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Liu W, Du JJ, Li ZH, Zhang XY, Zuo HD. Liver injury associated with acute pancreatitis: The current status of clinical evaluation and involved mechanisms. World J Clin Cases 2021; 9:10418-10429. [PMID: 35004974 PMCID: PMC8686151 DOI: 10.12998/wjcc.v9.i34.10418] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/16/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is a very common acute disease, and the mortality rate of severe AP (SAP) is between 15% and 35%. The main causes of death are multiple organ dysfunction syndrome and infections. The mortality rate of patients with SAP related to liver failure is as high as 83%, and approximately 5% of the SAP patients have fulminant liver failure. Liver function is closely related to the progression and prognosis of AP. In this review, we aim to elaborate on the clinical manifestations and mechanism of liver injury in patients with AP.
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Affiliation(s)
- Wei Liu
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Juan-Juan Du
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Zeng-Hui Li
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xin-Yu Zhang
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Hou-Dong Zuo
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
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Abdelmageed ME, Nader MA, Zaghloul MS. Targeting HMGB1/TLR4/NF-κB signaling pathway by protocatechuic acid protects against l-arginine induced acute pancreatitis and multiple organs injury in rats. Eur J Pharmacol 2021; 906:174279. [PMID: 34197778 DOI: 10.1016/j.ejphar.2021.174279] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 12/16/2022]
Abstract
Acute pancreatitis (AP) is a common pancreatic inflammation associated with substantial morbidity and mortality. AP may be mild or severe which can spread systemically causing multiple organs failure (MOF) and even death. In the current study, protocatechuic acid (PCA), a natural phenolic acid, was investigated for its possible protective potential against L-arginine induced AP and multiple organs injury (MOI) in rats. AP was induced by L-arginine (500 mg/100 g, ip). Two dose levels of PCA were tested (50 and 100 mg/kg, oral, 10 days before L-arginine injection). PCA successfully protected against L-arginine induced AP and MOI that was manifested by normalizing pancreatic, hepatic, pulmonary, and renal tissue architecture and restoring the normal values of pancreatic enzymes (amylase and lipase), serum total protein, liver enzymes (alanine transaminase (ALT) and aspartate transaminase (AST)) and kidney function biomarkers (blood urea nitrogen (BUN) and serum creatinine (Cr)) that were significantly elevated upon L-arginine administration. Additionally, PCA restored balanced oxidant/antioxidants status that was disrupted by L-arginine and normalized pancreatic levels of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) content. Moreover, PCA significantly decreased L-arginine induced elevation in pancreatic high motility group box protein 1 (HMGB1), toll like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF-κB), tumor necrosis factor- α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) expression. PCA significantly ameliorated L-arginine-induced AP and MOI through its anti-inflammatory and antioxidant effects. HMGB1/TLR4/NF-κB was the major pathway involved in the observed protective potential.
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Affiliation(s)
- Marwa E Abdelmageed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Manar A Nader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Marwa S Zaghloul
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
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El Morsy EM, Ahmed MA. Carvedilol attenuates l-arginine induced acute pancreatitis in rats through modulation of oxidative stress and inflammatory mediators. Chem Biol Interact 2020; 327:109181. [DOI: 10.1016/j.cbi.2020.109181] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Revised: 05/29/2020] [Accepted: 06/15/2020] [Indexed: 12/18/2022]
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Mateu A, De Dios I, Manso MA, Ramudo L. Oxidized phospholipids exert a dual effect on bile acid-induced CCL2 expression in pancreatic acini. Pancreatology 2017; 17:372-380. [PMID: 28291657 DOI: 10.1016/j.pan.2017.02.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 02/22/2017] [Accepted: 02/28/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND oxidized phospholipids (oxPLs) generated in inflammatory diseases could play a key role by inducing pro- and anti-inflammatory effects. OBJETIVES: we investigated the effect of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and oxidized POPC (oxPOPC) in the inflammatory response triggered in pancreatic acini. METHODS control acini were incubated in the absence or presence of either POPC or oxPOPC (≤100 μM). In additional experiments, oxPOPC effects were evaluated in sodium taurocholate (NaTc)-treated acini. CCL2 and TLR4 mRNA expression was analyzed by RT-qPCR. By western blot, JNK-MAPK, JAK and IκBα in cytoplasm as well as p65-NF-kB and p-STAT3 in the nucleus were evaluated. The involvement of TLR4, JNK-MAPK, JAK as well as NF-kB, STAT3 and PPARγ was assessed using pharmacological inhibition. RESULTS no effect was found in response to POPC. Conversely, in response to oxPOPC (10 μM), JNK-MAPK and JAK acted as TLR4-downstream signals, leading to CCL2 upregulation mainly through NF-kB activation. Moreover, TLR4 non-dependent mechanisms induced STAT3 activation in oxPOPC-treated acini. Mediated by PPARγ, oxPOPC (50 μM) inhibited the CCL2 overexpression found in NaTc-treated acini. CONCLUSIONS oxPOPC exerts pro- and anti-inflammatory effects in pancreatic acinar cells mediated by TLR4 and PPARγ signals, respectively. This dual action proved to be dependent on the concentration. The molecular mechanisms involved in the oxPL response could be useful for new therapeutic approaches to the treatment of oxPLs-related inflammatory pathologies.
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Affiliation(s)
- Alberto Mateu
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain
| | - Isabel De Dios
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain
| | - Manuel Antonio Manso
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain
| | - Laura Ramudo
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain.
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Nilotinib, a tyrosine kinase inhibitor exhibits protection against acute pancreatitis-induced lung and liver damage in rats. Naunyn Schmiedebergs Arch Pharmacol 2016; 390:291-300. [PMID: 27975299 DOI: 10.1007/s00210-016-1327-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 11/29/2016] [Indexed: 12/20/2022]
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Xiang H, Wang G, Qu J, Xia S, Tao X, Qi B, Zhang Q, Shang D. Yin-Chen-Hao Tang Attenuates Severe Acute Pancreatitis in Rat: An Experimental Verification of In silico Network Target Prediction. Front Pharmacol 2016; 7:378. [PMID: 27790147 PMCID: PMC5061810 DOI: 10.3389/fphar.2016.00378] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 09/28/2016] [Indexed: 12/12/2022] Open
Abstract
Yin-Chen-Hao Tang (YCHT) is a classical Chinese medicine compound that has a long history of clinical use in China for the treatment of inflammatory diseases. However, the efficacy and mechanisms of YCHT for the treatment of severe acute pancreatitis (SAP) are not known. The current study investigated the pharmacological properties of YCHT against SAP and its underlying mechanisms. A computational prediction of potential targets of YCHT was initially established based on a network pharmacology simulation. The model suggested that YCHT attenuated SAP progress by apoptosis inducement, anti-inflammation, anti-oxidation and blood lipid regulation. These effects were validated in SAP rats. YCHT administration produced the following results: (1) significantly inhibited the secretion of pancreatic enzymes and protected pancreatic tissue; (2) obviously increased the number of in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells and induced apoptosis; (3) markedly inhibited neutrophil infiltration to the impaired pancreas and reduced the inflammatory reaction; (4) notably enhanced the activities of antioxidant enzymes and decreased the nitric oxide synthase levels; (5) significantly reduced the levels of triglycerides, total cholesterol and low-density lipoprotein and increased high-density lipoprotein; and (6) significantly up-regulated peroxisome proliferator-activated receptor-γ (PPARγ) and down-regulated nuclear factor-kappa B (NF-κB). In summary, these results demonstrated that YCHT attenuated SAP progress by inducing apoptosis, repressing inflammation, alleviating oxidative stress and regulating lipid metabolism partially via regulation of the NF-κB/PPARγ signal pathway.
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Affiliation(s)
- Hong Xiang
- College (Institute) of Integrative Medicine, Dalian Medical UniversityDalian, China
| | - Guijun Wang
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical UniversityJinzhou, China
| | - Jialin Qu
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Shilin Xia
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Xufeng Tao
- College of Pharmacy, Dalian Medical UniversityDalian, China
| | - Bing Qi
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Qingkai Zhang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Dong Shang
- College (Institute) of Integrative Medicine, Dalian Medical UniversityDalian, China
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical UniversityDalian, China
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Criddle DN. Reactive oxygen species, Ca(2+) stores and acute pancreatitis; a step closer to therapy? Cell Calcium 2016; 60:180-9. [PMID: 27229361 DOI: 10.1016/j.ceca.2016.04.007] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 04/22/2016] [Accepted: 04/23/2016] [Indexed: 12/18/2022]
Abstract
Disruption of Ca(2+) homeostasis can lead to severe damage of the pancreas, resulting in premature activation of digestive enzymes, vacuolisation and necrotic cell death, features typical of acute pancreatitis (AP). Therefore a fine balance between Ca(2+) release from internal stores, Ca(2+) entry and extrusion mechanisms is necessary to avoid injury. Precipitants of AP induce Ca(2+) overload of the pancreatic acinar cell that causes mitochondrial dysfunction, via formation of the mitochondrial permeability transition pore (MPTP), loss of ATP production and consequent necrosis. Oxidative stress has been shown to occur in the development of AP and may modify Ca(2+) signalling events in the acinar cell. However, the precise pathophysiological involvement is currently unclear and antioxidant therapy in the clinic has largely proved ineffective. Possible reasons for this are discussed, including evidence that ROS generation may determine cell death patterns. In contrast, recent evidence has indicated the potential for AP therapy via the prevention of Ca(2+)-dependent mitochondrial damage. Multiple approaches are indicated from preclinical findings; 1) inhibition of Ca(2+) release by IP3R blockade, 2) inhibition of Ca(2+) entry through Orai1 blockade and 3) prevention of MPTP formation. Clinical trials of drugs which prevent mitochondrial dysfunction induced by Ca(2+) overload of pancreatic acinar cells are imminent and may provide patient benefit for a disease that currently lacks specific therapy.
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Affiliation(s)
- David N Criddle
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, and NIHR Liverpool Pancreas Biomedical Research Unit, University of Liverpool, L69 3BX, UK.
