Función antiinflamatoria y antioxidante del ácido ursólico en la pancreatitis aguda inducida por ceruleína en ratas / Anti-inflammatory and anti-oxidant role of ursolic acid in cerulein-induced acute pancreatitis in rats

Resumen Antecedentes: El ácido ursólico se encuentra en numerosas plantas y se ha informado que tiene efectos antiproteasas, antioxidantes, antiinflamatorios, antimicrobianos, nefroprotectores, hepatoprotectores y cardioprotectores. Objetivo: Este estudio tuvo como objetivo investigar los efectos del ácido ursólico en la pancreatitis aguda inducida por ceruleína. Material y métodos: Treinta y dos ratas albinas Wistar fueron asignadas aleatoriamente a cuatro grupos iguales: grupo simulado, grupo de pancreatitis aguda, grupo de tratamiento y grupo de ácido ursólico. Resultados: Los niveles de amilasa sérica en los grupos de pancreatitis aguda y de tratamiento fueron significativamente más altos que en los otros grupos (p < 0.05). Además, los niveles séricos de IL-1β, IL-6 y TNF-α fueron significativamente más altos en el grupo de pancreatitis aguda en comparación con el grupo de tratamiento. Aunque la actividad oxidante total del tejido pancreático en ambos grupos fue similar, la capacidad antioxidante total del tejido pancreático en el grupo de tratamiento fue significativamente mayor. Conclusión: Se observó que el ácido ursólico reduce el daño al páncreas y órganos remotos en la pancreatitis aguda, al igual que el estrés oxidativo.

Abstract Background: Ursolic acid (UA) is found in many plants, and has been reported to have anti-protease, antioxidant, anti-inflammatory, antimicrobial, nephroprotective, hepatoprotective, and cardioprotective effects. Objective: The purpose of this study was to investigate the effects of ursolic acid in cerulein-induced acute pancreatitis (AP). Materials and methods: Thirty-two Wistar albino rats were randomly assigned to 4 equal groups: Sham, acute pancreatitis, treatment, and ursolic acid group. Results: Serum amylase levels in the AP and treatment groups were significantly higher than in the others (p < 0.05). In addition, serum IL-1β, IL-6, and TNF-α levels were significantly higher in the AP group in comparison with the treatment group. Although pancreatic tissue total oxidant activity in the AP and treatment groups was similar, pancreatic tissue total antioxidant capacity was significantly higher in the treatment group than in the AP group. Conclusions: Damage to the pancreas and remote organs in AP was observed to be reduced by UA. In addition, oxidative stress was observed to be decreased by the effect of UA.

Docosahexaenoic Acid Inhibits Expression of Fibrotic Mediators in Mice With Chronic Pancreatitis

BACKGROUND: Chronic pancreatitis (CP) is an irreversible progressive disease that destroys exocrine parenchyma, which are replaced by fibrous tissue. As pancreatic fibrosis is a key feature of CP, reducing fibrotic protein content in the pancreas is crucial for preventing CP. Studies suggest that NF-κB facilitates the expression of fibrotic mediators in pancreas and protein kinase C-δ (PKC-δ) regulates NF-κB activation in stimulated pancreatic acinar cells. Docosahexaenoic acid (DHA) is an omega-3 fatty acid having anti-inflammatory and anti-fibrotic effects. It has been shown to inhibit NF-κB activity in cerulein-stimulated pancreatic acinar cells which is a cellular model of CP. In the present study, we investigated if DHA inhibits expression of fibrotic mediators by reducing PKC-δ and NF-κB expression in mouse pancreatic tissues with CP.METHODS: For six weeks, mice were weekly induced for acute pancreatitis to develop CP. Furthermore, acute pancreatitis was induced by hourly intraperitoneal injections of cerulein (50 μg/kg × 7). Mice were administered DHA (10 μM) via drinking water before and after CP induction.RESULTS: Cerulein-induced pancreatic damages like decreased pancreatic weight/total body weight, leukocyte infiltration, necrosis of acinar cells, and vacuolization were found to be inhibited by DHA. Additionally, DHA inhibited cerulein-induced fibrotic mediators like alpha-smooth muscle actin and fibronectin in pancreas. DHA reduced expression of PKC-δ and NF-κB p65 in pancreatic tissues of cerulein-treated mice.CONCLUSIONS: DHA may be beneficial in preventing CP by suppressing pancreatic expression of fibrotic mediators.

