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1
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Zhang H, Wang Z, Li J, Jia Y, Li F. Timing, initiation and function: An in-depth exploration of the interaction network among neutrophil extracellular traps related genes in acute pancreatitis. Int Immunopharmacol 2024; 141:112923. [PMID: 39137629 DOI: 10.1016/j.intimp.2024.112923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 07/25/2024] [Accepted: 08/08/2024] [Indexed: 08/15/2024]
Abstract
BACKGROUND Exogenous inhibition of neutrophil extracellular traps (NETs) was believed to alleviate acute pancreatitis (AP). This study aimed to comprehensively explore the key biological behavior of NETs including timing and pathogenesis in AP by integrating of single cell RNA sequencing(scRNA-seq) and bulk RNA-seq. METHODS Differentially expressed NETs-related genes and the hub genes of NETs were screened by bulk RNA-seq. ScRNA-seq was used to identify the cell types in pancreas of AP mice and to depict the transcriptomic maps in neutrophils. The mouse AP models were build to verify the timing of initiation of NETs and underlying pathogenesis of damage on pancreas acinar cells. RESULTS Tlr4 and Ccl3 were screened for hub genes by bulk RNA-seq. The trajectory analysis of neutrophils showed that high expression of Ccl3, Cybb and Padi4 can be observed in the middle stage during AP. Macrophages might be essential in the biological behavior of neutrophils and NETs. Through animal models, we presented that extensive NETs structures were formed at mid-stage of inflammation, accompanied by more serious pancreas and lung damage. NETs might promote necroptosis and macrophage infiltration in AP, and the damage on pancreatic injury could be regulated by Tlr4 pathway. Ccl3 was considered to recruit neutrophils and promote NETs formation. CONCLUSION The findings explored the underlying timing and pathogenesis of NETs in AP for the first time, which provided gene targets for further studies.
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Affiliation(s)
- Haoyu Zhang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, PR China; Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, PR China
| | - Zheng Wang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, PR China; Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, PR China
| | - Jie Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, PR China; Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, PR China
| | - Yuchen Jia
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, PR China; Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, PR China
| | - Fei Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, PR China; Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, PR China.
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Yu R, Hou C, Peng Y, Zhu X, Shi C, Huang D, Miao Y, Li Q. The mechanism underlying ICAM-1 and E-selectin-mediated hypertriglyceridemic pancreatitis-associated lung injury. Mol Immunol 2022; 152:55-66. [DOI: 10.1016/j.molimm.2022.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 10/03/2022] [Accepted: 10/05/2022] [Indexed: 11/07/2022]
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3
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Batcioglu K, Dogan T, Kustepe E, Uyumlu A, Yilmaztekin Y. Protective effect of Lycium barbarum on renal injury induced by acute pancreatitis in rats. Pharmacogn Mag 2022. [DOI: 10.4103/pm.pm_516_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Scigliano G, Scigliano GA. Methylene blue in covid-19. Med Hypotheses 2021; 146:110455. [PMID: 33341032 PMCID: PMC7728423 DOI: 10.1016/j.mehy.2020.110455] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/04/2020] [Accepted: 12/08/2020] [Indexed: 12/15/2022]
Abstract
SARS-CoV-2 infection generally begins in the respiratory tract where it can cause bilateral pneumonia. The disease can evolve into acute respiratory distress syndrome and multi-organ failure, due to viral spread in the blood and an excessive inflammatory reaction including cytokine storm. Antiviral and anti-cytokine drugs have proven to be poorly or in-effective in stopping disease progression, and mortality or serious chronic damage is common in severely ill cases. The low efficacy of antiviral drugs is probably due to late administration, when the virus has triggered the inflammatory reaction and is no longer the main protagonist. The relatively poor efficacy of anti-cytokine drugs is explained by the fact that they act on one or a few of the dozens of cytokines involved, and because other mediators of inflammation - reactive oxygen and nitrogen species - are not targeted. When produced in excess, reactive species cause extensive cell and tissue damage. The only drug known to inhibit the excessive production of reactive species and cytokines is methylene blue, a low-cost dye with antiseptic properties used effectively to treat malaria, urinary tract infections, septic shock, and methaemoglobinaemia. We propose testing methylene blue to contrast Covid-related acute respiratory distress syndrome, but particularly suggest testing it early in Covid infections to prevent the hyper-inflammatory reaction responsible for the serious complications of the disease.
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Affiliation(s)
- Giulio Scigliano
- Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Padova, 113, 20127 Milan, Italy.
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5
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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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Sundar V, Senthil Kumar KA, Manickam V, Ramasamy T. Current trends in pharmacological approaches for treatment and management of acute pancreatitis – a review. J Pharm Pharmacol 2020; 72:761-775. [DOI: 10.1111/jphp.13229] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 12/06/2019] [Indexed: 12/12/2022]
Abstract
Abstract
Objectives
Acute pancreatitis (AP) is an inimical disorder associated with overall mortality rates between 10-15%. It is a disorder of the exocrine pancreas which is characterized by local and systemic inflammatory responses primarily driven by oxidative stress and death of pancreatic acinar cells. The severity of AP ranges from mild pancreatic edema with complete recuperative possibilities to serious systemic inflammatory response resulting in peripancreatic/pancreatic necrosis, multiple organ failure, and death.
Key findings
We have retrieved the potential alternative approaches that are developed lately for efficacious treatment of AP from the currently available literature and recently reported experimental studies. This review summarizes the need for alternative approaches and combinatorial treatment strategies to deal with AP based on literature search using specific key words in PubMed and ScienceDirect databases.
Summary
Since AP results from perturbations of multiple signaling pathways, the so called “monotargeted smart drugs” of the past decade is highly unlikely to be effective. Also, the conventional treatment approaches were mainly involved in providing palliative care instead of curing the disease. Hence, many researchers are beginning to focus on developing alternate therapies to treat AP effectively. This review also summarizes the recent trends in the combinatorial approaches available for AP treatment.
