The 3-Hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitor, Lovastatin (Statin) Ameliorates CCK-Induced Acute Pancreatitis in Rats

Abstract

Acute pancreatitis (AP) is a clinical entity that is believed to have intracellular activation of digestive enzymes and autodigestion of the pancreas as its central pathophysiologic cause. The noninfectious destruction of pancreatic parenchyma quickly induces an inflammatory reaction at the site of injury. Histologically, AP is characterized by interstitial edema, vacuolization, inflammation and acinar cell necrosis. The diagnosis of AP is based on pancreatic edema index (pancreas weight/body weight) and pancreatic serum enzymes (pancreatic amylase, lipase, immunoreactive trypsin or elastase. 1,2)The induction of the heat shock response enhances the ability of the cells to overcome the effects of the stress.3) The heat shock proteins (HSPs) are involved in the synthesis, degradation, folding, transport, and translocation of proteins. 4,5) HSPs have been classified into six families according to their molecular mass. It is well known that the increased expression of HSPs have protective effects against caerulein-induced pancreatitis in rats or against choline-deficient ethionine-supplemented diet pancreatitis model. [6][7][8] Others reported that the pre-induction of HSP expression has a protective effect against caerulein-induced pancreatitis in mice. Many diseases result in increased levels of HSPs. But caerulein or CCK-induced pancreatitis reduces the levels of pancreatic HSPs. 9,10) Cytokines are important immunoregulatory mediators. Their contribution to the pathogenesis of acute and chronic gastroenterological disorders is obvious. Increased expression of interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF)-a can be detected in inflammatory bowel disease. Pro-inflammatory cytokines such as IL-1, TNF-a, and IL-6 are elevated during AP and are considered to be involved in the pathogenesis of pancreatitis-associated multiple organ dysfunction.11) Elevated serum levels of these cytokines have been demonstrated clinically as well as experimentally in different animal models of AP. 12)Among the neurohormonal regulators, Cholecystokinin (CCK) is a well known gastrointestinal hormone and neural agonist to induce the release of pancreatic digestive enzymes 13) . At supramaximal doses (doses greater than those that cause maximal secretion of digestive enzymes by the pancreatic acinar cell), CCK is able to cause pancreatic responses. 14,15) Statins, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are the most potent lipidlowering agents currently available, and are being prescribed in the treatment of hyperlipidemia. 16,17) Statins are also effective for the reduction of vascular inflammation. Thus, we set out to investigate the effects of statin as anti-inflammatory agent on AP. MATERIALS AND METHODSReagents Avidin-peroxidase and 2Ј-AZINO-bis (3-ethylbenzithiazoline-6-sulfonic acid) tablets substrate and CCK-8 were purchased from Sigma (St. Louis, MO, U.S.A.). Anti-HSP60 antibodies were purchased from Stressgen (British Columbia, Canada). Anti-rat IL-6, TNF-a and IL-1b ant...

Taurine Attenuates Liver Injury by Downregulating Phosphorylated p38 MAPK of Kupffer Cells in Rats with Severe Acute Pancreatitis

“…There is a therapeutic window between onset of symptoms and the development of distant organ damage in acute pancreatitis, allowing the employment of therapeutic and preventive options that might alter the natural history of the disease [41]. There was a dose-dependent effect of taurine in the treatment of acute pancreatitis, and the taurine pretreatment time point is from 10 min to 24 h to reduce experimental liver injury [15,42,43].…”

Statins and their role in acute pancreatitis: Case report and literature review

“…In addition to the above theoretical benefits, Choi et al [33] have demonstrated an increase in Heat Shock Protein (HSP) 60 (HSPs are responsible for maintaining cellular homeostasis and help cells survive stress conditions by repairing damaged proteins)and decrease in the release of inflammatory mediators (e.g., IL-1beta, TNF-alpha and IL-6) when statins were used in rats with cholecystokininoctapeptide (CCK)-induced pancreatitis. Subsequent animal studies have also demonstrated benefit of statin therapy in acute via reduction of IL-10 levels and myeloperoxidase activity [28] .…”

Statin Use in Patients With Acute Pancreatitis and Symptomatic Gallstone Disease

“…18,23 In animal models, statins have decreased the inflammatory mediators released during AP (interleukin [IL] 1A, IL-6, and tumor necrosis factor >). 24 The antagonist of IL-1 or anti-TNF has reduced severity and improved survival in AP in animal studies. 25 Our study indicated that long-term statin therapy did not modify or improve the outcome of AP measured by some clinical parameters (decreased need of emergency surgery, hospital stay, intensive care treatment, or mortality).…”