Vartanian, RK
Rahim, S
Kim, EH
Gerard, C
Gerard, N
Bunnett, NW
Kirkwood, KS
机构
[1] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA
[3] Associated Pathologists, Las Vegas, NV 89119 USA
[4] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA
[5] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA
关键词
neurogenic inflammation; tachykinin; cerulein; sensory nerves;
D O I
10.1038/sj.bjp.0703343
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 neurokinin-1 receptor (NK1-R) on endothelial cells and induces plasma extravasation, oedema, and neutrophil infiltration, a process termed neurogenic inflammation. We sought to determine the importance of neurogenic mechanisms in acute pancreatitis. 2 Pancreatic plasma extravasation was measured using the intravascular tracers Evans blue and Monastral blue after administration of specific NK1-R agonists/antagonists in rats and NK1-R(+/ +)/(-/-) mice. The effects of NK1-R genetic deletion/antagonism on pancreatic plasma extravasation, amylase, myeloperoxidase (MPO), and histology in cerulein-induced pancreatitis were characterized. 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 by the NK1-R antagonist CP 96,345. Selective agonists of the NK-3 or NK-3 receptors had no effect. 4 In rats, cerulein stimulated pancreatic plasma extravasation and serum amylase. 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 extravasation 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.
引用
收藏
页码:505 / 512
页数:8
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