The effect of quercetin on cerulein-induced acute pancreatitis / Efeito da quercetina sobre a pancreatite induzida por ceruleína

OBJECTIVE: The aim of this study was to evaluate the protective and therapeutic effects of quercetin on pancreatic injury in cerulein-induced acute pancreatitis. METHOD: Thirty-two rats were randomly divided into four groups, eight per group: (CT): untreated controls, (CER) treated with cerulein, 50 µg/kg body weight; (Q+CER) pre-treatment with quercetin, 100 mg/kg body weight, followed by cerulein, 50 µg/kg; (CER+Q) post-treatment, cerulein followed by quercetin, same doses. Cerulein was divided into four doses, given at 1-hour intervals by intraperitoneal injection. Quercetin was given either 1-hour before (in pre-treatment group) or 1-hour after (in post-treatment group) cerulein. Pancreatic malondialdehyde (MDA), carbonyl, myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), reduced and oxidized glutathione (GSH and GSSG, respectively) were measured. Histology of the pancreas was studied. RESULTS: (1) MDA, carbonyl, MPO, TNF-a and IL-6 levels were significantly higher in CER vs CT rats. (2) MDA, carbonyl, MPO and TNF-α decreased significantly in pre-treated rats vs. CER. (3) MDA, MPO, TNF-α, IL-6 were significantly lower in post-treated rats vs. CER. (4) The reduced vs. oxidized glutathione ratio (GSH/GSSG) of was significantly lower CER vs. CT rats. (5) Pre- and post-treatment with quercetin significantly increased this ratio. (6) Pancreatic histology showed that quercetin had no significant effect on the histological image of the pâncreas CONCLUSION: These results suggest that quercetin can attenuate the severity of cerulein-induced acute pancreatitis by acting as an antioxidant and anti-inflammatory agent and combating oxidative stress. Further studies are needed to clearly explain its utility on acute pancreatitis.

OBJETIVO: O objetivo deste estudo foi avaliar os efeitos protetores e terapêuticos da quercetina na lesão pancreática da pancreatite aguda induzida por ceruleína. MÉTODO: Trinta e dois ratos foram divididos aleatoriamente em quatro grupos, oito por grupo: (CT): controles não tratados (CER) tratados com ceruleína, 50 µg/kg de peso corporal; (Q+CER) pré-tratamento com quercetina, 100 mg / kg de peso corporal, seguido de ceruleína, 50 µg/kg; (CER+Q) pós-tratamento, ceruleína seguida de quercetina, mesmas doses. A ceruleína foi dividida em quatro doses, administradas a intervalos de 1 hora por injeção intraperitoneal. A quercetina foi administrada 1 hora antes (no grupo de pré-tratamento) ou 1 hora após (no pós-tratamento) a administração de ceruleína. Foram medidos o malondialdeído pancreático (MDA), carbonilo, mieloperoxidase (MPO), fator de necrose tumoral alfa (TNF-a), interleucina-6 (IL-6), glutationa reduzida e oxidada (GSH e GSSG, respetivamente). Foi estudada a histologia do pâncreas. RESULTADOS: Os níveis de MDA, carbonila, MPO, TNF-a e IL-6 foram significativamente maiores nos ratos CER vs. CT. MDA, carbonila, MPO e TNF-α diminuíram significativamente em ratos pré-tratados versus CER. MDA, MPO, TNF-α, IL-6 também foram significativamente menores em ratos pós-tratados versus CER. A proporção reduzida de glutationa oxidada (GSH/GSSG) foi significativamente menor ratos CER vs. CT; pré e pós-tratamento com quercetina aumentaram significativamente esta proporção. A histologia pancreática mostrou que a quercetina não teve efeito morfológico significativo. CONCLUSÃO: Estes resultados sugerem que a quercetina pode atenuar a gravidade da pancreatite aguda induzida por ceruleína, atuando como agente antioxidante e anti-inflamatório e combater o estresse oxidativo. Mais estudos são necessários para explicar claramente suas utilidades na pancreatite aguda.

