l-663536 and Pancreatitis

The peroxisome proliferator-activated receptor-α (PPAR-α) has attracted considerable attention for its anti-inflammatory properties; however, Toll-like receptor (TLR) pathways have an essential proinflammatory role in acute pancreatitis (AP). This study aimed to evaluate the attenuation of inflammation by PPAR-α and to investigate the interaction between PPAR-α and TLR pathways in AP.. Acute pancreatitis was induced in rats by administration of cerulein. The PPAR-α agonist WY14643 and/or antagonist MK886 was administered. The severity of AP was determined by measuring serum amylase, lipase, Ca(2+), pathological changes, myeloperoxidase activity, serum levels of interleukin (IL)-6, and intercellular adhesion molecule-1 (ICAM-1). The TLR2 and TLR4 messenger RNA (mRNA) and proteins were determined by real-time reverse transcriptase polymerase chain reaction and Western blotting, respectively. The mRNA expressions of target molecules of TLR pathways, including IL-6, IL-10, ICAM-1, and tumor necrosis factor α were also measured.. Treatment with WY14643 significantly decreased amylase, lipase, myeloperoxidase activity, pathological scores, IL-6, and ICAM-1 levels. The TLR2 and TLR4 mRNA and proteins were markedly decreased after treatment with WY14643, along with IL-6, ICAM-1, and tumor necrosis factor α mRNA levels. However, these effects were completely reversed by the coadministration of MK886.. Activation of PPAR-α played a protective role in AP, partially mediated by modulation of TLR pathways.

Topics: Amylases; Animals; Anti-Inflammatory Agents; Biomarkers; Blotting, Western; Calcium; Ceruletide; Cytokines; Disease Models, Animal; Gene Expression Regulation; Indoles; Intercellular Adhesion Molecule-1; Lipase; Male; Neutrophil Infiltration; Pancreas; Pancreatitis; Peroxidase; PPAR alpha; Pyrimidines; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Time Factors; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptor 9; Toll-Like Receptors

We tested the hypothesis that leukotriene B4 (LTB4) mediates pancreatic inflammation in rats via activation of the transient receptor potential vanilloid 1 (TRPV1).. Leukotriene B4 or a vehicle was administered to adult rats via celiac axis injection after pretreatment with the TRPV1 antagonist, capsazepine, or vehicle, and the severity of subsequent pancreatitis was assessed by measuring pancreatic edema, myeloperoxidase (MPO) activity, and histological grading. In a second experiment, acute pancreatitis was induced by common pancreaticobiliary duct ligation. Six hours after surgery, pancreatic tissue levels of LTB4 were determined by enzyme-linked immunosorbent assay. Also, the effects of inhibition of LTB4 biosynthesis by pretreatment with the 5-lipoxygenase-activating peptide inhibitor, MK-886, were determined.. Celiac axis administration of LTB4 significantly increased pancreatic edema and MPO activity, and produced histological evidence of pancreatic edema, neutrophil infiltration, and necrosis. Capsazepine pretreatment significantly reduced all inflammatory parameters in LTB4-induced pancreatitis. Pancreatic tissue levels of LTB4 were significantly elevated in rats that underwent common pancreaticobiliary duct ligation compared with control rats. MK-886 pretreatment significantly inhibited pancreatic edema, histological damage, and pancreatic MPO concentrations.. Common pancreaticobiliary duct obstruction causes an increase in pancreatic LTB4 concentrations that in turn mediates activation of TRPV1 resulting in acute pancreatitis.

Topics: Animals; Capsaicin; Cholestasis; Disease Models, Animal; Indoles; Inflammation Mediators; Leukotriene B4; Ligation; Lipoxygenase Inhibitors; Male; Models, Biological; Pancreatitis; Peroxidase; Rats; Rats, Sprague-Dawley; TRPV Cation Channels

In the present investigation we studied the concerted role of superoxide anion, platelet activating factor (PAF) and leukotriene B4 (LTB4) in the mechanism that results in polymorphonuclear leucocyte accumulation induced by oxygen free radicals in rat pancreas. This was done by comparing the effects of a PAF antagonist (BN-52021), a LTB4 inhibitor (MK-886) and superoxide dismutase (SOD) in a experimental rat model of inflammation elicited by the oxygen free radicals induced via infusion of xanthine/xanthine oxidase. Also, the effect of independent LTB4 infusion has been studied. The results show that increases in polymorphonuclear cell infiltration (evaluated by tissue histology), myeloperoxidase and LTB4 levels induced in pancreas by infusion of xanthine/xanthine oxidase were abolished by the administration of either the PAF antagonist, the LTB4 inhibitor, or SOD. The fact that BN-52021 could prevent neutrophil recruitment and LTB4 synthesis suggests that PAF is a necessary step for subsequent LTB4 synthesis and polymorphonuclear leucocyte accumulation.

Topics: Animals; Diterpenes; Free Radicals; Ginkgolides; Indoles; Lactones; Leukotriene B4; Lipase; Male; Neutrophils; Pancreas; Pancreatitis; Peroxidase; Platelet Activating Factor; Rats; Rats, Wistar; Superoxide Dismutase; Superoxides; Xanthine; Xanthine Oxidase; Xanthines