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Affiliation(s)
- Vaishnavi Sundar
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
| | | | - Venkatraman Manickam
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Tamizhselvi Ramasamy
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
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Garg PK, Singh VP. Organ Failure Due to Systemic Injury in Acute Pancreatitis. Gastroenterology 2019; 156:2008-2023. [PMID: 30768987 PMCID: PMC6486861 DOI: 10.1053/j.gastro.2018.12.041] [Citation(s) in RCA: 352] [Impact Index Per Article: 58.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/07/2018] [Accepted: 12/29/2018] [Indexed: 02/07/2023]
Abstract
Acute pancreatitis may be associated with both local and systemic complications. Systemic injury manifests in the form of organ failure, which is seen in approximately 20% of all cases of acute pancreatitis and defines "severe acute pancreatitis." Organ failure typically develops early in the course of acute pancreatitis, but also may develop later due to infected pancreatic necrosis-induced sepsis. Organ failure is the most important determinant of outcome in acute pancreatitis. We review here the current understanding of the risk factors, pathophysiology, timing, impact on outcome, and therapy of organ failure in acute pancreatitis. As we discuss the pathophysiology of severe systemic injury, the distinctions between markers and mediators of severity are highlighted based on evidence supporting their causality in organ failure. Emphasis is placed on clinically relevant end points of organ failure and the mechanisms underlying the pathophysiological perturbations, which offer insight into potential therapeutic targets to treat.
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Abstract
Acute and chronic pancreatitises are gastrointestinal inflammatory diseases, the incidence of which is increasing worldwide. Most (~ 80%) acute pancreatitis (AP) patients have mild disease, and about 20% have severe disease, which causes multiple organ failure and has a high mortality rate. Chronic pancreatitis (CP) is characterized by chronic inflammation and destruction of normal pancreatic parenchyma, which leads to loss of exocrine and endocrine tissues. Patients with CP also have a higher incidence of pancreatic ductal adenocarcinoma. Although a number of factors are associated with the development and progression of AP and CP, the underlying mechanism is unclear. Adhesion molecules play important roles in cell migration, proliferation, and signal transduction, as well as in development and tissue repair. Loosening of cell-cell adhesion between pancreatic acinar cells and/or endothelial cells increases solute permeability, resulting in interstitial edema, which promotes inflammatory cell migration and disrupts tissue structure. Oxidative stress, which is one of the important pathogenesis of pancreatitis, leads to upregulation of adhesion molecules. Soluble adhesion molecules are reportedly involved in AP. In this review, we focus on the roles of tight junctions (occludin, tricellulin, claudin, junctional adhesion molecule, and zonula occludin), adherens junctions (E-cadherin and p120-, α-, and β-catenin), and other adhesion molecules (selectin and intercellular adhesion molecules) in the progression of AP and CP. Maintaining the normal function of adhesion molecules and preventing their abnormal activation maintain the structure of the pancreas and prevent the development of pancreatitis.
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Affiliation(s)
- Takeshi Sato
- 0000 0001 1033 6139grid.268441.dDepartment of Gastroenterology, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama, Kanagawa 236-0004 Japan
| | - Wataru Shibata
- 0000 0001 1033 6139grid.268441.dDepartment of Gastroenterology, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama, Kanagawa 236-0004 Japan ,0000 0001 1033 6139grid.268441.dDivision of Translational Research, Advanced Medical Research Center, Yokohama City University, Fukuura 3-9, Kanazawa-ku, Yokohama, Kanagawa 236-0004 Japan
| | - Shin Maeda
- 0000 0001 1033 6139grid.268441.dDepartment of Gastroenterology, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama, Kanagawa 236-0004 Japan
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Abstract
OBJECTIVES Acute pancreatitis (AP) is commonly associated with the release of adhesion molecules such as E and P selectins. We designed the present study to evaluate the role of selectins as potential markers that could reflect the severity of the disease. METHODS One hundred fifty patients with AP constituted the patient group, whereas 70 healthy volunteers established the control group. In both groups, blood samples were taken for measurements of E selectin, P selectin, caspase-cleaved cytokeratin 18, and total soluble cytokeratin 18 levels on admission and days 1, 2, 4, and 6. RESULTS Values of E and P selectins on admission were both elevated compared with control subjects (P < 0.01). The nonsurvivors had higher values of E selectin (P < 0.04) and P selectin (P < 0.03) on admission. Levels of E and P selectin showed positive correlation with the length of stay (P < 0.05). E selectin on admission yielded a sensitivity of 75% and 78% specificity, whereas P selectin had a sensitivity of 67% and 91% specificity. CONCLUSIONS Selectin values in the early course of AP may play a role as indicators of overall prognosis, which may help physicians in better understanding the pathophysiology of a benign disease that may have serious and detrimental complications.
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10
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Jakkampudi A, Jangala R, Reddy BR, Mitnala S, Nageshwar Reddy D, Talukdar R. NF-κB in acute pancreatitis: Mechanisms and therapeutic potential. Pancreatology 2016; 16:477-88. [PMID: 27282980 DOI: 10.1016/j.pan.2016.05.001] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 05/03/2016] [Accepted: 05/04/2016] [Indexed: 12/11/2022]
Abstract
The incidence of acute pancreatitis (AP) is increasing globally and mortality could be high among patients with organ failure and infected necrosis. The predominant factors responsible for the morbidity and mortality of AP are systemic inflammatory response syndrome and multiorgan dysfunction. Even though preclinical studies have shown antisecretory agents (somatostatin), antioxidants (S-adenosyl methionine [SAM], selenium), protease inhibitors, platelet activating factor inhibitor (Lexipafant), and anti-inflammatory immunomodulators (eg. prostaglandin E, indomethacin) to benefit AP in terms of reducing the severity and/or mortality, most of these agents have shown heterogeneous results in clinical studies. Several years of experimental studies have implicated nuclear factor-kappa B (NF-κB) activation as an early and central event in the progression of inflammation in AP. In this manuscript, we review the literature on the role of NF-κB in the pathogenesis of AP, its early intraacinar activation, and how it results in progression of the disease. We also discuss why anti-protease, antisecretory, and anti-inflammatory agents are unlikely to be effective in clinical acute pancreatitis. NF-κB, being a central molecule that links the initial acinar injury to systemic inflammation and perpetuate the inflammation, we propose that more studies be focussed towards targeted inhibition of NF-κB activity. Direct NF-κB inhibition strategies have already been attempted in patients with various cancers. So far, peroxisome proliferator activator receptor gamma (PPAR-γ) ligand, pyrrolidine dithiocarbamate (PDTC), proteasome inhibitor and calpain I inhibitor have been shown to have direct inhibitory effects on NF-κB activation in experimental AP.