Peroxisome Proliferator-activated Receptor-gamma Inhibits the Activation of STAT3 in Cerulein-stimulated Pancreatic Acinar Cells

Cerulein-induced pancreatitis is similar to human edematous pancreatitis, characterized by the dysregulation of digestive enzyme production, edema formation, and an infiltration of inflammatory cells into the pancreas. We previously showed that the Janus kinase 2 (JAK2)/STAT3 pathway mediates inflammatory signaling in cerulein-stimulated pancreatic acinar cells. PPAR-γ has been implicated in the regulation of inflammatory responses in several cells. In the present study, we investigated the role of PPAR-γ in cerulein-induced activation of JAK2/STAT3 in pancreatic acinar cells. Treatment with cerulein induced the activation of JAK2/STAT3 and PPAR-γ expression in AR42J cells. Cerulein-induced PPAR-γ expression was inhibited by AG490, a JAK2/STAT3 inhibitor, in AR42J cells. An immunoprecipitation analysis showed that PPAR-γ binds to STAT3 in cerulein-stimulated AR42J cells. Down-regulation of PPAR-γ by siRNA increased STAT3 phosphorylation in AR42J cells stimulated with cerulein. These results show that PPAR-γ inactivates STAT3 by directly interacting with STAT3 in cerulein-stimulated pancreatic acinar cells. Overexpression of PPAR-γ may be beneficial for preventing pancreatitis by suppressing the activation of STAT3 in pancreatic acinar cells.

The effect of PPARγ agonists in acute pancreatitis with hepatic injury / 重庆医学

Objective To observe the peroxidase body growth activated receptor γ (PPARγ) agonist rosiglitazone on acute pancreatitis in mice with hepatic injury and to investigate the mechanism of hepatic injury .Methods Seventy‐two male Kunming mice were randomly allocated into three groups(24 cases for each group):acute pancreatitis group(AP group) ,rosiglitazone group (AP‐ROS group) ,saline group(NS group) .Mice were killed at 6 ,12 and 24 h after induction of acute pancreatitis .Serum amylase , ALT and AST activities were measured .The expressions of NF‐κB and PPARγmRNA were assessed by RT‐PCR .The expressions of NF‐κB and PPARγ protein were assessed by Western blot .Results Compared with NS group ,serum amylase ,ALT and AST levels at each time point significantly increased in AP group(P< 0 .01);serum amylase ,ALT and AST levels in AP‐ROS group were significantly lower than those in AP group(P<0 .01) .Compared with NS group ,the expressions of liver PPARγ mRNA and protein in AP group were markedly lower at 6 h and 12 h(P<0 .05) ,and the expressions of PPARγmRNA and protein in AP‐ROS group were significantly higher than those in NS group and AP group(P<0 .01) .The expressions of liver NF‐κB mRNA and NF‐κB p65 protein in AP group were significantly higher than those in NS group and AP‐ROS group at all time points(P<0 .01) .Con‐clusion There are clear relationships between NF‐κB and hepatic injury in acute pancreatitis .The expressions of PPARγin injuried hepatic decreased .Rosiglitazone can increase the expressions of PPARγand prevent the expressions of NF‐κB in hepatic during the early phase of acute pancreatitis .