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Inhibition of pancreatic oxidative damage by stilbene derivative dihydro-resveratrol: implication for treatment of acute pancreatitis. Sci Rep 2016; 6:22859. [PMID: 26971398 PMCID: PMC4789643 DOI: 10.1038/srep22859] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 02/23/2016] [Indexed: 01/14/2023] Open
Abstract
Trans-resveratrol is a natural stilbenoid possessing multifarious pharmacological benefits; however, when orally consumed, it is rapidly metabolised by colonic microflora and converted to dihydro-resveratrol. Thus, this microbial metabolite is of great therapeutic relevance. In the present study, upon the oral administration of dihydro-resveratrol (10–50 mg/kg), the severity of acute pancreatitis in the cerulein-treated rats was significantly ameliorated as evidenced by decreased α-amylase activities in the plasma and lessened oedema formation in the pancreatic parenchyma. In addition, the generation of intracellular reactive oxidative products, including malondialdehyde and protein carbonyls, was accordingly reduced, so as the production of pro-inflammatory cytokines. While inhibiting the activities of NADPH oxidase and myeloperoxidase, the depletion of glutathione was considerably restored. Importantly, the attenuation of pancreatic oxidative damage by dihydro-resveratrol was associated with a down-regulation of the nuclear factor-kappaB and phosphatidylinositol 3′-kinase-serine/threonine kinase signalling pathways. Furthermore, we demonstrated that the solubility of dihydro-resveratrol was at least 5 times higher than trans-resveratrol whilst exhibiting a much lower cytotoxicity. Collectively, the current findings accentuate new mechanistic insight of dihydro-resveratrol in pancreatic oxidative damage, and advocate its therapeutic potential for the management of acute pancreatitis, particularly for patients unresponsive to trans-resveratrol due to the lack of proper microbial strains.
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Carrasco C, Marchena AM, Holguín-Arévalo MS, Martín-Partido G, Rodríguez AB, Paredes SD, Pariente JA. Anti-inflammatory effects of melatonin in a rat model of caerulein-induced acute pancreatitis. Cell Biochem Funct 2014; 31:585-90. [PMID: 24779037 DOI: 10.1002/cbf.2942] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The purpose of our study was to evaluate the protective effect of melatonin in a rat model of caerulein-induced acute pancreatitis. For the induction of experimental acute pancreatitis, four subcutaneous injections of caerulein (20 mgkg–1 body weight) were given to Wistar rats at 2-h intervals. Melatonin was injected intraperitoneally (25 mg kg–1 body weight) 30 min before each caerulein injection. After 12 h, rats were sacrificed by decapitation. Blood and pancreas samples were collected and processed for serological and histopathological studies,respectively. Lipase, a-amylase, corticosterone, total antioxidant power and cytokines interleukin (IL)-1b, IL-4 and tumour necrosis factor(TNF)-a were determined using commercial kits. ANOVA and Tukey tests (P<0.05) were performed for the statistical analysis of the results.Results showed that the administration of melatonin reduced histological damage induced by caerulein treatment as well as the hyperamylasemia and hyperlipidemia. Corticosterone and antioxidant total power were also reverted to basal activities. Furthermore, melatonin pre-treatment reduced pro-inflammatory cytokines IL-1b and TNF-a and increased the serum levels of anti-inflammatory cytokine IL-4. In conclusion,the findings suggest that the protective effect of melatonin in caerulein-induced acute pancreatitis is mediated by the anti-inflammatory ability of this indolamine. Thus, melatonin may have a protective effect against acute pancreatitis.
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The protective effects of Shen-Fu injection on experimental acute pancreatitis in a rat model. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:248786. [PMID: 24738018 PMCID: PMC3964904 DOI: 10.1155/2014/248786] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Revised: 01/24/2014] [Accepted: 01/31/2014] [Indexed: 01/03/2023]
Abstract
Objectives. In the present study, we investigated the protective effects of Shen-Fu injection (SFI) on a caerulein-induced rat pancreatitis (AP) model.
Methods. SFI was given to rats in the SFI treated group through intraperitoneal injection. Blood and pancreas samples were collected for serological and histopathological studies. Results. Our results showed that AP caused significant decrease in tissue glutathione (GSH) and serum IL-4 and IL-10, while pancreatic malondialdehyde (MDA) and myeloperoxidase (MPO) were increased. Furthermore, TNF-α, IL-1β, amylase, and lipase levels were also significantly increased. On the other hand, SFI treatment reserved all these biochemical indices as well as histopathologic alterations that were induced by caerulein.
Conclusion. Our findings suggest that the SFI protects against caerulein-induced AP in rats via modulation of cytokines, oxidative stress, and Nuclear Factor-kappa B (NF-κB) activity.
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Armstrong JA, Cash N, Soares PMG, Souza MHLP, Sutton R, Criddle DN. Oxidative stress in acute pancreatitis: lost in translation? Free Radic Res 2013; 47:917-33. [PMID: 23952531 DOI: 10.3109/10715762.2013.835046] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Oxidative stress has been implicated in the pathogenesis of acute pancreatitis, a severe and debilitating inflammation of the pancreas that carries a significant mortality, and which imposes a considerable financial burden on the health system due to patient care. Although extensive efforts have been directed towards the elucidation of critical underlying mechanisms and the identification of novel therapeutic targets, the disease remains without a specific therapy. In experimental animal models of acute pancreatitis, increased oxidative stress and decreased antioxidant defences have been observed, changes also detected in patients clinically. However, despite the promise of studies evaluating the effects of antioxidants in these model systems, translation to the clinic has thus far been disappointing. This may reflect many factors involved in the design of both preclinical and clinical evaluations of antioxidant therapy, not least the fact that most experimental studies have focussed on pre-treatment rather than post-injury assessment. This review has examined evidence relating to the involvement of oxidative stress in the pathophysiology of acute pancreatitis, focussing on experimental models and the clinical experience, including the experimental techniques employed and potential of antioxidant therapy.
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Affiliation(s)
- J A Armstrong
- NIHR Liverpool Pancreas Biomedical Research Unit, RLBUHT , Liverpool , UK
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Yilmaz S, Uyar H, Aktepe F, Akaydin M, Cilekar M, Vurmaz A, Koca B, Kahraman A, Arikan Y. Laparoscopic preconditioning protects against oxidative injury in cerulein-induced pancreatitis rats (an experimental study). J Laparoendosc Adv Surg Tech A 2011; 22:34-9. [PMID: 22149396 DOI: 10.1089/lap.2011.0373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
Abstract
BACKGROUND Laparoscopic cholecystectomy, particularly in the same hospital stay, has been widely recommended to treat gallstone-pancreatitis over the last decade. Although pancreatitis produces severe oxidative injury, laparoscopy exerts an additional effect over that is produced by pancreatitis. The preconditioning phenomenon previously reported as protective in open surgery is a beneficial maneuver also in laparoscopic surgery. So in the present study we have tried to find out the effect of laparoscopic preconditioning over the pancreatitis in cerulein-induced pancreatitis rats. METHODS Acute pancreatitis was induced in 24 rats weighing between 280 and 350 g by three subcutaneous injection of 80 μg/kg of body weight cerulein. A 1-cm midline laparotomy was performed for all rats, and then they were randomly assigned to one of the following three groups (n=8 for each): Group I (control), Group II (laparoscopy), and Group III (laparoscopic preconditioning [L-Pre]). After that, a catheter was placed into the peritoneum for the creation of the pneumoperitoneum (Pp) in all the animals except the control group. The rats of Groups II and III were subjected to 60 minutes of Pp with 15 mm Hg intraabdominal pressure followed by 30 minutes of deflation. The L-Pre procedure was applied to Group III immediately before the laparoscopic procedure. Blood samples were taken for biochemical assays. Pancreas tissue samples were taken for light microscope analysis. RESULTS The light microscopy of the pancreas tissues revealed that cerulein injection caused edema and sparse inflammatory cell infiltration mimicking the edematous pancreatitis. However, the application of laparoscopy over the pancreatitis produced significant inflammatory cell infiltration, acinus vacuolization, and necrosis (in one case) in addition to edema. But, the laparoscopic preconditioning maneuver applied before the laparoscopy significantly decreased in particular acinary vacuolization and cell infiltration. Therefore the total sum of the histopathological score of the L-Pre group was significantly less than that of the laparoscopy group. The biochemical analysis of the groups revealed that laparoscopy caused significant elevation of malondialdehyde levels and decrease of reduced glutathione values. However, the addition of preceding preconditioning produced significant amelioration of these parameters. CONCLUSION Laparoscopic preconditioning may be a useful method to decrease the oxidative injury in cases undergoing cholecystectomy for biliary pancreatitis. But, it should be emphasized that this was a restricted experimental study, and further clinical studies are needed to adopt these results into clinical settings.
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Affiliation(s)
- Sezgin Yilmaz
- General Surgery Department, Afyon Kocatepe University, Afyon, Turkey.
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Booth DM, Mukherjee R, Sutton R, Criddle DN. Calcium and reactive oxygen species in acute pancreatitis: friend or foe? Antioxid Redox Signal 2011; 15:2683-98. [PMID: 21861696 PMCID: PMC3183657 DOI: 10.1089/ars.2011.3983] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
SIGNIFICANCE Acute pancreatitis (AP) is a debilitating and, at times, lethal inflammatory disease, the causes and progression of which are incompletely understood. Disruption of Ca(2+) homeostasis in response to precipitants of AP leads to loss of mitochondrial integrity and cellular necrosis. RECENT ADVANCES While oxidative stress has been implicated as a major player in the pathogenesis of this disease, its precise roles remain to be defined. Recent developments are challenging the perception of reactive oxygen species (ROS) as nonspecific cytotoxic agents, suggesting that ROS promote apoptosis that may play a vital protective role in cellular stress since necrosis is avoided. CRITICAL ISSUES Fresh clinical findings have indicated that antioxidant treatment does not ameliorate AP and may actually worsen the outcome. This review explores the complex links between cellular Ca(2+) signaling and the intracellular redox environment, with particular relevance to AP. FUTURE DIRECTIONS Recent publications have underlined the importance of both Ca(2+) and ROS within the pathogenesis of AP, particularly in the determination of cell fate. Future research should elucidate the subtle interplay between Ca(2+) and redox mechanisms that operate to modulate mitochondrial function, with a view to devising strategies for the preservation of organellar function.
