Background: Pancreatitis-associated ascitic fluid (PAAF) plays a critical role in the pathogenesis of acute pancreatitis. Taking into consideration that damaged pancreas exudes high concentrations of lipolytic enzymes in the peritoneal cavity, large amounts of lipid metabolism derived products could occur in PAAF. In this study, we have examined the involvement of the lipid fraction of PAAF generated in the early stages of experimental acute pancreatitis.
Methods: Pancreatitis was induced in rats by intraductal administration of 5% sodium taurocholate. After 3 h, PAAF was collected and its lipid fraction was obtained. Lipid composition and levels of lipid peroxidation were measured. Toxicity was evaluated by measuring the effects of the PAAF lipid fraction on cell viability of hepatic and macrophage cell lines. In vivo effects on the liver were also evaluated. Effects on the inflammatory response were determined by measuring the levels of nuclear factor kappa B (NFκB) activation, the effect on the inhibitory activity of 15-deoxy-PGJ2 and the possible interference on PPARγ activation.
Results: High concentrations of oxidised free fatty acids were detected in PAAF. Besides the direct cell toxicity, the PAAF-derived lipid extract interfered with the anti-inflammatory pathway mediated by PPARγ. Addition of this lipid extract to macrophage cell cultures had no direct effect on the activation of NFκB, but abolished the inhibitory activity of endogenous PPARγ agonists such as 15-deoxy-PGJ2.
Conclusions: Oxidised free fatty acids present in PAAF interfere with the endogenous regulatory mechanism of the inflammatory response, thus promoting an exacerbation of macrophage activation in acute pancreatitis.
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Competing interests: None.
Funding: This work was supported by the projects SAF2006-08449, CSIC 2006-2-0I-013 and FIS PI050599. Ciberhd is funded by the Instituto de Salud Carlos III.
Ethics approval: This study conformed to European Community Directive 86/609/EEC for the use of experimental animals and was approved by the Institutional Committee of Animal Care and Research.