Anti-inflammatory actions of perfluorooctanoic acid and peroxisome proliferator-activated receptors (PPAR) α and γ in experimental acute pancreatitis

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Abstract

Perfluorooctanoic acid (PFOA) and agonists of peroxisome proliferator-activated receptors (PPAR) α and γ were investigated for potential anti-inflammatory effects in cerulein-induced acute pancreatitis in rats. PFOA significantly reduced both leukocyte accumulation and prostanoid synthesis. The PPAR-α agonist clofibrate had no effect on leukocyte activation but significantly inhibited prostanoid synthesis whereas the PPAR-γ agonist rosiglitazone significantly reduced leukocyte activation but did not affect synthesis of prostaglandins in the pancreas. Neither PFOA, nor clofibrate or rosiglitazone had an effect on the formation of the inflammatory edema or elevated levels of lipase activity in the blood serum. In summary, PFOA attenuates the accumulation of activated leukocytes and reduces the synthesis of prostanoids in the pancreas during cerulein-induced acute pancreatitis. An activation of PPAR-α causes inhibition of prostanoid synthesis while activation of PPAR-γ inhibits leukocyte activation.

Introduction

Perfluorooctanoid acid (PFOA) has been shown to exert anti-inflammatory effects in carrageenan-induced skin inflammation [1]. Because agonist ligands at peroxisome proliferator-activated receptor alpha (PPAR-α) and gamma (PPAR-γ) had similar anti-inflammatory properties in this model, it was suggested that activation by PFOA of PPAR-α PPAR-γ could play a role in these anti-inflammatory effects. PPAR-α or PPAR-γ also seem to have anti-inflammatory properties in other experimental models [2], [3], [4], but their relative importance seems to depend on the model used. In experimental acute pancreatitis some data have been published for agonists of PPAR-γ [5], [6], but much less information is available for the possible effects of PPAR-α agonists. Only a recent report suggests that pancreatitis is augmented in PPAR-α knockout animals [7]. We have therefore investigated whether PFOA would have similar anti-inflammatory properties in a model of interstitial-edematous acute pancreatitis and whether such effects would be mimicked by PPAR-α and/or PPAR-γ activation.

Section snippets

Experimental procedure

Female Sprague–Dawley rats (200–250 g, Forschungsinstitut für Versuchstierzucht und -genetik, Himberg, Austria) were anesthetized with pentobarbitone sodium (40 mg/kg, i.p.). A jugular vein was cannulated for infusion of the cholecystokinin analogue cerulein (4 nmol/kg/h for 2 h); control animals received an infusion of an appropriate volume (8 ml/kg/h) of phosphate-buffered saline. PFOA (150 mg/kg), the PPAR-α agonist clofibrate (100 mg/kg) or the PPAR-γ agonist rosiglitazone (10 mg/kg) were

Inflammatory edema formation lipase activity in serum and pancreas

Four hours after the induction of acute pancreatitis by cerulein-induced exocrine hyperstimulation of the pancreas, water content of the pancreatic tissue had increased significantly by about 3–4 fold over basal values that were obtained in animals infused with phosphate-buffered saline (pbs) instead of cerulein (Table 1). Neither PFOA, nor clofibrate or rosiglitazone had any significant inhibitory effect on this edema formation. PFOA, clofibrate and rosiglitazone also had no effect on tissue

Discussion

Perfluorooctanoid acid (PFOA) is a compound that is widely used in a wide variety of industrial applications, but also has become under scrutiny because of its potential harmful effects [9]. However, PFOA also has been demonstrated to have anti-inflammatory properties. Thus, PFOA was found to be effective in reducing edema formation and thermal hyperalgesia in rat paw inflammation induced by the sulfated polysaccharide carrageenan [1]. In this model, PFOA largely attenuated the inflammatory

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