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Affiliation(s)
- David M Booth
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
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Onur E, Paksoy M, Baca B, Akoglu H. Hyperbaric oxygen and N-acetylcysteine treatment in L-arginine-induced acute pancreatitis in rats. J INVEST SURG 2011; 25:20-8. [PMID: 22047166 DOI: 10.3109/08941939.2011.593694] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND This study was designed to evaluate the combined effects of hyperbaric oxygen (HBO) and N-acetylcysteine (NAC) on acute necrotizing pancreatitis in rats. METHODS Experiments were performed in 50 male Wistar rats, which were divided into five groups (N = 10 for each group). The first group received normal saline (0.9% NaCl) intraperitoneal and served as the control group. In the second group, acute pancreatitis was induced by 3.2-g/kg body weight L-arginine intraperitoneal twice at an interval of 1 hr, which has been shown previously to produce severe necrotizing acute pancreatitis. In the third group, NAC treatment (1000 mg/kg) was given after 1 hr of the induction of acute pancreatitis twice 24 hr apart. In the fourth group, animals received HBO, 6 hr after the induction of pancreatitis twice 12 hr apart. In the fifth group, animals received together NAC as in Group 3 and HBO treatment as in Group 4. Groups 1, 2, and 3 were left under normal atmospheric pressures. Twelve hours after last treatment, the animals were killed by exsanguinations. Blood samples were studied for amylase, calcium, and lactate dehydrogenase (LDH), pancreatic histology, pancreatic tissue malondialdehyde, superoxide dismutase, and glutathione levels. RESULTS Acute pancreatitis is reduced by the treatment of NAC, HBO, NAC + HBO. HBO + NAC groups performed statistically the best in preventing L-arginine-induced acute necrotising pancreatitis. CONCLUSIONS NAC especially combined with HBO, decreases oxidative stress parameters, serum amylase, calcium, and LDH levels, as well as histopathologic score.
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Affiliation(s)
- Ender Onur
- Department of General Surgery, Fatih Sultan Mehmet Research and Training Hospital, Istanbul, Turkey.
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Effects of dexamethasone on intercellular adhesion molecule 1 expression and inflammatory response in necrotizing acute pancreatitis in rats. Pancreas 2010; 39:1057-63. [PMID: 20442680 DOI: 10.1097/mpa.0b013e3181da0f3e] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES Adhesion molecules are involved in the inflammatory response during acute pancreatitis (AP). We investigated the effect of dexamethasone (Dx) on intercellular adhesion molecule 1 (ICAM-1) expression during AP and its consequences on leukocyte recruitment and pancreatic damage. METHODS Acute pancreatitis was induced in rats by 3.5% sodium taurocholate for 3 hours and 6 hours. Dexamethasone (1 mg/kg) was administered either 30 minutes before or 1 hour after inducing AP. Messenger RNA ICAM-1 expression in pancreas and lung, membrane-bound ICAM-1 in acinar cells, and ICAM-1 plasma levels were analyzed. Histological examination of the pancreas and neutrophil infiltration in pancreas and lung were also measured. RESULTS Prophylactic and therapeutic administration of Dx down-regulated ICAM-1 expression in pancreas and lung from early AP. Dexamethasone given before AP reduced the pancreatic damage, but lung inflammation was not prevented. Therapeutic Dx treatment was ineffective in avoiding leukocyte recruitment into the pancreas and lung in rats with AP. High ICAM-1 concentration was found in plasma during AP, which was not reduced by Dx treatments. CONCLUSIONS Dexamethasone down-regulates ICAM-1 expression, but it does not completely prevent leukocyte recruitment during sodium taurocholate-induced AP.
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Abstract
Hemorrhagic shock (HS) leads to reactive oxygen species production. However, clinicians do not have access to bedside measurements of the redox status during HS. Cyclic voltammetry (CyV) is a simple electrochemical method of measuring redox status. The aims of this study were to 1) report the first application of cyclic voltammetry to measure the acute changes in serum redox status after HS, 2) to contrast it with another severe systemic disease with a different redox pathology (acute pancreatitis [AP]), and 3) to describe the response of CyV over time in a resolving model of AP. In the acute study, 24 male Wistar rats were randomized into three groups: groups 1 (control), 2 (AP), and 3 (HS). In the time-course study, 28 rats were randomized to a sham-control as well as 6 and 24 h post-AP cohorts, respectively.Cyclic voltammetry was performed using a three-electrode system. In the acute study, the first and second voltammetric peaks increased significantly in HS. In contrast, within the AP group, only the first voltammetric peak showed a significant increase. The first voltammetric peak correlated with plasma protein carbonyls (PCs) and with thiobarbituric acid-reactive substances, whereas the second voltammetric peak correlated positively with plasma protein carbonyls. In the second study, the first voltammetric peak correlated with physiological improvements. Here, we showed that serum CyV could respond to the serum redox change in HS and AP. Cyclic voltammetry warrants evaluation as a potential real-time beside measure of a patient's redox status during shock.
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Batcioglu K, Gul M, Uyumlu AB, Esrefoglu M. Liver lipid peroxidation and antioxidant capacity in cerulein-induced acute pancreatitis. Braz J Med Biol Res 2010; 42:776-82. [PMID: 19738983 DOI: 10.1590/s0100-879x2009000900001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2008] [Accepted: 06/15/2009] [Indexed: 01/27/2023] Open
Abstract
The aim of this study was to evaluate the role of oxidative damage in pancreatitis-induced hepatic injury. Thirty-five rats were divided into five groups (each of 7 rats): control, cerulein (100 microg/kg body weight), cerulein and pentoxifylline (12 mg/kg body weight), cerulein plus L-NAME (10 mg/kg body weight) and cerulein plus L-arginine (160 mg/kg body weight). The degree of hepatic cell degeneration differed significantly between groups. Mean malondialdehyde levels were 7.00 +/- 2.29, 20.89 +/- 10.13, 11.52 +/- 4.60, 18.69 +/- 8.56, and 8.58 +/- 3.68 nmol/mg protein for the control, cerulein, pentoxifylline, L-NAME, and L-arginine groups, respectively. Mean catalase activity was 3.20 +/- 0.83, 1.09 +/- 0.35, 2.05 +/- 0.91, 1.70 +/- 0.60, and 2.85 +/- 0.47 U/mg protein for the control, cerulein, pentoxifylline, L-NAME, and L-arginine groups, respectively, and mean glutathione peroxidase activity was 0.72 +/- 0.25, 0.33 +/- 0.09, 0.37 +/- 0.04, 0.34 +/- 0.07 and 0.42 +/- 0.1 U/mg protein for the control, cerulein, pentoxifylline, L-NAME, and L-arginine groups, respectively. Cerulein-induced liver damage was accompanied by a significant increase in tissue malondialdehyde levels (P < 0.05) and a significant decrease in catalase (P < 0.05) and GPx activities (P < 0.05). L-arginine and pentoxifylline, but not L-NAME, protected against this damage. Oxidative injury plays an important role not only in the pathogenesis of AP but also in pancreatitis-induced hepatic damage.
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Affiliation(s)
- K Batcioglu
- Department of Biochemistry, Inonu University, Malatya, Turkey.
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Ramudo L, Manso MA. N-acetylcysteine in acute pancreatitis. World J Gastrointest Pharmacol Ther 2010; 1:21-6. [PMID: 21577291 PMCID: PMC3091141 DOI: 10.4292/wjgpt.v1.i1.21] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Revised: 01/13/2010] [Accepted: 01/20/2010] [Indexed: 02/06/2023] Open
Abstract
Premature trypsinogen activation and production of oxygen free radicals (OFR) are early pathogenic events which occur within acinar cells and trigger acute pancreatitis (AP). OFR exert their harmful effects on various cell components causing lipid peroxidation, disturbances in calcium homeostasis and DNA damage, which lead to increased cell injury and eventually cell death. This review presents the most recent data concerning the effects of N-Acetylcysteine (NAC), in the treatment of AP. NAC is an antioxidant capable of restoring the levels of Glutathione, the most important cellular antioxidant. Studies show the beneficial effects of NAC treatment in preventing OFR production and therefore attenuating oxidative damage. Additionally, NAC treatment has been shown to prevent the increase in cytosolic Ca2+ concentration and reduce the accumulation of enzymes in acinar cells during AP. The prevention, by NAC, of these pathological events occurring within acinar would contribute to reducing the severity of AP. NAC is also capable of reducing the activation of transcription factors especially sensitive to the cellular redox state, such as Nuclear factor-κB, signal transducer and activator of transcription-3 and mitogen-activated protein kinase. This leads to a down-regulation of cytokines, adhesion molecules and chemokine expression in various cell types during AP. These findings point to NAC as a powerful therapeutic treatment, attenuating oxidative-stress-induced cell injury and other pathological events at early stages of AP, and potentially contributing to reducion in the severity of disease.
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Affiliation(s)
- Laura Ramudo
- Laura Ramudo, Manuel A Manso, Department of Physiology and Pharmacology, University of Salamanca, Salamanca 37007, Spain
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Early inhibition of prostaglandin synthesis by n-3 fatty acids determinates histologic severity of necrotizing pancreatitis. Pancreas 2009; 38:436-41. [PMID: 19295455 DOI: 10.1097/mpa.0b013e318198283b] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Previously, we observed decreased histopathological severity of acute necrotizing pancreatitis (ANP) by parenteral nutrition with n-3 fatty acids. Thus, we now sequentially analyzed the impact of n-3 fatty acids on prostaglandin and leukotriene synthesis in ANP. METHODS One hundred ninety-eight Sprague-Dawley rats (11 groups, n = 18) underwent intraductal glycodesoxycholat instillation and 6-hour cerulein infusion. Afterward, saline was infused in groups 2, 4, 6, 8, and 10, whereas groups 3, 5, 7, 9, and 11 received infusion rich in n-3 fatty acids (Omegaven, Fresenius Kabi, Bad Homburg, Germany). Animals were killed after 6 (group 1), 10 (groups 2 and 3), 14 (groups 4 and 5), 18 (groups 6 and 7), 22 (groups 8 and 9), and 26 hours (groups 10 and 11). The pancreas was histopathologically examined, and the pancreatic eicosanoid metabolism (prostaglandin E2, prostaglandin F1alpha [PGF1alpha], and leukotrienes) and lipid peroxidation (thiobarbituric acid-reactive substance, superoxide dismutase, and glutathione peroxidase) were analyzed. RESULTS Between the 14th and 26th hours, histopathologic scores (edema, inflammation, bleeding, and necrosis) were reduced in the n-3 fatty acid group compared with the corresponding saline group. Pancreatic prostaglandin E2 and PGF1alpha were decreased between the 10th and 18th hour by n-3 fatty acids; PGF1alpha was reduced after 26 hours compared with the corresponding saline group. Lipid peroxidation was decreased by n-3 fatty acids after 14 hours (thiobarbituric acid-reactive substance); however, there was no difference concerning lipid peroxidation protective enzymes (glutathione peroxidase and superoxide dismutase). CONCLUSIONS Parenteral therapy with n-3 fatty acids decreased histopathologic severity in ANP by early inhibition of prostaglandin (E2 and F1alpha) synthesis and reduction of lipid peroxidation.