Influence of PI3K gamma on pancreatic acinar cells autophagy in experimental acute pancreatitis in mice / 中华胰腺病杂志

ObjectiveTo investigate the influence of phosphoinositide 3-Kinase-C2-gamma (PI3Kγ)on pancreas acinar cells autophagy in experimental acute pancreatitis in mice and explore its significance.MethodsEighteen C57BL/6 wild type (WT) and eighteen PI3Kγ knockout (KO) mice were randomly divided into control group (n =6) and acute panereatitis (AP) group (n =12),respectively.AP models were induced by intraperitoneal injection of 50 μg cerulein/kg body weight,once the other hour for seven times.The mice were sacrificed 7 hours after model induction.The pathological changes of the pancreas were observed through microscope,LC3 dots were determined by immunofluorescence,the trypsin activity was measured by fluorescence spectrophotometer,and the expression of autophagy related protein beclin1,p62 and LC3- Ⅱ were measured by Western blot.ResultsThe autophagy vacuoles counts in pancreatic tissue of WT mice and KO mice were (5.14 ±0.85),(2.25 ±0.54)/HPF,the LC3 immunofluorescence dots counts were (78.6 ±9.38),( 26.4 ± 4.21 )/HPF,the trypsin activities were ( 0.827 ± 0.126 ),( 0.358 ± 0.098 ) pmol/mg protein,the difference between the two groups was statistically significant ( P ＜ 0.05 ).The p62 protein expression was greatly decreased in WT mice compared with their KO counterpart (0.11 vs 0.92,P ＜ 0.05 ),while the expressions of LC3 Ⅱ,beclin1 were greatly increased in WT mice compared with their KO counterpart ( 1.82 vs 0.93,1.43 vs 1.05,P ＜ 0.05 ).Conclusions PI 3 Kγmay up- regulate autophagy of pancreatic acinar cells during acute pancreatitis in mice,then promote trypsinogen activation and necrosis of acinar cells.

The effect of peroxisome proliferator-activated receptor gamma ligand on signaling pathway in pancreatic acinar calls / 中华消化杂志

Objective To investigate the putative relationship between peroxisome proliferators activated receptor gamma (PPARγ) and nuclear factor (NF)-κB in cerulein-treated pancreatic aeinar AR42J cells. Methods The AR42J cells were allocated to control group, pioglitazone group (treated with 40 μmol/L of pioglitazone), pioglitazone + cerulein group (treated with 40 μmol/L of pioglitazone+ 10~(-8) mol/L of cerulein) and pioglitazone + cerulein + PPARγ antagonist (GW9662) group (treated with 40 μmol/L of pioglitazone + 5 μmol/L of GW9662 + 10~(-8) mol/L of cerulein). Activity of NF-κB and PPARγ expression were detected 30 minuts after stimulated by cerulein with or without the presence of pioglitazone. The protein expressions of NF-κB and PPARγ, antibody to IκBα phosphorylation, the differential expression between IκB kinase (IKK)β and IκBa, the IKKβ activity as well as changes of pIκBa were examined by Western blotting. The nuclear accumulation of NF-κB (p65 and p50 subunits) was determined by immunofluorescence and Western blotting. The interaction between NF-κB p65 and IκBα was observed by immunopreeitation. Results Treatment of AR42J cells with pioglitazone attenuated cerulein induced cytosolic activity of IKK protein (1.6 : 3.7)or IκBa phosphorylation (0.9 : 1.5), strengthened the integration of IκBα and NF-κB (0.8:0.3), inhibited transcription activity of p50 and p65 NF-κB dimer and nuclear accumulation (P<0.01). Adversely, the inhibitory effect of pioglitazone on NF-κB activity induced by cerulein was almost reversed by GW9662 (P<0.05). Conclusion These findings provide evidence for the involvement of PPARγ in the activity of NF-κB in cerulein treated AR42J cells.