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Affiliation(s)
- Aparna Jakkampudi
- Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India
| | - Ramaiah Jangala
- Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India
| | - B Ratnakar Reddy
- Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India
| | - Sasikala Mitnala
- Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India
| | - D Nageshwar Reddy
- Dept. of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Rupjyoti Talukdar
- Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India; Dept. of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India.
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11
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Pathophysiological mechanisms in acute pancreatitis: Current understanding. Indian J Gastroenterol 2016; 35:153-66. [PMID: 27206712 DOI: 10.1007/s12664-016-0647-y] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 03/16/2016] [Indexed: 02/04/2023]
Abstract
The precise mechanisms involved in the pathophysiology of acute pancreatitis (AP) are still far from clear. Several earlier studies have focused mainly on pancreatic enzyme activation as the key intracellular perturbation in the pancreatic acinar cells. For decades, the trypsin-centered hypothesis has remained the focus of the intra-acinar events in acute pancreatitis. Recent advances in basic science research have lead to the better understanding of various other mechanisms such as oxidative and endoplasmic stress, impaired autophagy, mitochondrial dysfunction, etc. in causing acinar cell injury. Despite all efforts, the clinical outcome of patients with AP has not changed significantly over the years. This suggests that the knowledge of the critical molecular pathways in the pathophysiology of AP is still limited. The mechanisms through which the acinar cell injury leads to local and systemic inflammation are not well understood. The role of inflammatory markers and immune system activation is an area of much relevance from the point of view of finding a target for therapeutic intervention. Some data are available from experimental animal models but not much is known in human pancreatitis. This review intends to highlight the current understanding in this area.
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12
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Virus-inhibiting activity of dihydroquercetin, a flavonoid from Larix sibirica, against coxsackievirus B4 in a model of viral pancreatitis. Arch Virol 2016; 161:929-38. [PMID: 26780775 DOI: 10.1007/s00705-016-2749-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 12/30/2015] [Indexed: 01/06/2023]
Abstract
Members of the family Picornaviridae, in particular, enteroviruses, represent a serious threat to human health. They are responsible for numerous pathologies ranging from mild disease to fatal outcome. Due to the limited number of safe and effective antivirals against enteroviruses, there is a need for search and development of novel drugs with various mechanisms of activity against enteroviruses-induced pathologies. We studied the effect of dihydroquercetin (DHQ), a flavonoid from larch wood, on the course of pancreatitis of white mice caused by coxsackievirus B4 (CVB4). DHQ was applied intraperitoneally at doses of 75 or 150 mg/kg/day once a day for 5 days postinfection (p.i.) starting on day 1 p.i., and its effect was compared to that of the reference compound ribavirin. The application of DHQ resulted in a dose-dependent decrease in the virus titer in pancreatic tissue, reaching, at the highest dose, 2.4 logs on day 5 p.i. Also, the application of DHQ led to restoration of antioxidant activity of pancreatic tissue that was impaired in the course of pancreatitis. Morphologically, pancreatic tissue of DHQ-treated animals demonstrated less infiltration with inflammatory cells and no signs of tissue destruction compared to placebo-treated mice. Both ribavirin- and DHQ-treated animals developed fewer foci of pancreatic inflammation per mouse, and these foci contained fewer infiltrating cells than those in placebo-treated mice. The effect of DHQ was comparable to or exceeded that of ribavirin. Taken together, our results suggest high antiviral activity of DHQ and its promising potential in complex treatment of viral pancreatitis.
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He X, Yu J, Guo W, Zuo T, Shi Q, Zhao K, Wang W. Effects of thymosin β4 on a rat model of severe acute pancreatitis. Exp Ther Med 2015; 10:2389-2395. [PMID: 26668646 DOI: 10.3892/etm.2015.2798] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Accepted: 08/10/2015] [Indexed: 12/16/2022] Open
Abstract
The aim of the present study was to investigate the effects of thymosin β4 on a rat model of severe acute pancreatitis (SAP) induced by sodium taurocholate (STC) and the underlying mechanism. SAP was induced by the retrograde infusion of 5% STC (1 ml/kg) into the bile-pancreatic duct. In certain rats, thymosin β4 (30 mg/kg) was administered intraperitoneally 30 min prior to the infusion of STC. The severity of pancreatitis was evaluated by the measurement of serum amylase, lipase, tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and myeloperoxidase (MPO) levels, and histological grading. Nuclear factor (NF)-κB activation was evaluated by immunohistochemistry and western blot analysis. Intercellular adhesion molecule (ICAM)-1 protein expression in the pancreas was studied using western blot analysis. Prophylactic administration of thymosin β4 was found to attenuate serum amylase and lipase activity and the serum concentrations of proinflammatory cytokines. In addition, it attenuated pathological pancreatic injury, pancreatic MPO activity, and the activation of NF-κB and ICAM-1 in the pancreas. These results suggest that thymosin β4 exerts a protective effect against STC-induced pancreatic injury.