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Impact of trapping and handling on Leukocyte Coping Capacity in bank voles ( Clethrionomys glareolus) and wood mice ( Apodemus sylvaticus). Anim Welf 2009. [DOI: 10.1017/s0962728600000014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
AbstractSmall mammals are routinely live-trapped and subsequently handled for a range of ecological and behavioural studies. Despite the techniques commonly employed being potentially stressful for the individual animals involved, it has hitherto been difficult to quantify the physiological impact. Here, we report on the first instance of using the Leukocyte Coping Capacity technique (LCC) in bank voles (Clethrionomys glareolus) and wood mice (Apodemus sylvaticus) to investigate the physiological impact of routine trapping and handling techniques. Twenty microlitres of blood were obtained from 40 animals, of which 25 were handled following standard protocols and 15 were not. We found that even a short period of acute stress is sufficient to trigger an immune response which was measurable using the LCC technique. These results further validate the use of the LCC technique for measuring the physiological impact of standard trapping and handling treatments on wild mammals.
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Akyuz C, Sehirli AO, Topaloglu U, Ogunc AV, Cetinel S, Sener G. Protective Effects of Proanthocyanidin on Cerulein-induced Acute Pancreatic Inflammation in Rats. Gastroenterology Res 2009; 2:20-28. [PMID: 27956946 PMCID: PMC5139881 DOI: 10.4021/gr2009.02.1276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Background The aim of this study was to assess the possible protective effect of proanthocyanidin against cerulein-induced acute pancreatic inflammation (AP) and oxidative injury. Methods Sprague-Dawley rats were pretreated with proanthocyanidine (100 mg/kg, orally) or saline 15 min before cerulein was given by 20 µg/kg subcutaneously at 1-h intervals within 4 hours. Six hours after cerulein or saline injections, the animals were killed by decapitation. Blood samples were collected to analyze amylase, lipase, and proinflammatory cytokines (TNF-α and IL-1b). Pancreas tissues were taken for the determination of tissue glutathione (GSH) and malondialdehyde (MDA) levels, Na+, K+-ATPase and myeloperoxidase (MPO) activities. Formation of reactive oxygen species in pancreatic tissue samples was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes, while the extent of tissue injury was analyzed microscopically. Results Acute pancreatitis caused a significant decrease in tissue GSH level and Na+, K+-ATPase activity, which was accompanied with significant increases in the pancreatic MDA, luminol and lucigenin chemiluminescences (CL) levels and MPO activity. Similarly TNF-α and IL-1β levels were elevated in the pancreatic group as compared to control group. On the other hand, proanthocyanidin treatment reversed all these biochemical indices, as well as histopathological alterations that were induced by cerulein. Conclusions Proanthocyanidine can ameliorate pancreatic injury induced by cerulein in rats, this result suggests that proanthocyanidin may have utility in treating acute pancreatititis.
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Affiliation(s)
- Cebrail Akyuz
- Department of 5 Surgery, Haydarpasa Numune Education and Research Hospital
| | | | - Umit Topaloglu
- Department of 5 Surgery, Haydarpasa Numune Education and Research Hospital
| | | | - Sule Cetinel
- Marmara University, School of Medicine, Department of Histology & Embryology, Istanbul, Turkey
| | - Goksel Sener
- Department of 5 Surgery, Haydarpasa Numune Education and Research Hospital
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Akay S, Ozutemiz O, Yenisey C, Genc Simsek N, Yuce G, Batur Y. Use of activated protein C has no avail in the early phase of acute pancreatitis. HPB (Oxford) 2008; 10:459-63. [PMID: 19088933 PMCID: PMC2597320 DOI: 10.1080/13651820802140729] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2007] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Sepsis and acute pancreatitis have similar pathogenetic mechanisms that have been implicated in the progression of multiple organ failure. Drotrecogin alfa, an analogue of endogenous protein C, reduces mortality in clinical sepsis. Our objective was to evaluate the early therapeutic effects of activated protein C (APC) in a rat model of acute necrotizing pancreatitis. SUBJECTS AND METHOD Acute necrotizing pancreatitis was induced by intraductal injection of 5% Na taurocholate. Hourly bolus injections of saline or recombinant human APC (drotrecogin alfa) was commenced via femoral venous catheter four hours after the induction of acute pancreatitis. The experiment was terminated nine hours after pancreatitis induction. Animals in group one (n=20) had a sham operation while animals in group two (n=20) received saline and animals in group three (n=20) received drotrecogin alfa boluses after acute pancreatitis induction. Pancreatic tissue for histopathologic scores and myeloperoxidase, glutathione reductase, glutathione peroxidase, and catalase activities were collected, and blood for serum amylase, urea, creatinine, and interleukin-6 measurements was withdrawn. RESULTS Serum amylase activity was significantly lower in the APC treated group than the untreated group (17,435+/-432 U/L vs. 27,426+/-118 U/L, respectively). While the serum interleukin-6 concentration in the APC untreated group was significantly lower than the treated group (970+/-323 pg/mL vs. 330+/-368 pg/mL, respectively). CONCLUSION In the early phase of acute pancreatitis, drotrecogin alfa treatment did not result in a significant improvement in oxidative and inflammatory parameters or renal functions.
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Affiliation(s)
- Sinan Akay
- Ege University Hospital Gastroenterology DepartmentIzmirTurkey
| | - Omer Ozutemiz
- Ege University Hospital Gastroenterology DepartmentIzmirTurkey
| | - Cigdem Yenisey
- Adnan Menderes University Biochemistry DepartmentAydinTurkey
| | | | - Gul Yuce
- Ege University Hospital Pathology DepartmentIzmirTurkey
| | - Yucel Batur
- Ege University Hospital Gastroenterology DepartmentIzmirTurkey
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Kiziler AR, Aydemir B, Gulyasar T, Unal E, Gunes P. Relationships among iron, protein oxidation and lipid peroxidation levels in rats with alcohol-induced acute pancreatitis. Biol Trace Elem Res 2008; 124:135-43. [PMID: 18408897 DOI: 10.1007/s12011-008-8127-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2007] [Revised: 02/12/2008] [Accepted: 03/10/2008] [Indexed: 12/22/2022]
Abstract
It has been previously shown that alcohol induces the damage of pancreatic parenchyma tissue, but the mechanism of this damage is still poorly understood. Assuming that oxygen radical damage may be the involved, we measured markers of oxidative damage in pancreatic tissue, blood serum, plasma, and whole blood of rats with early-stage alcohol-induced acute pancreatitis. Thirty-eight male Wistar rats were divided into three groups: the control group (group 1), the acute pancreatitis group 1 day (group 2), and 3 days (group 3) after the injection of ethyl alcohol into the common biliary duct, respectively. The levels of Fe in tissue and serum, whole blood viscosity, plasma viscosity, fibrinogen and homocysteine (Hcy) levels, erythrocyte and plasma malondialdehyde (MDA), and tissue and plasma protein carbonyl levels were found to be significantly higher in groups 2 and 3 than in group 1. However, the levels of reduced glutathione (GSH) in tissue and erythrocytes were significantly lower in groups 2 and 3 than in group 1. These results suggest that elevated Fe levels in serum and pancreatic tissue in rats with early-stage alcohol-induced acute pancreatitis is associated with various hemorheological changes and with oxidative damage of the pancreas.
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Affiliation(s)
- Ali Riza Kiziler
- Department of Biophysics, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey.
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24
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Campo GM, Avenoso A, Campo S, Nastasi G, Traina P, D'Ascola A, Calatroni A. Chondroitin-4-sulphate reduced oxidative injury in caerulein-induced pancreatitis in mice: the involvement of NF-kappaB translocation and apoptosis activation. Exp Biol Med (Maywood) 2008; 233:741-752. [PMID: 18408139 DOI: 10.3181/0711-rm-318] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Activation of nuclear factor kappaB (NF-kappaB) and caspases may greatly amplify inflammation and cell damage in addition to that directly exerted by free radicals. Since reactive oxygen species (ROS) are involved in acute pancreatitis, we studied whether the administration of chondroitin-4-sulphate (C4S), in addition to its antioxidant activity, was able to modulate NF-kappaB and caspase activation in an experimental model of caerulein-induced acute pancreatitis in mice. Hyperstimulating doses of caerulein (50 microg/ kg), five injections per mouse given at hourly intervals produced the following: high serum lipase and amylase activity; lipid peroxidation, evaluated by 8-isoprostane concentrations; loss of antioxidant defenses such as glutathione reductase (GR) activity; NF-kappaB activation and loss of cytoplasmic IkappaBalpha protein; increases in tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), caspase-3, and caspase-7 gene expression and their related protein; accumulation and activation of neutrophils in the damaged tissue, evaluated by elastase (ELA) determination; and pancreatic injury, evaluated by histologic analysis. Pretreatment of mice with different doses of C4S, given 1 hr before caerulein injections and 1 and 2 hrs after the last caerulein injection, reduced lipid peroxidation, inhibited NF-kappaB translocation and cytoplasmic IkappaBalpha protein loss, decreased TNF-alpha, IL-6, and caspase gene expression and their related protein levels, limited endogenous antioxidant depletion, and reduced tissue neutrophils accumulation and tissue damage. Since molecules with antioxidant activity can block NF-kappaB and apoptosis activation, we suggest that C4S administration is able to block NF-kappaB and caspase activation by reducing the oxidative burst.
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Affiliation(s)
- Giuseppe M Campo
- Department of Biochemical, Physiological and Nutritional Sciences, School of Medicine, University of Messina, Policlinico Universitario, 98125, Messina, Italy.
