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. 2005 Oct 28;11(40):6322-9.
doi: 10.3748/wjg.v11.i40.6322.

Pioglitazone, a specific ligand of peroxisome proliferator-activated receptor-gamma, protects pancreas against acute cerulein-induced pancreatitis

Peter C Konturek  1 , Artur Dembinski, Zygmunt Warzecha, Grzegorz Burnat, Piotr Ceranowicz, Eckhart G Hahn, Marcin Dembinski, Romana Tomaszewska, Stanislaw J Konturek
Affiliations

Pioglitazone, a specific ligand of peroxisome proliferator-activated receptor-gamma, protects pancreas against acute cerulein-induced pancreatitis

Peter C Konturek et al. World J Gastroenterol. .

Abstract

Aim: To determine the effect of pioglitazone, a specific peroxisome proliferator-activated receptor-gamma (PPARgamma) ligand, on the development of acute pancreatitis (AP) and on the expression of heat shock protein 70 (HSP70) in the pancreas.

Methods: AP was induced in rats by subcutaneous infusion of cerulein for 5 h. Pancreatic blood flow was measured by laser Doppler flowmetry. Plasma lipase activity, interleukin-1beta (IL-1beta) and IL-10 were determined. Pancreatic weight and histology were evaluated and pancreatic DNA synthesis and blood flow as well as pancreatic mRNA for IL-1beta and HSP70 were assessed in rats treated with pioglitazone alone or in combination with cerulein.

Results: Pioglitazone administered (10-100 mg/kg i.g.) 30 min before cerulein, attenuated dose-dependently the pancreatic tissue damage in cerulein-induced pancreatitis (CIP) as demonstrated by the improvement of pancreatic histology, reduction in plasma lipase activity, plasma concentration of pro-inflammatory IL-1beta and its gene expression in the pancreas and attenuation of the pancreatitis-evoked fall in pancreatic blood flow. CIP increased pancreatic HSP70 mRNA and protein expression in the pancreas and this effect was enhanced by pioglitazone treatment.

Conclusion: Pioglitazone attenuates CIP and the beneficial effect of this pioglitazone is multifactorial probably due to its anti-inflammatory activities, to the suppression of IL-1beta and to the overexpression of HSP70. PPARgamma ligands could represent a new therapeutic option in the treatment of AP.

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Figures

Figure 1
Figure 1
Pancreatic weight in rats with or without CIP pretreated with saline or pioglitazone at a dose 50 mg/kg. Mean±SE of eight rats in each experimental group. Asterisk indicates a significant change as compared to the value in rats infused with saline. Cross indicates a significant change as compared to rats with CIP alone. aP<0.05 vs CIP alone.
Figure 2
Figure 2
Histological changes (edema, infiltration, and vacuolization) observed in rats with or without CIP and pretreated with saline or pioglitazone at a dose 50 mg/kg. Mean±SE of eight rats in each experimental group. Asterisk indicates a significant change as compared to the value in rats infused with saline. Cross indicates a significant change as compared to rats with CIP alone.aP<0.05 vs CIP alone.
Figure 3
Figure 3
Plasma lipase activity in rats with or without CIP and pretreated with saline or pioglitazone at a dose 50 mg/kg. Mean±SE of eight rats in each experimental group. Asterisk indicates a significant change as compared to the value in rats infused with saline. Cross indicates a significant change as compared to rats with CIP alone. aP<0.05 vs CIP alone.
Figure 4
Figure 4
Pancreatic DNA synthesis in rats with or without CIP and pretreated with saline or pioglitazone at a dose 50 mg/kg. Mean±SE of eight rats in each experimental group. Asterisk indicates a significant change as compared to the value in rats infused with saline. Cross indicates a significant change as compared to rats with CIP alone. aP<0.05 vs CIP alone.
Figure 5
Figure 5
Pancreatic blood flow in rats with or without CIP and pretreated with saline or pioglitazone at a dose 50 mg/kg. Mean±SE of eight rats in each experimental group. Asterisk indicates a significant change as compared to the value in rats infused with saline. Cross indicates a significant change as compared to rats with CIP alone.aP<0.05 vs CIP alone.
Figure 6
Figure 6
Plasma IL-1b and IL-10 levels in rats with or without CIP and pretreated with saline or pioglitazone at a dose 50 mg/kg. Mean±SE of eight rats in each experimental group. Asterisk indicates a significant change as compared to the value in rats infused with saline. Cross indicates a significant change as compared to rats with CIP alone.aP<0.05 vs CIP alone.
Figure 7
Figure 7
Expression of IL-1b mRNA and densitometric analysis of IL-1b mRNA expression (IL-1b/GAPDH ratio) in rats infused with saline without pancreatitis (control), rats with CIP and rats with CIP pretreated with pioglitazone. (A,B) Asterisk indicates a significant change as compared to the value in rats infused with saline. Cross indicates a significant change as compared to rats with CIP alone.aP<0.05 vs CIP alone.
Figure 8
Figure 8
Expression of HSP70 mRNA and densitometric analysis of HSP70 mRNA expression (HSP70/GAPDH ratio) in rats infused with saline without pancreatitis (control), rats with CIP and rats with CIP pretreated with pioglitazone. (A,B) Asterisk indicates a significant change as compared to the value in rats infused with saline. Cross indicates a significant change as compared to rats with CIP alone.aP<0.05 vs CIP alone.
Figure 9
Figure 9
Expression of HSP70 protein and densitometric analysis of HSP70 protein expression (HSP70/b-actin ratio) in rats infused with saline without pancreatitis (control), rats with CIP and rats with CIP pretreated with pioglitazone. (A,B) Asterisk indicates a significant change as compared to the value in rats infused with saline. Cross indicates a significant change as compared to rats with CIP alone.aP<0.05 vs CIP alone.
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