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Affiliation(s)
- Xiaobo He
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jia Yu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Wenyi Guo
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Teng Zuo
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Qiao Shi
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Kailiang Zhao
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Pan Z, Feng L, Long H, Wang H, Feng J, Chen F. Effects of Local Pancreatic Renin-Angiotensin System on the Microcirculation of Rat with Severe Acute Pancreatitis. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2015; 19:299-307. [PMID: 26170733 PMCID: PMC4499641 DOI: 10.4196/kjpp.2015.19.4.299] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 11/19/2014] [Accepted: 12/02/2014] [Indexed: 12/23/2022]
Abstract
Severe acute pancreatitis (SAP) is normally related to multiorgan dysfunction and local complications. Studies have found that local pancreatic renin-angiotensin system (RAS) was significantly upregulated in drug-induced SAP. The present study aimed to investigate the effects of angiotensin II receptors inhibitor valsartan on dual role of RAS in SAP in a rat model and to elucidate the underlying mechanisms. 3.8% sodium taurocholate (1 ml/kg) was injected to the pancreatic capsule in order for pancreatitis induction. Rats in the sham group were injected with normal saline in identical locations. We also investigated the regulation of experimentally induced SAP on local RAS expression in the pancreas through determination of the activities of serum amylase, lipase and myeloperoxidase, histological and biochemical analysis, radioimmunoassay, fluorescence quantitative PCR and Western blot analysis. The results indicated that valsartan could effectively suppress the local RAS to protect against experimental acute pancreatitis through inhibition of microcirculation disturbances and inflammation. The results suggest that pancreatic RAS plays a critical role in the regulation of pancreatic functions and demonstrates application potential as AT1 receptor antagonists. Moreover, other RAS inhibitors could be a new therapeutic target in acute pancreatitis.
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Affiliation(s)
- Zhijian Pan
- Department of Gastroenterology Surgery, The Central Hospital of Wuhan, Tongji Medical College Huazhong University of Science & Technology, Wuhan 430014, Hubei, China
| | - Ling Feng
- Department of gynecology and obstetrics, Fifth Hospital of Wuhan, Wuhan 430050, Hubei, China
| | - Haocheng Long
- Department of General Surgery, Fifth Hospital of Wuhan, Wuhan 430050, Hubei, China
| | - Hui Wang
- Department of Gastroenterology Surgery, The Central Hospital of Wuhan, Tongji Medical College Huazhong University of Science & Technology, Wuhan 430014, Hubei, China
| | - Jiarui Feng
- Department of General Surgery, Fifth Hospital of Wuhan, Wuhan 430050, Hubei, China
| | - Feixiang Chen
- Department of General Surgery, Fifth Hospital of Wuhan, Wuhan 430050, Hubei, China
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Difference in Early Activation of NF-κB and MCP-1 in Acinar-Cell-Rich versus Fibrotic Human Pancreas Exposed to Surgical Trauma and Hypoxia. Gastroenterol Res Pract 2014; 2014:460363. [PMID: 25147563 PMCID: PMC4131420 DOI: 10.1155/2014/460363] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 07/13/2014] [Accepted: 07/15/2014] [Indexed: 01/23/2023] Open
Abstract
Objectives. Previously we have shown that a pancreas with over 40% acinar cells is exposed to postoperative pancreatitis and other complications after pancreaticoduodenectomy (PD). Our aim was to analyze the expression of NF-κB and MCP-1 in the cut edge of human pancreas after PD in both acinar-cell-rich and fibrotic pancreata. Methods. Several pancreatic samples from six patients, three with acinar-cell-rich and three with fibrotic pancreata, were exposed to surgical trauma in PD, and thereafter to hypoxemia for 15 minutes, 2-2.5 hours, 4 hours, or 6 hours, to mimic postoperative conditions of the pancreatic remnant in a patient. Immunohistochemical analysis of inflammation markers (NF-κB, MCP-1) was performed. Results. In the acinar-cell-rich pancreata, intra-acinar NF-κB and MCP-1 expression increased from mild at 15 minutes to high during the first 4 hours, whereas in ductal cells MCP-1 staining was highly intense at both time points. Acinar cell NF-κB and MCP-1 expression and ductal cell MCP-1 expression were also observed in the fibrotic pancreata, but the activation remained low throughout the 6 hours. Conclusions. In acinar-cell-rich pancreas, an extensive inflammatory cascade begins almost immediately after surgical trauma. Fibrosis may limit the progression of inflammatory process in pancreas.
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Mostaço-Guidolin LB, Kohlenberg EK, Smith M, Hewko M, Major A, Sowa MG, Ko ACT. Quantitative nonlinear optical assessment of atherosclerosis progression in rabbits. Anal Chem 2014; 86:6346-54. [PMID: 24892226 DOI: 10.1021/ac5005635] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Quantification of atherosclerosis has been a challenging task owing to its complex pathology. In this study, we validated a quantitative approach for assessing atherosclerosis progression in a rabbit model using a numerical matrix, optical index for plaque burden, derived directly from the nonlinear optical microscopic images captured on the atherosclerosis-affected blood vessel. A positive correlation between this optical index and the severity of atherosclerotic lesions, represented by the age of the rabbits, was established based on data collected from 21 myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits with age ranging between new-born and 27 months old. The same optical index also accurately identified high-risk locations for atherosclerotic plaque formation along the entire aorta, which was validated by immunohistochemical fluorescence imaging.
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Affiliation(s)
- Leila B Mostaço-Guidolin
- National Research Council Canada , Medical Devices Portfolio, 435 Ellice Avenue, Winnipeg, MB, Canada R3B 1Y6
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Stevenson NL, Martin-Martin B, Freeman J, Kriston-Vizi J, Ketteler R, Cutler DF. G protein-coupled receptor kinase 2 moderates recruitment of THP-1 cells to the endothelium by limiting histamine-invoked Weibel-Palade body exocytosis. J Thromb Haemost 2014; 12:261-272. [PMID: 24735118 PMCID: PMC4238739 DOI: 10.1111/jth.12470] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Accepted: 11/21/2013] [Indexed: 01/13/2023]
Abstract
BACKGROUND G protein-coupled receptors (GPCRs) are a major family of signaling molecules, central to the regulation of inflammatory responses. Their activation upon agonist binding is attenuated by GPCR kinases (GRKs), which desensitize the receptors through phosphorylation. G protein-coupled receptor kinase 2(GRK2) down-regulation in leukocytes has been closely linked to the progression of chronic inflammatory disorders such as rheumatoid arthritis and multiple sclerosis. Because leukocytes must interact with the endothelium to infiltrate inflamed tissues, we hypothesized that GRK2 down-regulation in endothelial cells would also be pro-inflammatory. OBJECTIVES To determine whether GRK2 down-regulation in endothelial cells is pro-inflammatory. METHODS siRNA-mediated ablation of GRK2 in human umbilical vein endothelial cells (HUVECs) was used in analyses of the role of this kinase. Microscopic and biochemical analyses of Weibel-Palade body (WPB) formation and functioning, live cell imaging of calcium concentrations and video analyses of adhesion of monocyte-like THP-1 cells provide clear evidence of GRK2 function in histamine activation of endothelial cells. RESULTS G protein-coupled receptor kinase 2 depletion in HUVECs increases WPB exocytosis and P-selectin-dependent adhesion of THP-1 cells to the endothelial surface upon histamine stimulation, relative to controls. Further, live imaging of intracellular calcium concentrations reveals amplified histamine receptor signaling in GRK2-depleted cells, suggesting GRK2 moderates WPB exocytosis through receptor desensitization. CONCLUSIONS G protein-coupled receptor kinase 2 deficiency in endothelial cells results in increased pro-inflammatory signaling and enhanced leukocyte recruitment to activated endothelial cells. The ability of GRK2 to modulate initiation of inflammatory responses in endothelial cells as well as leukocytes now places GRK2 at the apex of control of this finely balanced process.