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Manso MA, Ramudo L, De Dios I. Extrapancreatic organ impairment during acute pancreatitis induced by bile-pancreatic duct obstruction. Effect of N-acetylcysteine. Int J Exp Pathol 2007; 88:343-9. [PMID: 17877536 PMCID: PMC2517330 DOI: 10.1111/j.1365-2613.2007.00538.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Multiple organ failure is frequently associated with acute pancreatitis (AP). Our aim was to study pulmonary, hepatic and renal complications developed in the course of AP experimentally induced in rats by bile-pancreatic duct obstruction (BPDO), differentiating the complications caused by AP itself, from those directly caused by bile duct obstruction (BDO), after ligating the choledocus. N-acetylcysteine (NAC) was administered as a therapeutic approach. Myeloperoxidase activity revealed neutrophil infiltration in lungs from 12 h after BDO, even if AP was not triggered. Lactate dehydrogenase (LDH) activity indicated hepatocyte death from 48 h after BDO, and from 24 h following BPDO-induced AP onwards, an effect delayed until 48 h by NAC treatment. Rats with single cholestasis (BDO) and rats with BPDO-induced AP showed a significant increase in plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin concentration from 12 h onwards, whose values were reduced by NAC treatment at early BPDO. No renal failure was found during 120 h of bile-pancreatic obstruction. Our results showed lung and liver impairment as a result of BDO, even if AP does not develop. Pancreatic damage and extrapancreatic complications during AP induced by BPDO were palliated by NAC treatment.
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Affiliation(s)
- Manuel A Manso
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
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26
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de Dios I, Ramudo L, García-Montero AC, Manso MA. Redox-sensitive modulation of CD45 expression in pancreatic acinar cells during acute pancreatitis. J Pathol 2007; 210:234-9. [PMID: 16886168 DOI: 10.1002/path.2037] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
CD45, a transmembrane protein tyrosine phosphatase required for signal transduction in leukocytes, has recently been found in pancreatic acinar cells. We have investigated the relationship between kinetic expression of CD45 on acinar cells during acute pancreatitis (AP) and the ability of these cells to produce tumour necrosis factor-alpha (TNF-alpha) through mechanisms sensitive to the cellular redox state. Flow cytometric analysis showed a significant decrease in the constitutive expression of CD45 in acinar cells from six hours onwards after inducing AP by bile-pancreatic duct obstruction (BPDO) in parallel with a significant increase in acinar TNF-alpha production. Changes in protein expression on the acinar cell surface preceded CD45 mRNA down-regulation, which was not found until 12 hours after BPDO. N-Acetylcysteine treatment delayed and reduced the down-regulation of CD45 expression induced by AP and prevented acinar cells from producing TNF-alpha. Our results show that CD45 expression is down-regulated in acinar cells during acute pancreatitis by redox-sensitive mechanisms, and they support the notion that CD45 negatively controls the production of cytokines in pancreatic acinar cells.
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Affiliation(s)
- I de Dios
- Department of Physiology and Pharmacology, University of Salamanca, Spain.
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Criddle DN, Gerasimenko JV, Baumgartner HK, Jaffar M, Voronina S, Sutton R, Petersen OH, Gerasimenko OV. Calcium signalling and pancreatic cell death: apoptosis or necrosis? Cell Death Differ 2007; 14:1285-94. [PMID: 17431416 DOI: 10.1038/sj.cdd.4402150] [Citation(s) in RCA: 135] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Secretagogues, such as cholecystokinin and acetylcholine, utilise a variety of second messengers (inositol trisphosphate, cADPR and nicotinic acid adenine dinucleotide phosphate) to induce specific oscillatory patterns of calcium (Ca(2+)) signals in pancreatic acinar cells. These are tightly controlled in a spatiotemporal manner, and are coupled to mitochondrial metabolism necessary to fuel secretion. When Ca(2+) homeostasis is disrupted by known precipitants of acute pancreatitis, for example, hyperstimulation or non-oxidative ethanol metabolites, Ca(2+) stores (endoplasmic reticulum and acidic pool) become depleted and sustained cytosolic [Ca(2+)] elevations replace transient signals, leading to severe consequences. Sustained mitochondrial depolarisation, possibly via opening of the mitochondrial permeability transition pore (MPTP), elicits cellular ATP depletion that paralyses energy-dependent Ca(2+) pumps causing cytosolic Ca(2+) overload, while digestive enzymes are activated prematurely within the cell; Ca(2+)-dependent cellular necrosis ensues. However, when stress to the acinar cell is milder, for example, by application of the oxidant menadione, release of Ca(2+) from stores leads to oscillatory global waves, associated with partial mitochondrial depolarisation and transient MPTP opening; apoptotic cell death is promoted via the intrinsic pathway, when associated with generation of reactive oxygen species. Apoptosis, induced by menadione or bile acids, is potentiated by inhibition of an endogenous detoxifying enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1), suggesting its importance as a defence mechanism that may influence cell fate.
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Affiliation(s)
- D N Criddle
- MRC Secretory Research Group, Department of Physiology, University of Liverpool, Liverpool, L69 3BX, UK.
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Wang YH, Feng ZJ, Hao X. Relationship between acute pancreatitis and oxidative stress. Shijie Huaren Xiaohua Zazhi 2007; 15:1266-1272. [DOI: 10.11569/wcjd.v15.i11.1266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Under the imbalance between generation of reactive oxygen species and inadequate antioxidant defense systems, oxidative stress can cause cell damage either directly or indirectly through altering signaling pathways. It is the etiopathogenisis and also the consequence of many diseases. Oxidative injury plays an important role not only in the pathogenesis of acute pancreatitis (AP) but also in pancreatitis-induced damages of other organs such as heart, liver, lung, kidney, alimentary canal and so on. Oxidative stress can produce a higher level of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which induce inflammatory reaction and microcirculation disturbance, and cell necrosis or apoptosis, leading to pancreatic inflammation and multiple organ dysfunction syndromes. The antioxidants can decrease the production of oxygen free radicals (or directly scavenge them), protect the antioxidant enzyme activity, reinforce the antioxidative capacity of bodies, and consequently play an obvious therapeutic effect on AP.
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Criddle DN, Gillies S, Baumgartner-Wilson HK, Jaffar M, Chinje EC, Passmore S, Chvanov M, Barrow S, Gerasimenko OV, Tepikin AV, Sutton R, Petersen OH. Menadione-induced reactive oxygen species generation via redox cycling promotes apoptosis of murine pancreatic acinar cells. J Biol Chem 2006; 281:40485-92. [PMID: 17088248 DOI: 10.1074/jbc.m607704200] [Citation(s) in RCA: 276] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Oxidative stress may be an important determinant of the severity of acute pancreatitis. One-electron reduction of oxidants generates reactive oxygen species (ROS) via redox cycling, whereas two-electron detoxification, e.g. by NAD(P)H:quinone oxidoreductase, does not. The actions of menadione on ROS production and cell fate were compared with those of a non-cycling analogue (2,4-dimethoxy-2-methylnaphthalene (DMN)) using real-time confocal microscopy of isolated perfused murine pancreatic acinar cells. Menadione generated ROS with a concomitant decrease of NAD(P)H, consistent with redox cycling. The elevation of ROS was prevented by the antioxidant N-acetyl-l-cysteine but not by the NADPH oxidase inhibitor diphenyliodonium. DMN produced no change in reactive oxygen species per se but significantly potentiated menadione-induced effects, probably via enhancement of one-electron reduction, since DMN was found to inhibit NAD(P)H:quinone oxidoreductase detoxification. Menadione caused apoptosis of pancreatic acinar cells that was significantly potentiated by DMN, whereas DMN alone had no effect. Furthermore, bile acid (taurolithocholic acid 3-sulfate)-induced caspase activation was also greatly increased by DMN, whereas DMN had no effect per se. These results suggest that acute generation of ROS by menadione occurs via redox cycling, the net effect of which is induction of apoptotic pancreatic acinar cell death. Two-electron detoxifying enzymes such as NAD(P)H:quinone oxidoreductase, which are elevated in pancreatitis, may provide protection against excessive ROS and exert an important role in determining acinar cell fate.
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Affiliation(s)
- David N Criddle
- MRC Secretory Research Group, Department of Physiology and Division of Surgery and Oncology, University of Liverpool, Liverpool L69 3BX, United Kingdom.
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Eşrefoğlu M, Gül M, Ateş B, Yilmaz I. Ultrastructural clues for the protective effect of ascorbic acid and N-acetylcysteine against oxidative damage on caerulein-induced pancreatitis. Pancreatology 2006; 6:477-85. [PMID: 16864970 DOI: 10.1159/000094665] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2005] [Accepted: 01/23/2006] [Indexed: 12/11/2022]
Abstract
BACKGROUND Oxygen free radicals (OFR) have been implicated in the induction of acute pancreatitis (AP). AIMS The aim of this study was to determine the effect of ascorbic acid and N-acetylcysteine (NAC), potent antioxidants, against oxidative stress in AP. METHODS AP was induced by two i.p. injections of caerulein at 2-hour intervals (50 microg/kg BW). One group received additionally an antioxidant mixture composed of L(+)-ascorbic acid (14.3 mg/kg BW) and NAC (181 mg/kg BW) i.p. The rats were sacrificed 12 h after the last injection. Oxidative stress markers were evaluated. Light-microscopic and ultrastructural examination was performed. RESULTS Formation of vacuoles, mitochondrial damage, and dilatation of rough endoplasmic reticulum, margination and clumping of chromatin were major ultrastructural alterations in AP group. Ascorbic acid + NAC prevented these changes. Small vacuoles were present within the cytoplasm of some of the acinar cells. Pancreas damage was accompanied by an increase in tissue malondialdehyde (MDA) levels (p < 0.05), whereas a decrease was seen in catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) activities and total glutathione (GSH) levels (p < 0.005). Ascorbic acid + NAC decreased MDA levels but increased CAT, SOD, GPx activities and GSH levels (p < 0.005). CONCLUSION These results suggest that ascorbic acid + NAC is potentially capable of limiting pancreatic damage produced during AP via protecting fine structure of acinar cells and tissue antioxidant enzyme activities.