Membrane Proteome Analysis of Cerulein-Stimulated Pancreatic Acinar Cells: Implication for Early Event of Acute Pancreatitis

BACKGROUND/AIMS: Cerulein pancreatitis is similar to human edematous pancreatitis with dysregulation of the production and secretion of digestive enzymes, edema formation, cytoplasmic vacuolization and the death of acinar cells. We hypothesized that membrane proteins may be altered as the early event during the induction of acute pancreatitis. Present study aims to determine the differentially expressed proteins in the membranes of cerulein-treated pancreatic acinar cells. METHODS: Pancreatic acinar AR42J cells were treated with 10(-8) M cerulein for 1 hour. Membrane proteins were isolated from the cells and separated by two-dimensional electrophoresis using pH gradients of 5-8. Membrane proteins were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis of the peptide digests. The differentially expressed proteins, whose expression levels were more or less than three-fold in cerulein-treated cells, were analyzed. RESULTS: Two differentially expressed proteins (mannan-binding lectin-associated serine protease-2, heat shock protein 60) were up-regulated while four proteins (protein disulfide isomerase, gamma-actin, isocitrate dehydrogenase 3, seven in absentia homolog 1A) were down-regulated by cerulein treatment in pancreatic acinar cells. These proteins are related to cell signaling, oxidative stress, and cytoskeleton arrangement. CONCLUSIONS: Oxidative stress may induce cerulein-induced cell injury and disturbances in defense mechanism in pancreatic acinar cells.

Altered Gene Expression in Cerulein-Stimulated Pancreatic Acinar Cells: Pathologic Mechanism of Acute Pancreatitis

Acute pancreatitis is a multifactorial disease associated with the premature activation of digestive enzymes. The genes expressed in pancreatic acinar cells determine the severity of the disease. The present study determined the differentially expressed genes in pancreatic acinar cells treated with cerulein as an in vitro model of acute pancreatitis. Pancreatic acinar AR42J cells were stimulated with 10(-8) M cerulein for 4 h, and genes with altered expression were identified using a cDNA microarray for 4,000 rat genes and validated by real-time PCR. These genes showed a 2.5-fold or higher increase with cerulein: lithostatin, guanylate cyclase, myosin light chain kinase 2, cathepsin C, progestin-induced protein, and pancreatic trypsin 2. Stathin 1 and ribosomal protein S13 showed a 2.5-fold or higher decreases in expression. Real-time PCR analysis showed time-dependent alterations of these genes. Using commercially available antibodies specific for guanylate cyclase, myosin light chain kinase 2, and cathepsin C, a time-dependent increase in these proteins were observed by Western blotting. Thus, disturbances in proliferation, differentiation, cytoskeleton arrangement, enzyme activity, and secretion may be underlying mechanisms of acute pancreatitis.

Cerulein Pancreatitis: Oxidative Stress, Inflammation, and Apoptosis

Cerulein pancreatitis is similar to human edematous pancreatitis, manifesting with dysregulation of digestive enzyme production and cytoplasmic vacuolization, the death of acinar cells, edema formation, and infiltration of inflammatory cells into the pancreas. Reactive oxygen species are involved in nuclear factor-kappaB activation, cytokine expression, apoptosis and pathogenesis of pancreatitis. There is recent evidence that cerulein activates NADPH oxidase, which is a major source of reactive oxygen species during inflammation and apoptosis in pancreatic acinar cells. In addition, the Janus kinase/signal transducer and activator of transcription pathway has been suggested as being involved in inflammatory signaling in the pancreas. This review discusses the involvement of oxidative stress in inflammation and apoptosis in pancreatic acinar cells stimulated with cerulein as an in vitro model of pancreatitis.