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Affiliation(s)
- N L Stevenson
- Endothelial Cell Biology Laboratory, MRC Laboratory for Molecular Cell Biology, UCL, London, UK
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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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Yang LJ, Wan R, Shen JQ, Shen J, Wang XP. Effect of L-cysteine on remote organ injury in rats with severe acute pancreatitis induced by bile-pancreatic duct obstruction. Hepatobiliary Pancreat Dis Int 2013; 12:428-35. [PMID: 23924502 DOI: 10.1016/s1499-3872(13)60067-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Remote organ failure occurs in cases of acute pancreatitis (AP); however, the reports on AP induced by pancreatic duct obstruction are rare. In this study we determined the effect of L-cysteine on pancreaticobiliary inflammation and remote organ damage in rats after pancreaticobiliary duct ligation (PBDL). METHODS AP was induced by PBDL in rats with 5/0 silk. Sixty rats were randomly divided into 4 groups. Groups A and B were sham-operated groups that received injections of saline or L-cysteine (10 mg/kg) intraperitoneally (15 rats in each group). Groups C and D were PBDL groups that received injections of saline or L-cysteine (10 mg/kg) intraperitoneally (15 rats in each group). The tissue samples of the pancreas and remote organs such as the lung, liver, intestine and kidney were subsequently examined for pathological changes under a light microscope. The samples were also stored for the determination of malondialdehyde and glutathione levels. Blood urea nitrogen (BUN), plasma amylase, ALT and AST levels were determined spectrophotometrically using an automated analyzer. Also, we evaluated the effect of L-cysteine on remote organ injury in rats with AP induced by retrograde infusion of 3.5% sodium taurocholate (NaTc) into the bile-pancreatic duct. RESULTS Varying degrees of injury in the pancreas, lung, liver, intestine and kidney were observed in the rats 24 hours after PBDL. The severity of injury to the lung, liver and intestine was attenuated, while injury status was not changed significantly in the pancreas and kidney after L-cysteine treatment. Oxidative stress was also affected by L-cysteine in PBDL-treated rats. The concentration of tissue malondialdehyde decreased in the pancreas and remote organs of PBDL and L-cysteine administrated rats, and the concentration of glutathione increased more significantly than that of the model control group. However, L-cysteine administration reduced the severity of injury in remote organs but not in the pancreas in rats with NaTc-induced AP. CONCLUSION L-cysteine treatment attenuated multiple organ damage at an early stage of AP in rats and modulated the oxidant/antioxidant imbalance.
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Affiliation(s)
- Li-Juan Yang
- Department of Gastroenterology, and Shanghai Key Laboratory of Pancreatic Diseases, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, China
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Heme oxygenase 1-generated carbon monoxide and biliverdin attenuate the course of experimental necrotizing pancreatitis. Pancreas 2013; 42:265-71. [PMID: 23000891 DOI: 10.1097/mpa.0b013e318264cc8b] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The cytoprotective enzyme heme oxygenase 1 (HO-1) is highly up-regulated in acute pancreatitis (AP). In this study, we tested its metabolites as potential therapeutic agents for AP in rats. METHODS Acute necrotizing pancreatitis was induced by retrograde intraductal injection of sodium taurocholate in rats. Biliverdin hydrochloride (BV HCl) (50 μmol/kg subcutaneously), the carbon monoxide, donor methylene chloride (MC) (500 mg/kg orally), or iron-chelating desferrioxamine (DFO) (125 mg/kg subcutaneously) were administered in a therapeutic manner starting with the first dose 4 hours after taurocholate injection to mimic the effects of HO-1 metabolites. RESULTS Administration of BV HCl, MC, or DFO showed significant reduction of inflammatory activity in comparison to controls leading to lower myeloperoxidase activity in the pancreas, less edema, lower ascites volumes, and preservation of tissue integrity (P < 0.05). Administration of either BV HCl or MC markedly increased 5-day survival rate (70% and 75% vs 40%; P < 0.05), whereas DFO had no significant effect on survival (60%). When given in therapeutic manner, all 3 substances led to diminished nuclear factor κB activity in the pancreas (P < 0.05). CONCLUSIONS Therapeutic use of BV HCl and MC led to marked reduction of mortality in experimental pancreatitis. Thus, HO-1 metabolites may present a novel therapeutic approach in AP treatment.
