Effect of CP-96,345 on the expression of adhesion molecules in acute pancreatitis in mice.
We investigated the effect of a specific neurokinin-1 receptor (NK1R) antagonist, CP-96,345, on the regulation of the expression of adhesion molecules ICAM-1, VCAM-1, E-selectin, and P-selectin as well as leukocyte recruitment during acute pancreatitis (AP). AP was induced in male Balb/C mice by 10 consecutive hourly intraperitoneal injections of caerulein. In the treatment groups, CP-96,345 was administered at 2.5 mg/kg ip either 30 min before or 1 h after the first caerulein injection. Animals were killed, and the lungs and pancreas were isolated for RNA extraction and RT-PCR or for immunohistochemical staining. mRNA expression of the four adhesion molecules was upregulated in the pancreas during AP. Treatment with CP-96,345 effectively reduced the mRNA expression of P-selectin and E-selectin but not ICAM-1 and VCAM-1. In the lung, ICAM-1, E-selectin, and P-selectin mRNA expression increased during AP. Antagonist treatment suppressed this elevation. Similar expression patterns were seen in the immunohistochemical stainings. Intravital microscopy of the pancreatic microcirculation revealed the effect of CP-96,345 on leukocyte recruitment. The present study provides important information on the relationship between NK1R activation and the regulation of adhesion molecules. Also, this study points to the differential regulation of inflammation in the pancreas and lung with AP.
Lau
Hon Yen
HY
Dept. of Pharmacology, Yong Loo Lin School of Medicine, National Univ. of Singapore, Bldg. MD2, 18 Medical Dr., Singapore 117597.
Bhatia
Madhav
M
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002108:Ceruletide; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D008168:Lung / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D064729:Neurokinin-1 Receptor Antagonists; D010179:Pancreas / Q000503:physiopathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D013373:Substance P / Q000037:antagonists & inhibitors*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
D001713:Biphenyl Compounds; D064729:Neurokinin-1 Receptor Antagonists; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D013373:Substance P; D002108:Ceruletide; D009195:Peroxidase; D000681:Amylases; C066892:CP 96345