The effect of CP96,345 on the expression of tachykinins and neurokinin receptors in acute pancreatitis.
Acute pancreatitis (AP) is a life-threatening condition that involves an acute inflammatory process in the pancreas. The involvement of tachykinins and neurokinin receptors in acute pancreatitis has been described only recently, despite their long-established role in inflammatory conditions. Among these, substance P (SP) is believed to play a central role in exacerbating the inflammatory process by acting through neurokinin-1 receptor (NK1R). Treatment with the NK1R antagonist, CP96,345, results in protection against caerulein-induced acute pancreatitis in mice. However, the mechanism by which NK1R and SP worsen the condition is still unclear. In the present study, we have investigated the effect of NK1R blockage on the expression of preprotachykinin genes and neurokinin receptors in acute pancreatitis. In the pancreas, CP96,345 treatment resulted in suppression of the elevation of SP concentration, preprotachykinin-A gene (PPT-A) mRNA expression, and NK1R mRNA and protein expression. In the lungs, the antagonist was found to suppress the increase in SP concentration, PPT-A mRNA expression and preprotachykinin-C gene (PPT-C) mRNA expression. However, the antagonist treatment further promoted the accumulation of pulmonary NK1R mRNA and protein expression. Neurokinin-2 receptor (NK2R) mRNA expression was not detected in normal pancreas. However, up-regulated expression of the mRNA for this receptor was observed during acute pancreatitis and treatment with CP96,345 further increased this expression. Pulmonary NK2R mRNA expression was found to be reduced during acute pancreatitis and CP96,345 treatment normalized this reduction. Neurokinin-3 receptor (NK3R) mRNA expression was absent in both pancreas and lung. These data have provided valuable information regarding the regulation of tachykinins and neurokinin receptors during acute pancreatitis.
Lau
Hon Yen
HY
Department of Pharmacology, National University of Singapore, Singapore.
Bhatia
Madhav
M
D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D008168:Lung / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D010179:Pancreas / Q000737:chemistry; D010195:Pancreatitis / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D018040:Receptors, Neurokinin-1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D018041:Receptors, Neurokinin-2 / Q000235:genetics; D018042:Receptors, Neurokinin-3 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013373:Substance P / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D015320:Tachykinins / Q000235:genetics / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D011498:Protein Precursors; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D013373:Substance P; D015320:Tachykinins; C066892:CP 96345; C423233:Tac4 protein, mouse