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Prevention effects of ND-07, a novel drug candidate with a potent antioxidative action and anti-inflammatory action, in animal models of severe acute pancreatitis. Eur J Pharmacol 2012; 687:28-38. [PMID: 22575522 DOI: 10.1016/j.ejphar.2012.04.048] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Revised: 04/17/2012] [Accepted: 04/21/2012] [Indexed: 12/17/2022]
Abstract
Oxidative stress and inflammation both play major roles in the development of the acute pancreatitis. Currently, a pancreatic enzyme inhibitor with limited efficacy is only clinically available in a few countries, and antioxidants or non-steroidal anti-inflammatory drugs (NSAIDs) provide only partial tissue protection in acute pancreatitis animal models. Here, we introduce a new drug candidate for treating acute pancreatitis named ND-07 [chemical name: 2-acetoxy-5-(2-4-(trifluoromethyl)-phenethylamino)-benzoic acid] that exhibits both potent antioxidative and anti-inflammatory activities. In an electron spin resonance (ESR) study, ND-07 almost blocked hydroxyl radical generation as low as 0.05 μM and significantly suppressed DNA oxidation and cell death in a lipopolysaccharide (LPS)-stimulated pancreatic cell line. In a cerulein plus LPS-induced acute pancreatitis model, ND-07 pretreatment showed significant tissue protective effects, with reductions of serum amylase and lipase levels and pancreatic wet weights. ND-07 not only diminished the plasma levels of malondialdehyde (MDA) and nitric oxide but also significantly decreased prostaglandin E₂ (PGE₂) and expression of tumor necrotizing factor-alpha (TNF-α) in the pancreatic tissue. In a severe acute necrotizing pancreatitis model induced by a choline deficient, ethionine-supplemented (CDE) diet, ND-07 dramatically protected the mortality even without any death, providing attenuation of pancreas, lung, and liver damages as well as the reductions in serum levels of lactate dehydrogenase (LDH), amylase and lipase, MDA levels in the plasma and pancreatic tissues, plasma levels of TNF-α, and interleukin-1 (IL-1β). These findings suggest that current dual synergistic action mechanisms of ND-07 might provide a superior protection for acute pancreatitis than conventional drug treatments.
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Zerumbone attenuates the severity of acute necrotizing pancreatitis and pancreatitis-induced hepatic injury. Mediators Inflamm 2012; 2012:156507. [PMID: 22529518 PMCID: PMC3317088 DOI: 10.1155/2012/156507] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2011] [Revised: 11/11/2011] [Accepted: 12/10/2011] [Indexed: 12/11/2022] Open
Abstract
This paper investigated the potential effects of zerumbone pretreatment on an acute necrotizing pancreatitis rat model induced by sodium taurocholate. The pancreatitis injury was evaluated by serum AMY, sPLA2, and pancreatic pathological score. Pancreatitis-induced hepatic injury was measured by ALT, AST, and hepatic histopathology. The expression of I-κBα and NF-κB protein was evaluated by western blot and immunohistochemistry assay while ICAM-1 and IL-1β mRNA were examined by RT-PCR. The results showed that AMY, sPLA2, ALT, and AST levels and histopathological assay of pancreatic and hepatic tissues were significantly reduced following administration of zerumbone. Applying zerumbone also has been shown to inhibit NF-κB protein and downregulation of ICAM-1 and IL-1β mRNA. The present paper suggests that treatment of zerumbone on rat attenuates the severity of acute necrotizing pancreatitis and pancreatitis-induced hepatic injury, via inhibiting NF-κB activation and downregulating the expression of ICAM-1 and IL-1β.
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Alhan E, Türkyılmaz S, Erçin C, Kural BV, Flinte D. Does nuclear factor-kappa B in peripheral mononuclear cells have a prognostic role during acute necrotizing pancreatitis in rats? Eur Surg Res 2011; 48:34-9. [PMID: 22189444 DOI: 10.1159/000334306] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2008] [Accepted: 09/06/2011] [Indexed: 01/13/2023]
Abstract
AIM To investigate the prognostic role of nuclear factor-kappa B (NF-κB) activity in peripheral blood mononuclear cells (PBMNCs) during acute necrotizing pancreatitis (ANP) in rats. METHODS ANP was induced by an intravenous infusion of cerulein over 6 h superimposed on glycodeoxycholic acid (10 mmol/l) into the biliary-pancreatic duct for 10 min. The rats were divided into five groups and the first group served as the control. ANP was induced in the remaining groups, which were followed for 6, 12, 24 and 48 h. The mortality rate, serum amylase, alanine transferase (ALT), urea, creatinine and calcium, pancreatic histology, and NF-κB activity in PBMNCs were investigated. The NF-κB activity in PBMNCs was measured as two subunits of NF-κB, p50 and p65. RESULTS A significant increase in mortality rate, pancreatic damage, serum activity of amylase and ALT, urea and NF-κB p65 activity in PBMNCs were observed. There was a significant correlation between the mortality rate and pancreatic damage in conjunction with time, but there was no correlation between NF-κB p65 activity in PBMNCs and the mortality rate. CONCLUSION The measurement of p65 levels of NF-kB in PBMNCs has no prognostic role during ANP in rats.
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Affiliation(s)
- E Alhan
- Department of Surgery, Karadeniz Technical University, Trabzon, 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
OBJECTIVES Nuclear factor-kappaB (NF-kappaB) is a potent mediator in several steps of acute pancreatitis. Leflunomide is a novel immunomodulating drug that is also a potent inhibitor of NF-kappaB activation. The aim of this study was to investigate the effects of leflunomide pretreatment in severe necrotizing pancreatitis in rats. METHODS Fifty rats were randomly divided into 5 groups. Severe necrotizing pancreatitis was induced by retrograde injection of 3% sodium taurocholate into the common biliopancreatic duct. Leflunomide (10 mg/kg) was given intragastrically for 2 doses before the experiment. Serum amylase activity, pancreatic histopathologic condition, malondialdehyde level, myeloperoxidase enzyme activity, nitric oxide level, and pulmonary changes were assessed. RESULTS Leflunomide pretreatment significantly ameliorated pancreatic hemorrhage, edema, and neutrophil infiltration and decreased histopathological score compared with the untreated severe necrotizing pancreatitis group (pathological score [mean +/- SEM]: 6.70 +/- 1.19 vs 12.36 +/- 1.08 in the leflunomide treated and untreated groups, respectively, P < 0.01). Pulmonary changes was decreased in the leflunomide treated group (3.90 +/- 0.45 vs 4.75 +/- 0.25, respectively). Change in pulmonary alveolar distention was significant. Although serum amylase levels also decreased, the difference was not significant (5922 +/- 3290 vs 15547 +/- 5090 U/mL). CONCLUSIONS Leflunomide is a beneficial agent in the severe form of acute pancreatitis in rats and should be considered as a potential agent for treatment of acute pancreatitis.
