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(American Journal of Pathology. 2005;166:721-728.)
© 2005 American Society for Investigative Pathology

Therapeutic Effects of Troglitazone in Experimental Chronic Pancreatitis in Mice

David J. van Westerloo*{dagger}, Sandrine Florquin{ddagger}, Anita M. de Boer{ddagger}, Joost Daalhuisen*, Alex F. de Vos*, Marco J. Bruno{dagger} and Tom van der Poll*§

From the Laboratory of Experimental Internal Medicine* and the Departments of Gastroenterology and Hepatology,{dagger} Pathology,{ddagger} and Infectious Diseases, Tropical Medicine, and AIDS,§ Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Peroxisome proliferator-activated receptor (PPAR)-{gamma} controls growth, differentiation, and inflammation. PPAR-{gamma} agonists exert anti-inflammatory effects in vitro and inhibit the activation of pancreas stellate cells, implicated in the formation and progression of fibrosis. We determined the influence of troglitazone, a ligand for PPAR-{gamma}, on pancreatic damage and fibrosis in experimental chronic pancreatitis. Mice received six hourly intraperitoneal injections with 50 µg/kg of cerulein or saline, three times a week for 6 weeks. One week after the last injection all mice were sacrificed. Untreated mice were compared with mice treated with troglitazone either during weeks 1 to 6 or weeks 4 to 6. All mice that received cerulein injections displayed histopathological signs of chronic pancreatitis at week 7. Troglitazone treatment improved all markers for severity of pancreatitis. Moreover, early and postponed troglitazone treatments were equally effective in diminishing intrapancreatic fibrosis as quantified by Sirius red staining, hydroxyproline content, and laminin staining as well as the increased number of pancreatic stellate cells and pancreas levels of transforming growth factor-ß. Thus, troglitazone attenuated pancreatic damage and inflammation in experimental chronic pancreatitis and remained beneficial in a therapeutic setting when given after initial damage had been established.




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