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Affiliation(s)
- Mukaddes Eşrefoğlu
- Department of Histology and Embryology, Faculty of Medicine, Inonu University, Malatya, Turkey.
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Kubisch CH, Gukovsky I, Lugea A, Pandol SJ, Kuick R, Misek DE, Hanash SM, Logsdon CD. Long-term ethanol consumption alters pancreatic gene expression in rats: a possible connection to pancreatic injury. Pancreas 2006; 33:68-76. [PMID: 16804415 DOI: 10.1097/01.mpa.0000226878.81377.94] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Long-term ethanol consumption does not cause acute pancreatitis but rather sensitizes the pancreas to subsequent insults. The mechanisms responsible for this sensitization are unknown. To determine whether alterations in pancreatic gene expression might participate in ethanol-mediated sensitization, we performed gene-profiling analysis. METHODS Animals were fed ethanol-containing Lieber-DeCarli or control diet (pair-fed). After 8 weeks, pancreatic RNA expression was analyzed using Affimetrix GeneChips. Changes in specific genes were verified using quantitative reverse transcriptase-polymerase chain reaction. RESULTS Long-term ethanol feeding caused a significant alteration of pancreatic gene expression. Selection criteria of changes more than 3-fold and P < 0.05 yielded 114 probe sets. Activating transcription factor 3, heat shock protein 70, heat shock protein 27, and mesotrypsinogen were increased, whereas pancreatitis associate protein, folate carrier, and metallothionein were decreased. CONCLUSIONS Ethanol had a profound effect on pancreatic gene expression. The genes identified as elevated and reduced in this study may contribute to pancreatic sensitivity to stress. This study indicates for the first time the identities of multiple genes whose expression levels are dramatically influenced by long-term ethanol feeding. The identified genes may help explain the relationship between long-term ethanol abuse and pancreatic disease and lead to possible preventative or therapeutic approaches to ethanol-induced pancreatic disease.
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MESH Headings
- Activating Transcription Factor 3/genetics
- Activating Transcription Factor 3/metabolism
- Animals
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Ethanol/toxicity
- Gene Expression Profiling
- Gene Expression Regulation
- HSP70 Heat-Shock Proteins/genetics
- HSP70 Heat-Shock Proteins/metabolism
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Male
- Oligonucleotide Array Sequence Analysis
- Pancreas/drug effects
- Pancreas/metabolism
- Pancreatitis, Alcoholic/chemically induced
- Pancreatitis, Alcoholic/genetics
- Pancreatitis, Alcoholic/metabolism
- Pancreatitis-Associated Proteins
- RNA, Messenger/metabolism
- Rats
- Rats, Wistar
- Time Factors
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Affiliation(s)
- Constanze H Kubisch
- Department of Cancer Biology, MD Anderson Cancer Center, University of Texas, Houston, TX 77230-1429, USA
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32
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Chvanov M, Petersen OH, Tepikin A. Free radicals and the pancreatic acinar cells: role in physiology and pathology. Philos Trans R Soc Lond B Biol Sci 2006; 360:2273-84. [PMID: 16321797 PMCID: PMC1569596 DOI: 10.1098/rstb.2005.1757] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Reactive oxygen and nitrogen species (ROS and RNS) play an important role in signal transduction and cell injury processes. Nitric oxide synthase (NOS)-the key enzyme producing nitric oxide (NO)-is found in neuronal structures, vascular endothelium and, possibly, in acinar and ductal epithelial cells in the pancreas. NO is known to regulate cell homeostasis, and its effects on the acinar cells are reviewed here. ROS are implicated in the early events within the acinar cells, leading to the development of acute pancreatitis. The available data on ROS/RNS involvement in the apoptotic and necrotic death of pancreatic acinar cells will be discussed.
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Affiliation(s)
- M Chvanov
- The University of Liverpool The Physiological Laboratory Crown Street, Liverpool L69 3BX, UK.
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33
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Yamasaki M, Takeyama Y, Shinkai M, Ohyanagi H. Pancreatic and bile duct obstruction exacerbates rat caerulein-induced pancreatitis: a new experimental model of acute hemorrhagic pancreatitis. J Gastroenterol 2006; 41:352-60. [PMID: 16741615 DOI: 10.1007/s00535-005-1767-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2005] [Accepted: 11/17/2005] [Indexed: 02/04/2023]
Abstract
BACKGROUND Pancreatic duct obstruction induces edematous but not hemorrhagic pancreatitis even when combined with maximal secretory stimulation. The aim of the present study was to test the hypothesis that pancreatic and bile duct obstruction exacerbates edematous pancreatitis induced by supramaximal secretory stimulation by caerulein. METHODS In in vivo studies using rats, biliopancreatic duct ligation was combined with supramaximal stimulation of caerulein, and pancreatic histology, serum amylase level, pancreatic edema, and intrapancreatic trypsin activation were evaluated. In in vitro studies, the pancreatic acini were isolated from the rats with biliopancreatic duct ligation, and amylase secretion, intracellular trypsin activation, and acinar cell fragility were evaluated. RESULTS Biliopancreatic duct ligation exacerbated caerulein-induced pancreatitis from edematous to hemorrhagic only when the obstruction preceded caerulein administration. The amylase secretion from the acini was inhibited, and intracellular trypsin activation and the acinar cell fragility on the supramaximal stimulation with cholecystokinin in vitro were enhanced by the preceding in vivo biliopancreatic duct obstruction. CONCLUSIONS Preceding biliopancreatic duct obstruction exacerbates caerulein-induced pancreatitis. Enhancement of intracellular trypsin activation is possibly involved in this mechanism.
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Affiliation(s)
- Mitsuo Yamasaki
- Department of Surgery, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-sayama 595-8511, Japan
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34
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Szabolcs A, Reiter RJ, Letoha T, Hegyi P, Papai G, Varga I, Jarmay K, Kaszaki J, Sari R, Rakonczay Z, Lonovics J, Takacs T. Effect of melatonin on the severity of L-arginine-induced experimental acute pancreatitis in rats. World J Gastroenterol 2006; 12:251-258. [PMID: 16482626 PMCID: PMC4066035 DOI: 10.3748/wjg.v12.i2.251] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2005] [Revised: 06/28/2005] [Accepted: 07/28/2005] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the effect of melatonin pre- and post-treatment on the severity of L-arginine (L-Arg) -induced experimental pancreatitis in rats. METHODS Male Wistar rats (25) were divided into five groups. Those in group A received two injections of 3.2g/kg body weight L-Arg i.p. at an interval of 1h. In group MA, the rats were treated with 50 mg/kg body weight melatonin i.p. 30 min prior to L-Arg administration. In group AM, the rats received the same dose of melatonin 1h after L-Arg was given. In group M, a single dose of melatonin was administered as described previously. In group C the control animals received physiological saline injections i.p. All rats were exsanguinated 24 h after the second L-Arg injection. RESULTS L-Arg administration caused severe necrotizing pancreatitis confirmed by the significant elevations in the serum amylase level, the pancreatic weight/body weight ratio (pw/bw), the pancreatic IL-6 content and the myeloperoxidase activity, relative to the control values. Elevation of the serum amylase level was significantly reduced in rats given melatonin following L-Arg compared to rats injected with L-Arg only. The activities of the pancreatic antioxidant enzymes (Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and catalase (CAT)) were significantly increased 24 h after pancreatitis induction. Melatonin given in advance of L-Arg significantly reduced the pancreatic CAT activity relative to that in the rats treated with L-Arg alone. In the liver, L-Arg significantly increased the lipid peroxidation level, and the glutathione peroxidase and Cu/Zn-SOD activities, whereas the Mn-SOD activity was reduced as compared to the control rats. Melatonin pre-treatment prevented these changes. CONCLUSION Melatonin is an antioxidant that is able to counteract some of the L-Arg-induced changes during acute pancreatitis, and may therefore be helpful in the supportive therapy of patients with acute necrotizing pancreatitis.
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Affiliation(s)
- Annamaria Szabolcs
- First Department of Medicine, University of Szeged, Faculty of Medicine, H-6720, Szeged, Koranyi fasor 8, Hungary.
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35
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Eşrefoğlu M, Gül M, Ates B, Batçioğlu K, Selimoğlu MA. Antioxidative effect of melatonin, ascorbic acid and N-acetylcysteine on caerulein-induced pancreatitis and associated liver injury in rats. World J Gastroenterol 2006; 12:259-64. [PMID: 16482627 PMCID: PMC4066036 DOI: 10.3748/wjg.v12.i2.259] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of oxidative injury in pancreatitis-induced hepatic damage and the effect of antioxidant agents such as melatonin, ascorbic acid and N-acetyl cysteine on caerulein-induced pancreatitis and associated liver injury in rats.
METHODS: Thirty-eight female Wistar rats were used. Acute pancreatitis (AP) was induced by two i.p. injections of caerulein at 2-h intervals (at a total dose of 100 µg/kg b.wt). The other two groups received additional melatonin (20 mg/kg b.wt) or an antioxidant mixture containing L(+)-ascorbic acid (14.3 mg/kb.wt.) and N-acetyl cysteine (181 mg/kg b.wt.) i.p. shortly before each injection of caerulein. The rats were sacrificed by decapitation 12 h after the last injection of caerulein. Pancreatic and hepatic oxidative stress markers were evaluated by changes in the amount of lipid peroxides measured as malondialdehyde (MDA) and changes in tissue antioxidant enzyme levels, catalase (CAT) and glutathione peroxidase (GPx). Histopathological examination was performed using scoring systems.