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Chen H, Sun YP, Li Y, Liu WW, Xiang HG, Fan LY, Sun Q, Xu XY, Cai JM, Ruan CP, Su N, Yan RL, Sun XJ, Wang Q. Hydrogen-rich saline ameliorates the severity of l-arginine-induced acute pancreatitis in rats. Biochem Biophys Res Commun 2010; 393:308-13. [DOI: 10.1016/j.bbrc.2010.02.005] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2010] [Accepted: 02/02/2010] [Indexed: 11/26/2022]
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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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Zhao H, Zhao X, Bai C, Wang X. Potential factors of interorgan signals in the development of pancreatitis-associated acute lung injury and acute respiratory distress syndrome. ACTA ACUST UNITED AC 2009. [DOI: 10.1080/17471060500223365] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Influence of baicalin and octreotide on NF-kappaB and p-selectin expression in liver and kidney of rats with severe acute pancreatitis. Inflammation 2009; 32:1-11. [PMID: 19030975 DOI: 10.1007/s10753-008-9096-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
To observe the influence of Baicalin and Octreotide on liver and kidney of rats with severe acute pancreatitis (SAP) and discuss the related mechanism. SAP rats were randomly divided into model control, Baicalin treated and Octreotide treated group (n = 45). The same number of normal rats were included in sham-operated group (n = 45). In all groups, the mortality rate, pathological changes as well as expression levels of NF-kappaB p65 and P-selectin protein in liver and kidney were observed at 3, 6 and 12 h after operation. The survival rate of treated group was 100% at 12 h significantly higher than that of model control group (P < 0.05). The pathological changes of liver and kidney in treated groups were alleviated to different degrees, the NF-kappaB protein expression levels and pathological severity scores in liver and kidney of treated groups were significantly lower than those of model control group (P < 0.05 or P < 0.001). The hepatic P-selectin protein expression level in Baicalin treated group was significantly lower than that of model control group at 3 h (P < 0.01), and renal P-selectin expression level in Baicalin treated group at 3 and 6 h were significantly lower than those of model control group and Octreotide treated group (P < 0.01). (1) Early treatment with Baicalin or Octreotide have obvious protecting effects on liver and kidney injuries in SAP with their mechanisms associated to inhibiting NF-kappaB and P-selectin expression of liver and kidney. (2) Comparing the pharmacologic effects of Octreotide and Baicalin, we believe Baicalin as a new drug with its protecting effects on liver and kidney of SAP rats similar to Octreotide is worth further studying. (3) The advantages of tissue microarrays in pathological examination include time and energy saving and highly efficient. But the restriction of small diameter weakens the representation of tissues to various extents, which may lead to the deviation of analysis.
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Pereda J, Escobar J, Sandoval J, Rodríguez JL, Sabater L, Pallardó FV, Torres L, Franco L, Viña J, López-Rodas G, Sastre J. Glutamate cysteine ligase up-regulation fails in necrotizing pancreatitis. Free Radic Biol Med 2008; 44:1599-609. [PMID: 18279677 DOI: 10.1016/j.freeradbiomed.2008.01.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2007] [Revised: 01/07/2008] [Accepted: 01/11/2008] [Indexed: 12/22/2022]
Abstract
Glutathione depletion is a key factor in the development of acute pancreatitis. Our aim was to study the regulation of glutamate cysteine ligase, the rate-limiting enzyme in glutathione synthesis, in edematous or necrotizing pancreatitis in rats. Glutathione levels were kept low in necrotizing pancreatitis for several hours, with no increase in protein or mRNA levels of glutamate cysteine ligase subunits, despite binding of RNA polymerase II to their promoters and coding regions. The survival signal pathway mediated by ERK and c-MYC was activated, and c-MYC was recruited to the promoters. The failure in gene up-regulation seems to be due to a marked increase in cytosolic ribonuclease activity. In contrast, in edematous pancreatitis glutathione levels were depleted and rapidly restored, and protein and mRNA expression of glutamate cysteine ligase increased markedly due to enhanced transcription mediated by recruitment of c-MYC, NF-kappaB, and SP-1 to the promoters. No increase in cytosolic ribonuclease activity was found in this case. We propose a novel pathophysiological mechanism to differentiate necrotizing from edematous pancreatitis, which is the inefficient up-regulation of glutamate cysteine ligase caused by increased cytosolic ribonuclease activity in the severe form of the disease. This mechanism would abrogate a rapid recovery of glutathione levels.
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Affiliation(s)
- Javier Pereda
- Department of Physiology, University of Valencia, 46100 Burjasot (Valencia), Spain
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Axelsson J, Andersson E, Andersson R, Lasson Å. Nuclear factor-κB activation in response to active site-inhibited factor VIIa pretreatment during acute pancreatitis in the rat. JOURNAL OF ORGAN DYSFUNCTION 2008; 4:85-92. [DOI: 10.1080/17471060801886167] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Vonlaufen A, Apte MV, Imhof BA, Frossard JL. The role of inflammatory and parenchymal cells in acute pancreatitis. J Pathol 2007; 213:239-248. [PMID: 17893879 DOI: 10.1002/path.2231] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2007] [Accepted: 07/27/2007] [Indexed: 12/20/2022]
Abstract
The infiltration of inflammatory cells into the pancreas is an early and central event in acute pancreatitis that promotes local injury and systemic complications of the disease. Recent research has yielded the important finding that resident cells of the pancreas (particularly acinar and pancreatic stellate cells) play a dynamic role in leukocyte attraction via secretion of chemokines and cytokines and expression of adhesion molecules. Significant progress has been made in recent years in our understanding of the role of leukocyte movement (adhesion to the blood vessel wall, transmigration through the blood vessel wall and infiltration into the parenchyma) in the pathophysiology of acute pancreatitis. This review discusses recent studies and describes the current state of knowledge in the field. It is clear that detailed elucidation of the numerous processes in the inflammatory cascade is an essential step towards the development of improved therapeutic strategies in acute pancreatitis. Studies to date suggest that combination therapy targeting different steps of the inflammatory cascade may be the treatment of choice for this disease.
