Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute pancreatitis induced by cerulein

Byline: Salvatore Cuzzocrea (1), Barbara Pisano (2), Laura Dugo (1), Angela Ianaro (2), Domenico Britti (3), Nimesh S. A. Patel (4), Rosanna Di Paola (1), Tiziana Genovese (1), Massimo Di Rosa (2), Achille P. Caputi (1), Christoph Thiemermann (3) Keywords: PPAR- ; Pancreatitis; Adhesion molecules; Inflammation; Neutrophil infiltration Abstract: Objective In the present study, we investigated the effects of rosiglitazone (10 mg/kg, i.p.), a PPAR-I3 agonist, on the development of acute pancreatitis. Design Intraperitoneal injection of cerulein in mice induced an acute pancreatitis characterized by edema, neutrophil infiltration elevated serum levels of amylase and lipase. This experimental model was performed to test the anti-inflammatory activity of rosiglitazone. Setting University research laboratory. Interventions Male CD mice (20--22 g) were allocated into four groups (n=10 for each group): (a) Cerulein+vehicle group. Mice were treated hourly (x5) with cerulein (50 ug/kg, in saline solution, i.p.) (b) Rosiglitazone group (same as the Cerulein+vehicle group but were administered rosiglitazone, 10 mg/kg bolus, 30 min prior to cerulein) (c) Sham+saline group. Mice were treated with saline instead of cerulein (d) Sham+Rosiglitazone. Identical to Rosiglitazone group except that the saline was administered instead of cerulein. Mice were killed at 6 h after the induction of pancreatitis. Blood samples, pancreas, and lungs were collected. Measurements and results Infiltration of pancreatic and lung tissue with neutrophils was associated with enhanced lipid peroxidation. Immunohistochemical examination demonstrated a marked increase in immunoreactivity for nitrotyrosine and for ICAM-1 in the pancreas of cerulein-treated mice. In contrast, the degree of (a) pancreatic inflammation and tissue injury, (b) upregulation/formation of ICAM-1 and nitrotyrosine, and (c) neutrophils infiltration was markedly reduced in pancreatic tissue obtained from rosiglitazone-treated mice. Conclusion These findings support the view that rosiglitazone and other potent PPAR-I3 agonists may be useful in the therapy of acute pancreatitis. Author Affiliation: (1) Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, 98123, Messina, Italy (2) Department of Experimental Pharmacology, Universita 'Federico II', Napoli, Italy (3) Department of Clinical Veterinary Science, University of Teramo, Teramo, Italy (4) The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London, UK Article History: Registration Date: 09/01/2004 Received Date: 01/10/2003 Accepted Date: 06/01/2004 Online Date: 24/02/2004