RESULTS: The degree of hepatic cell degeneration, intracellular vacuolization, vascular congestion, sinusoidal dilatation and inflammatory infiltration showed a significant difference between caerulein and caerulein + melatonin (P = 0.001), and careulein and caerulein + L(+)-ascorbic acid + N-acetyl cysteine groups (P = 0.002). The degree of aciner cell degeneration, pancreatic edema, intracellular vacuolization and inflammatory infiltration showed a significant difference between caerulein and caerulein + melatonin (P = 0.004), and careulein and caerulein + L(+)-ascorbic acid + N-acetyl cysteine groups (P = 0.002). Caerulein-induced pancreatic and liver damage was accompanied with a significant increase in tissue MDA levels (P = 0.01, P = 0.003, respectively) whereas a significant decrease in CAT (P = 0.002, P = 0.003, respectively) and GPx activities (P = 0.002, P = 0.03, respectively). Melatonin and L(+)-ascorbic acid + N-acetyl cysteine administration significantly decreased MDA levels in pancreas (P = 0.03, P = 0.002, respectively) and liver (P = 0.007, P = 0.01, respectively). Administration of these agents increased pancreatic and hepatic CAT and GPx activities. Melatonin significantly increased pancreatic and hepatic CAT (P = 0.002, P = 0.001, respectively) and GPx activities (P = 0.002, P = 0.001). Additionally, L(+)-ascorbic acid+N-acetyl cysteine significantly increased pancreatic GPx (P = 0.002) and hepatic CAT and GPx activities (P = 0.001, P = 0.007, respectively)
CONCLUSION: Oxidative injury plays an important role not only in the pathogenesis of AP but also in pancreatitis-induced hepatic damage. Antioxidant agents such as melatonin and ascorbic acid + N-acetyl cysteine, are capable of limiting pancreatic and hepatic damage produced during AP via restoring tissue antioxidant enzyme activities.
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Affiliation(s)
- Mukaddes Eşrefoğlu
- Department of Histology and Embryology, Faculty of Medicine, Inonu Universitesi, 44280, Malatya, Turkey.
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36
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Eşrefoğlu M, Gül M, Ateş B, Selimoğlu MA. Ultrastructural clues for the protective effect of melatonin against oxidative damage in cerulein-induced pancreatitis. J Pineal Res 2006; 40:92-7. [PMID: 16313504 DOI: 10.1111/j.1600-079x.2005.00288.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The role of oxidative stress has been evaluated in experimental models of acute pancreatitis (AP). The aim of this study is to investigate the effect of melatonin on the ultrastructural changes in cerulein-induced AP in rats. Acute pancreatitis was induced by two i.p. injections of cerulein at 2-hr intervals (50 microg/kg BW). One group received additionally melatonin (20 mg/kg BW) i.p. before each injection of cerulein. The rats were sacrificed 12 hr after the last injection. Pancreatic oxidative stress markers were evaluated by changes in the amount of lipid peroxides and changes in the antioxidant enzyme levels, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total glutathione (GSH) levels. Ultrastructural examination was performed using a transmission electron microscope. Formation of numerous, large autophagosomes, mitochondrial damage, dilatation of rough endoplasmic reticulum (RER) and Golgi apparatus, margination and clumping of nuclear chromatin were the major ultrastructural alterations observed in the AP group. Melatonin administration prevented mitochondrial and nuclear changes and dilatation of RER and Golgi apparatus. Rare, small autophagosomes were present within the cytoplasm of some of the acinar cells. Pancreatic damage was accompanied by a significant increase in tissue MDA levels (P < 0.05) and a significant decrease in CAT, SOD, GPx activities and GSH levels (P < 0.005). Melatonin administration significantly reduced MDA levels but increased CAT, SOD, GPx activities and GSH levels (P < 0.005). Melatonin also reduced serum amylase and lipase activities, which were significantly elevated in AP (P < 0.05 and P < 0.005 respectively). These results suggest that oxidative injury is important in the pathogenesis of AP. Melatonin is potentially capable of limiting pancreatic damage produced during AP by protecting the fine structure of acinar cells and tissue antioxidant enzyme activities.
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Affiliation(s)
- Mukaddes Eşrefoğlu
- Department of Histology and Embryology, Faculty of Medicine, Inonu University, Malatya, Turkey.
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37
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Vaquero-Raya EC, Molero-Richard X. Especies reactivas de oxígeno en las enfermedades inflamatorias del páncreas: ¿una posible diana terapéutica? GASTROENTEROLOGIA Y HEPATOLOGIA 2005; 28:473-84. [PMID: 16185583 DOI: 10.1157/13078997] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Chronic and acute pancreatitis can be understood as distinct stages of an inflammatory spectrum in the pancreas. Although its pathogenesis is not well defined, oxidative stress seems to be clearly involved in its development. During acute pancreatitis, there is an extraordinary and rapid formation of reactive oxygen species that leads to the extinction of pancreatic antioxidant reserves, causes direct tissue damage and activates oxidative cellular mediators, giving rise to the lesion. However, classical antioxidants have not been shown to have clear benefits in patients with acute pancreatitis. Chronic pancreatitis seems to be the result of a recurrent lesion and defective repair, leading to pancreatic atrophy and fibrosis. In this process, oxidative stress is an efficient stimulus to maintain pancreatic stellar cells active, the fibrogenic motor of chronic pancreatitis. Although antioxidant supplements relieve abdominal pain in these patients, the direction of future antioxidant therapies lies in identifying oxidative mechanisms with the potential for intervention.
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Affiliation(s)
- E C Vaquero-Raya
- Servicio de Aparato Digestivo, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
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38
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Ramudo L, Manso MA, Sevillano S, de Dios I. Kinetic study of TNF-alpha production and its regulatory mechanisms in acinar cells during acute pancreatitis induced by bile-pancreatic duct obstruction. J Pathol 2005; 206:9-16. [PMID: 15761843 DOI: 10.1002/path.1747] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cytokines play a critical role in acute pancreatitis (AP) but the contribution of different cell sources to cytokine production is unclear. Unfortunately, there are no data concerning the molecular mechanisms involved in the inflammatory response in humans during AP. For this reason, the aim of this study was to analyse the ability of acinar cells, in comparison with leukocytes, to produce TNF-alpha at different stages of AP induced in rats by bile-pancreatic duct obstruction (BPDO) and to investigate the time course of oxidant-sensitive mechanisms involved in cytokine production. The role of oxygen free radicals as messengers of the mechanisms underlying acinar cell TNF-alpha production was assessed in BPDO rats treated with N-acetylcysteine (NAC). While monocytes were not able to produce TNF-alpha until 12 h after inducing AP, acinar cells triggered TNF-alpha production from 6 h after BPDO, at which time the pancreas develops maximal oxidative stress. Phosphorylated p38-MAPK and activated NF-kappaB were detected in acinar cells from 6 h after BPDO. NAC treatment reduced pancreatic glutathione depletion during the early stages of AP and attenuated the activation of p38-MAPK and NF-kappaB for 48 h following BPDO. As a result, acinar cells in NAC-treated rats failed to produce TNF-alpha during AP. In addition, NAC delayed monocyte TNF-alpha production, thereby maintaining low TNF-alpha levels in plasma during BPDO. In conclusion, acinar cells contribute directly to the inflammatory response during BPDO-induced AP by producing TNF-alpha even before inflammatory cells in the peripheral blood. The blockade of oxidant-mediated signal transduction pathways induced by NAC treatment prevented acinar cell TNF-alpha production.
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Affiliation(s)
- Laura Ramudo
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
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39
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Ramudo L, Manso MA, De Dios I. Biliary pancreatitis-associated ascitic fluid activates the production of tumor necrosis factor-alpha in acinar cells. Crit Care Med 2005; 33:143-8; discussion 248. [PMID: 15644661 DOI: 10.1097/01.ccm.0000150654.13653.5b] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
OBJECTIVE Acute pancreatitis is associated with increased cytokine release from different cell sources. We have investigated the ability of acinar cells, in comparison with inflammatory peripheral blood cells, to produce tumor necrosis factor (TNF)-alpha in response to pancreatitis-associated ascitic fluid (PAAF). DESIGN Controlled, randomized animal study. SETTING University research laboratory. SUBJECTS Male Wistar rats. INTERVENTIONS Flow cytometry using phycoerythrin-labeled monoclonal anti-TNF-alpha antiserum. MEASUREMENTS AND MAIN RESULTS PAAF (20%, v:v) obtained from rats with acute pancreatitis induced by bile-pancreatic duct obstruction significantly increased TNF-alpha production in acinar cells, as measured by flow cytometry using phycoerythrin-labeled monoclonal anti-TNF-alpha antiserum. Neither heating of PAAF nor the addition of soybean trypsin inhibitor or neutralizing amounts of anti-TNF-alpha monoclonal antiserum reduced the acinar cell TNF-alpha production. Monocytes and lymphocytes did not produce TNF-alpha in response to PAAF. Likewise, the typical monocyte and lymphocyte stimulating factors-lipopolysaccharide (10 microg/microL) and phorbol 12-myristate 13-acetate (250 ng/mL) plus ionomycin (1 microg/mL), respectively-were not able to produce TNF-alpha in acinar cells. By comparison of the two acinar cell populations differentiated by flow cytometry, R2 cells (with higher forward scatter values) showed a greater ability to produce TNF-alpha in response to PAAF than R1 cells. Acinar cell nuclear factor-kappaB was activated, but TNF-alpha production was not totally inhibited in presence of N-acetyl cysteine (30, 100 mM). CONCLUSIONS The production of TNF-alpha from different cell sources is selectively activated. PAAF may be involved in the pathophysiology of acute pancreatitis by TNF-alpha production in acinar cells through mechanisms partially mediated by nuclear factor-kappaB activation. PAAF components, such as TNF-alpha or trypsin, are not responsible for acinar cell activation. TNF-alpha was induced by heat-resistant PAAF factors, displaying acinar cells with higher forward scatter (R2) a greater ability to increase the TNF-alpha production than R1 cells.
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Affiliation(s)
- Laura Ramudo
- Department of Physiology and Pharmacology. University of Salamanca, Salamanca. Spain
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40
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Barlas A, Cevik H, Arbak S, Bangir D, Sener G, Yeğen C, Yeğen BC. Melatonin protects against pancreaticobiliary inflammation and associated remote organ injury in rats: role of neutrophils. J Pineal Res 2004; 37:267-75. [PMID: 15485553 DOI: 10.1111/j.1600-079x.2004.00168.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Although the role of oxidative stress in acute pancreatitis (AP) has been studied in several animal models, little data are available regarding AP induced by pancreatic duct obstruction. We characterized the protective effects of melatonin on pancreaticobiliary inflammation and associated remote organ injury. In Sprague-Dawley rats, either the common pancreaticobiliary duct (PBDL; n = 28) or bile duct (BDL; n = 28) was ligated or a sham operation was applied (n = 14). Either melatonin (10 mg/kg) or vehicle (saline; 1 mL/kg) was administered intraperitoneally (i.p.) immediately before the surgery and twice a day until the rats were decapitated at 6 or 72 h. The pancreas, liver, kidneys and lungs were removed and tissue samples were stored for the determination of malondialdehyde (MDA) and glutathione (GSH) levels and myelopreoxidase activity. The results demonstrate that pathogenesis of acute obstructive pancreatitis involves not only the oxidative damage of the pancreatic and hepatic tissues, as assessed by increased MDA and reduced GSH levels, but the lungs and kidneys are also challenged by oxidant injury. Similarly, hepatic oxidative injury caused by cholestasis was also accompanied by pulmonary, renal and even pancreatic damage. The biochemical findings were also verified histologically. Melatonin, probably because of its free-radical scavenging and antioxidant activity, which involves an inhibitory effect on tissue neutrophil infiltration, protected all the affected tissues.