Oxidative stress is enhanced by hypothermia imposed on cerulein-induced pancreatitis in rats

BACKGROUND: Hypothermia is a frequent event in severe acute pancreatitis (AP) and its real effects on the normal pancreas have not been well demonstrated. Moreover, neither have its effects on the outcome of acute pancreatitis been fully investigated. One hypothesis is that oxidative stress may be implicated in lesions caused or treated by hypothermia. AIM OF THE STUDY: To investigate the effect of hypothermia in cerulein-induced acute pancreatitis (CIAP) in rats and the role played by oxidative stress in this process. METHODS: Male Wistar rats were divided into hypothermic and normothermic groups. Hypothermia was induced with a cold mattress and rectal temperature was kept at 30°C for one hour. Acute pancreatitis was induced with 2 doses of cerulein (20 ìg/kg) administered at a one-hour interval. Serum amylase, pancreas vascular permeability by Evan's blue method, pancreas wet-to-dry weight ratio and histopathology were analyzed in each group. RESULTS: When compared with normothermic rats, hypothermic animals, with cerulein-induced acute pancreatitis, showed higher levels of pancreatic vascular permeability (p < 0.05), pancreas wet-to-dry weight ratio (p = 0.03), and histologically verified edema (p < 0.05), but similar serum amylase levels. The hypothermic group showed a higher oxidized-reduced glutathione ratio than the normothermic group. CONCLUSION: Moderate hypothermia produced a greater inflammatory response in established acute pancreatitis induced by cerulein in rats. Moreover, this study suggests that oxidative stress may be one of the mechanisms responsible for the worse outcome in hypothermic rats with cerulein-induced acute pancreatitis.

BACKGROUND: Hipotermia é um evento freqüente em episódios de pancreatite aguda, contudo seu efeito real sobre pâncreas normal ainda não esta bem demonstrado. Além do mais, o efeito da hipotermia no decorrer da pancreatite aguda também não está completamente esclarecido. Uma das hipóteses sobre as causas das lesões causadas ou tratadas por hipotermia aventa a implicação de estresse oxidativo. OBJETIVOS: Investigar o efeito da hipotermia em ratos com pancreatite aguda induzida por ceruleína e o papel do estresse oxidativo neste processo. MÉTODOS: Ratos Wistar machos foram divididos em grupos hipotérmicos e normotérmicos. Hipotermia foi induzida com uma bolsa gelada de forma que a temperatura retal permanecesse em 30°C por uma hora. Pancreatite aguda foi induzida com duas aplicações de ceruleína (20 ìg/kg) administradas com intervalo de uma hora. A amilase sérica, a permeabilidade vascular do pâncreas, a razão peso seco/peso úmido do pâncreas, a histopatologia e os níveis de glutationa foram analisados em cada grupo. RESULTADOS: Ratos hipotérmicos, com pancreatite aguda induzida por ceruleína, apresentaram maiores níveis de permeabilidade vascular no pâncreas (p < 0.05), razão peso seco/peso úmido do pâncreas (p = 0.03), e edema histológico (p < 0.05), mas os níveis de amilase sérica permaneceram iguais aos níveis apresentados pelos ratos normotérmicos. O grupo hipotérmico apresentou maior relação glutationa oxidada/glutationa reduzida em relação ao grupo normotérmico. CONCLUSÃO: Hipotermia moderada produziu uma maior resposta inflamatória em ratos com pancreatite aguda estabelecida, induzida por ceruleína, sugerindo que este efeito pode estar ligado a um maior índice de estresse oxidativo em ratos com pancreatite aguda.

The effect of nafamostat mesilate on the prevention of cerulein-induced acute pancreatitis / 대한내과학회지

