S Hisada1, K Shimizu, K Shiratori, M Kobayashi. 1. Department of Gastroenterology and Pathology, Tokyo Women's Medical University, School of Medicine, Japan.
Abstract
PURPOSE: Thiazolidinedione derivatives (TZDs) are known to be ligands of peroxisome proliferator-activated receptor gamma (PPARgamma). In this study, we investigated the effect of a TZD, troglitazone, on inflammation and fibrogenesis in the pancreas of an experimental model of chronic pancreatitis. MATERIAL AND METHODS: Male WBN/Kob rats with spontaneous chronic pancreatitis were fed rat chow containing 0.2% troglitazone from 1 to 4 months of age. Immunohistochemical studies of rat pancreas were carried out with monoclonal mouse antibody against human alpha-smooth muscle actin (alpha-SMA) or rabbit polyclonal antibody against collagen type I, collagen type III, or fibronectin. Cytokine production was measured by enzyme-linked immunosorbent assay. The inhibitory action of troglitazone on nuclear factor-kappaB (NF-kappaB) binding activity in activated macrophages was also investigated. RESULTS: Long-term administration of troglitazone reduced inflammatory cell infiltration and fibrosis in the pancreas of WBN/Kob rats, and expression of alpha-SMA, procollagen I, III, and fibronectin was significantly reduced by troglitazone. The increase in TNF-alpha production by activated macrophages was significantly decreased by troglitazone. Peritoneal macrophages isolated from WBN/Kob rats produced a large amount of TNF-alpha, whereas those from troglitazone-treated WBN/Kob rats produced only a marginal amount of TNF-alpha. Lipopolysaccharide-induced NF-kappaB binding activity in peritoneal macrophages was also significantly reduced by troglitazone. CONCLUSIONS: Troglitazone prevented the progression of chronic pancreatitis via inhibition of ECM synthesis and proinflammatory cytokine production mediated by the inhibition of NF-kappaB activity.
PURPOSE:Thiazolidinedione derivatives (TZDs) are known to be ligands of peroxisome proliferator-activated receptor gamma (PPARgamma). In this study, we investigated the effect of a TZD, troglitazone, on inflammation and fibrogenesis in the pancreas of an experimental model of chronic pancreatitis. MATERIAL AND METHODS: Male WBN/Kob rats with spontaneous chronic pancreatitis were fed rat chow containing 0.2% troglitazone from 1 to 4 months of age. Immunohistochemical studies of rat pancreas were carried out with monoclonal mouse antibody against human alpha-smooth muscle actin (alpha-SMA) or rabbit polyclonal antibody against collagen type I, collagen type III, or fibronectin. Cytokine production was measured by enzyme-linked immunosorbent assay. The inhibitory action of troglitazone on nuclear factor-kappaB (NF-kappaB) binding activity in activated macrophages was also investigated. RESULTS: Long-term administration of troglitazone reduced inflammatory cell infiltration and fibrosis in the pancreas of WBN/Kob rats, and expression of alpha-SMA, procollagen I, III, and fibronectin was significantly reduced by troglitazone. The increase in TNF-alpha production by activated macrophages was significantly decreased by troglitazone. Peritoneal macrophages isolated from WBN/Kob rats produced a large amount of TNF-alpha, whereas those from troglitazone-treated WBN/Kob rats produced only a marginal amount of TNF-alpha. Lipopolysaccharide-induced NF-kappaB binding activity in peritoneal macrophages was also significantly reduced by troglitazone. CONCLUSIONS:Troglitazone prevented the progression of chronic pancreatitis via inhibition of ECM synthesis and proinflammatory cytokine production mediated by the inhibition of NF-kappaB activity.