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Affiliation(s)
- Afşar Barlas
- Department of General Surgery, Marmara University School of Medicine, Istanbul, Turkey
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41
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Tsang SW, Ip SP, Leung PS. Prophylactic and therapeutic treatments with AT 1 and AT 2 receptor antagonists and their effects on changes in the severity of pancreatitis. Int J Biochem Cell Biol 2004; 36:330-9. [PMID: 14643897 DOI: 10.1016/s1357-2725(03)00257-7] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Previous studies showed that a local pancreatic renin-angiotensin system (RAS) was upregulated in experimental acute pancreatitis. RAS inhibition could attenuate pancreatic inflammation and fibrosis, which casts a new light on the role of the pancreatic RAS in pancreatitis. The present study explores the prophylactic and therapeutic potentials, and possible molecular mechanism for the antagonism of angiotensin II receptors on the changes in the severity of pancreatic injury induced by acute pancreatitis. Experimental pancreatitis was induced by an intraperitoneal injection of supra-maximal dose of cerulein. The differential effects of angiotensin II receptors inhibitors losartan and PD123319 on the pancreatic injury were assessed by virtue of using the pancreatic water content, biochemical and histological analyses. Blockade of the AT(1) receptor by losartan at a dose of 200microg/kg could markedly ameliorate the pancreatic injury induced by cerulein, as evidenced by biochemical and histopathological studies. However, blockade of the AT(2) receptor by PD123319 appeared not to provide any beneficial role in cerulein-induced pancreatic injury. Both prophylactic and therapeutic treatments with losartan were effective against cerulein-induced pancreatic injury. The protective action of losartan was linked to an inhibition of NAD(P)H oxidase activity, thus consequential oxidative modification of pancreatic proteins in the pancreas. Inhibition of the AT(1) receptor, but not AT(2) receptor, may play a beneficial role in ameliorating the severity of acute pancreatitis. The differential effects of AT(1) and AT(2) inhibitors on cerulein-induced pancreatic injury might be due to the distinctive mechanism of the AT(1) and AT(2) receptors on the activation of NAD(P)H oxidase. Thus the protective role of AT(1) receptor antagonist, losartan, could be mediated by the inhibition of NAD(P)H oxidase-dependent generation of reactive oxygen species (ROS).
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Affiliation(s)
- Siu Wai Tsang
- Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Shatin, PR China
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42
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Vanco J, Svajlenová O, Ramanská E, Muselík J, Valentová J. Antiradical activity of different copper(II) Schiff base complexes and their effect on alloxan-induced diabetes. J Trace Elem Med Biol 2004; 18:155-61. [PMID: 15646262 DOI: 10.1016/j.jtemb.2004.07.003] [Citation(s) in RCA: 109] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Considering the important role of antioxidants in biological systems, the group of copper(II) complexes derived from salicylaldehyde and alpha- or beta-alanine and its thiourea derivative and copper(II) complexes derived from pyruvic acid and beta-alanine were studied. The antiradical activity of the tested compounds was studied by both in vitro and in vivo methods. The chemical methods based on inhibition of INT-formazane or 3-nitrotyrosine formation were used for the evaluation of SOD-mimic and antiperoxynitrite activity, respectively. In the case of in vivo activity evaluation, an alloxan-induced diabetes mellitus model in mice was used, the mechanism of action of alloxan being closely connected with the formation of free radicals selectively damaging the pancreatic beta-cells. Since all the substances studied showed different positive effects, it is obvious that they have not acted only as a source of copper(II) ions but their effect is related to their specific chelate structure. The obtained results are a contribution to the knowledge of copper(II) Schiff base complexes with ligands of aldimine or ketimine type and form the basis for further preclinical tests of these bioactive agents in biological models of oxidative stress.
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Affiliation(s)
- Ján Vanco
- Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho, Brno, Czech Republic.
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Sevillano S, de la Mano AM, Manso MA, Orfao A, De Dios I. N-acetylcysteine prevents intra-acinar oxygen free radical production in pancreatic duct obstruction-induced acute pancreatitis. Biochim Biophys Acta Mol Basis Dis 2003; 1639:177-84. [PMID: 14636949 DOI: 10.1016/j.bbadis.2003.09.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Although oxygen free radicals (OFR) are considered to be one of the pathophysiological mechanisms involved in acute pancreatitis (AP), the contribution of acinar cells to their production is not well established. The aim of the present study was to determine the effect of N-acetylcysteine (NAC) in the course of AP induced by pancreatic duct obstruction (PDO) in rats, directly analysing by flow cytometry the quantity of OFR generated in acinar cells. NAC (50 mg/kg) was administered 1 h before and 1 h after PDO. Measurements by flow cytometry of OFR generated in acinar cells were taken at different PDO times over 24 h, using dihydrorhodamine-123 as fluorescent dye. Histological studies of pancreas and measurements of neutrophil infiltration in the pancreas, pancreatic glutathione (GSH), malondialdehyde (MDA) levels, plasma amylase activity and hemoconcentration were carried out in order to assess the severity of AP at different stages. NAC effectively blunted GSH depletion at early AP stages and prevented OFR generation found in acinar cells as a consequence of AP induced by PDO. This attenuation of the redox state impairment reduced cellular oxidative damage, as reflected by less severe pancreatic lesions, normal pancreatic MDA levels, as well as diminished neutrophil infiltration in pancreas. Hyperamylasemia and hemoconcentration following AP induction were ameliorated by NAC administration at early stages, when oxidative stress seems to be critical in the development of pancreatitis. In conclusion, NAC reinforces the antioxidant defences in acinar cells, preventing OFR generation therefore attenuating oxidative damage and subsequently reducing the severity of PDO-induced AP at early stages of the disease.
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Affiliation(s)
- S Sevillano
- Department of Physiology and Pharmacology, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca, Spain
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44
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Sevillano S, de Dios I, de la Mano AM, Manso MA. N-acetylcysteine induces beneficial changes in the acinar cell cycle progression in the course of acute pancreatitis. Cell Prolif 2003; 36:279-89. [PMID: 14521521 PMCID: PMC6495142 DOI: 10.1046/j.1365-2184.2003.00284.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Oxygen free radicals (OFR) are produced in the course of acute pancreatitis (AP). In addition to injurious oxidative effects, they are also involved in the regulation of cell growth. The aim of the present study was to examine the relationship between the effectiveness of N-acetyl-l-cysteine (NAC) to prevent the generation of OFR and the changes in the cell-cycle pattern of acinar cells in the course of AP induced in rats by pancreatic duct obstruction (PDO). NAC (50 mg/kg) was administered 1 h before and 1 h after PDO. Flow-cytometric measurement of OFR generation in acinar cells was carried out using dihydrorhodamine as fluorescent dye. Plasma amylase activity, pancreatic glutathione (GSH) content and TNF-alpha plasma levels were also measured. The distribution of acinar cells throughout the different cell-cycle phases was analysed at different AP stages by flow cytometry using propidium iodide staining. NAC administration reduced the depletion of pancreatic GSH content and prevented OFR generation in acinar cells of rats with PDO-induced acute pancreatitis. As a result, AP became less severe as reflected by the significant improvement of hyper-amylasaemia and maintenance of plasma TNF-alpha levels at values not significantly different from controls were found. NAC administration inhibited progression of cell-cycle phases, maintaining acinar cells in quiescent state at early PDO times. The protection from oxidative damage by NAC treatment during early AP, allows the pancreatic cell to enter S-phase actively at later stages, thereby allowing acinar cells to proliferate and preventing the pancreatic atrophy provoked by PDO-induced AP. The results provide evidence that OFR play a critical role in the progression of acinar cell-cycle phases. Prevention of OFR generation of acinar cells in rats with PDO-induced AP through NAC treatment, not only protects pancreas from oxidative damage but also promotes beneficial changes in the cell cycle progression which reduce the risk of pancreatic atrophy.
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Affiliation(s)
- S Sevillano
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
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de la Mano AM, Sevillano S, Manso MA, de Dios I. Effect of long-term CCK blockade on the pancreatic acinar cell renewal in rats with acute pancreatitis. Peptides 2003; 24:535-41. [PMID: 12860197 DOI: 10.1016/s0196-9781(03)00112-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
This study determines the effect of 7-day pretreatment with L364,718 (a potent cholecystokinin (CCK) receptor antagonist) on pancreatic cell turnover during the course of acute pancreatitis (AP) induced in the rat by bile-pancreatic duct obstruction (BPDO). Cell cycle distribution and apoptosis were analyzed by flow cytometry using propidium iodide (PI) and Annexin V staining. Besides altering the pancreatic redox status, long-term CCK blockade inhibited the normal proliferation of acinar cells as indicated by the significant increase in G(0)/G(1)-phase cells and the decrease in G(2)/M-cells found in control rats treated with L364,718 for 7 days. A progressive depletion in pancreatic GSH was found from 3 to 24h after BPDO with similar values in L364,718-pretreated and non-treated rats, which led to a maximum peak in malondialdehyde (MDA) levels 6h after BPDO. However, plasma amylase activity and ascites volume indicated higher severity of AP in L364,718-pretreated rats. CCK blockade enhanced the alterations that appear in cell cycle distribution of acinar cells during AP demonstrated by the significantly higher increase in G(0)/G(1)-cells and decrease in S-cells found in L364,718-treated rats 48h after BPDO. Our results indicate that the renewal of acinar cells deleted by apoptosis 48h after BPDO worsens if CCK is blocked before inducing AP.
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Affiliation(s)
- Ana M de la Mano
- Department of Physiology and Pharmacology, University of Salamanca, 37008 Salamanca, Spain
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