BACKGROUND: Many protease inhibitors show a protective effect for acute pancreatitis as seen in animal models. In previous studies, the protease inhibitors were administered before induction of pancreatitis, and there are few published reports examining effects when these agents were administered after induction of pancreatitis. The timing of drug administration may provide an explanation for the ineffectiveness of protease inhibitors for the treatment of patients with acute pancreatitis. Herein, we assessed the protective effect of nafamostat mesilate (NM), a potent protease inhibitor, in a mouse model of cerulean-induced pancreatitis and compared the results of administering the drug before and after the induction of pancreatitis. METHODS: Cerulein, a cholecystokinin analogue, was injected into mice intraperitoneally to induce pancreatitis. The mice received intravenous NM administration before and after the induction of pancreatitis. The serum concentration of amylase and lipase was measured, histological changes were measured, and the tissue expression of myeloperoxidase was measured to assess the degree of inflammation. Expression of p38 MAPK (mitogen-activated protein kinase), phospho-p38 MAPK, and IL-6 (interleukin-6) in tissue was evaluated. RESULTS: Acute pancreatitis was induced successfully by intraperitoneal injection of cerulein. Acute pancreatitis could be prevented when NM was administered before the induction of pancreatits. However, the effect was not guaranteed when given after the induction of pancreatitis. For a group of mice with induced pancreatitis, tissue expression of phospho-p38 MAPK was prominent and there was no marked difference in the expression of IL-6 between groups with or without induced pancreatitits. CONCLUSIONS: Although the efficacy of NM for treatment of acute pancreatitis is doubtful, pretreatment with NM for an expected condition like endoscopic retrograde cholangiopancreatography (ERCP), might be helpful for the prevention of pancreatitis.

Study on lipopolysaccharide tolerance and its mechanism in experimental acute pancreatitis mice / 中华消化杂志

Objective To investigate lipopolysaccharide (LPS) tolerance and its possible mechanism in experimental acute pancreatitis(AP) mice. Methods Two hundreds and ten C56BL/6J mice were randomized into normal saline(NS)+LPS group( n =105)and AP +LPS group( n =105). Both groups were subdivided into seven groups according to different dose of LPS. AP model was induced by intra- abdominal administration of cerulein (50 ?g/kg) for seven times at 1 hour interval. LPS was given 6 hours after first cerulein injection . Cerulein was replaced by NS in NS+LPS group. Ten mice in each sub- group were randomly selected to investigate mortality rate for 7 days. Another 5 mice were killed at 12 hours after the first cerulein injection. Liver, lung, kidney, pancreas and serum were reserved to evaluate pathological changes and measurement of amylase (AMS) and lactate dehydrogenase (LDH) levels. Gene expression profiles of leucocyte in NS+LPS(15 mg/kg)subgroup and AP+LPS(15 mg/kg)subgroup were studied with oligonucleotide microarrays of 12 479 full length mouse genes respectively for three times to screen the different genes between two groups. Results Mortality rates in both groups were increased, and correlated with the dosage of LPS. Mortality rate in AP+LPS group was significantly lower than that in NS+LPS group with the same LPS dose( P

Effects of small molecular antioxidants on cerulein-induced acute pancreatitis in rat

It has been suggested that oxygen free radicals are involved in the initiation process of acute pancreatitis, although its pathogenesis is not clear. This study evaluates the roles of oxygen radicals and the effects of small molecular antioxidants (rebamipide, N-acetyl-cysteine, allopurinol, beta-carotene) on the development of cerulein-induced acute pancreatitis. Acute edematous pancreatitis was induced by the intravenous infusion of cerulein at supramaximal dose of 10 mug/kg/hour for 3.5 hours. The effects of antioxidants, rebamipide (100 mg/kg, i.p.), N-acetyl-cysteine (200 mg/kg, i.v.), allopurinol (20 mg/kg/hour), beta-carotene (50 mg/kg, i.p.), were examined. Cerulein administration resulted in a significant increase in serum amylase activity and pancreatic malondialdehyde (MDA), but not glutathione peroxidase (GSHpx). The glutathione (GSH) content in pancreatic tissue decreased dramatically. Pretreatment of N-acetyl-cysteine significantly decreased the cerulein-induced hyperamylasemia and maintained GSH content in pancreas, but MDA was slightly decreased. In addition, N-acetyl-cysteine ameliorated histological damage. Allopurinol and beta-carotene attenuated cerulein-induced hyperamylasemia, but histologically there was no difference from control. These results indicate that oxygen free radicals play an important role in the initiation of experimental acute pancreatitis. N-acetyl-cysteine is an effective antioxidant that ameliorates the cerulein-induced acute pancreatitis, and the possible therapeutic application of antioxidants against acute pancreatitis needs a further evaluation.