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Affiliation(s)
- A Vonlaufen
- Pancreatic Research Group, South Western Sydney Clinical School, University of New South Wales, Sydney, Australia.
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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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Liu RL, Liu ML, Ma LL, Wu W. Effect of ulinastatin on nuclear factor-κB expression in acute necrotic pancreatitis in rats. Shijie Huaren Xiaohua Zazhi 2005; 13:2700-2703. [DOI: 10.11569/wcjd.v13.i22.2700] [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
AIM: To evaluate the effect of ulinastatin (UTI) on the expression of nuclear factor-κB (NF-κB) and related cytokines in acute necrotic pancreatitis (ANP) in rats.
METHODS: Thirty Sprague-Dawley rats were random-ly divided into sham operation (SO) group, ANP group and UTI treatment group. The levels of NF-κB, interleu-kin-6 (IL-6), tumor necrosis factor-α (TNF-α) and ser-um amylase in rats were detected. ANP model was in-duced by retrograde administration of 50 g/L sodium taurocholate into biliary-pancreatic duct.
RESULTS: In ANP group, the levels of serum amylase (195907.51±38618.39 nkat/L), TNF-α (41.37±7.54 ng/L), IL-6 (32.32±8.62 ng/L) as well as the expression of pancreatic and pulmonary NF-κB were all increased as compared with those in SO group (all P <0.01). Aft-er treatment with UTI, the levels of serum amylase (69804.30±19432.55 nkat/L), TNF-α (18.66±6.45 ng/L), IL-6 (23.41±7.65 ng/L) as well as the expression of pa-ncreatic and pulmonary NF-κB were all significantly de-creased as compared with those in SO and ANP group (P <0.01).
CONCLUSION: In the pathogenesis of ANP, activated NF-κB and up-regulated TNF-α and IL-6 aggravated the injuries of pancreas and lung tissues. UTI plays a protective role in ANP by inhibiting the activation of NF-κB, so as to alleviate the injuries of pancreas and lung tissues.
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Liu XM, Liu QG, Xu J, Pan CE. Microcirculation disturbance affects rats with acute severe pancreatitis following lung injury. World J Gastroenterol 2005; 11:6208-11. [PMID: 16273652 PMCID: PMC4436642 DOI: 10.3748/wjg.v11.i39.6208] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [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 study the effects of microcirculation disturbance (MD) on rats with acute severe pancreatitis (ASP).
METHODS: We developed ASP rat models, and anatomized separately after 1, 3, 5, 7, and 9 h. We took out blood and did hemorrheologic examination and erythrocyte osmotic fragility test, checked up the water content, capillary permeability, and genetic expression of intercellular adhesion molecule-1 (ICAM-1) in lung tissues, examined the apoptosis degree of blood vessel endothelium while we tested related gene expression of Bax and Bcl-2 in lung tissues. We did the same examination in control group.
RESULTS: The viscosity of total blood and plasma, the hematocrit, and the erythrocyte osmotic fragility were all increased. Fibrinogen was decreased. The water content in lung tissues and capillary permeability were increased. Apoptosis degree of blood vessel endothelium was increased too. ICAM-1 genetic expression moved up after 1 h and reached its peak value after 9 h.
CONCLUSION: MD plays an important role in ASP following acute lung injury (ALI). The functional damage of blood vessel endothelium, the apoptosis of capillary vessel endothelium, WBC edging-concentration and the increasing of erythrocyte fragility are the main reasons of ALI.
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Affiliation(s)
- Xue-Min Liu
- Department of Hepatobiliary Surgery, Xi'an Jiaotong University First Hospital, Xi'an 710061, Shaanxi Province, China.
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Mayerle J, Schnekenburger J, Krüger B, Kellermann J, Ruthenbürger M, Weiss FU, Nalli A, Domschke W, Lerch MM. Extracellular cleavage of E-cadherin by leukocyte elastase during acute experimental pancreatitis in rats. Gastroenterology 2005; 129:1251-67. [PMID: 16230078 DOI: 10.1053/j.gastro.2005.08.002] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2004] [Accepted: 02/02/2005] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Cadherins play an important role in cell-cell contact formation at adherens junctions. During the course of acute pancreatitis, adherens junctions are known to dissociate-a requirement for the interstitial accumulation of fluid and inflammatory cells-but the underlying mechanism is unknown. METHODS Acute pancreatitis was induced in rats by supramaximal cerulein infusion. The pancreas and lungs were either homogenized for protein analysis or fixed for morphology. Protein sequencing was used to identify proteolytic cleavage sites and freshly prepared acini for ex vivo studies with recombinant proteases. Results were confirmed in vivo by treating experimental pancreatitis animals with specific protease inhibitors. RESULTS A 15-kilodalton smaller variant of E-cadherin was detected in the pancreas within 60 minutes of pancreatitis, was found to be the product of E-cadherin cleavage at amino acid 394 in the extracellular domain that controls cell-contact formation, and was consistent with E-cadherin cleavage by leukocyte elastase. Employing cell culture and ex vivo acini leukocyte elastase was confirmed to cleave E-cadherin at the identified position, followed by dissociation of cell contacts and the internalization of cleaved E-cadherin to the cytosol. Inhibition of leukocyte elastase in vivo prevented E-cadherin cleavage during pancreatitis and reduced leukocyte transmigration into the pancreas. CONCLUSIONS These data provide evidence that polymorphonuclear leukocyte elastase is involved in, and required for, the dissociation of cell-cell contacts at adherens junctions, the extracellular cleavage of E-cadherin, and, ultimately, the transmigration of leukocytes into the epithelial tissue during the initial phase of experimental pancreatitis.
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Affiliation(s)
- Julia Mayerle
- Department of Gastroenterology, Endocrinology and Nutrition, Ernst-Moritz-Arndt-Universität Greifswald, Germany
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Shi C, Andersson R, Zhao X, Wang X. Potential role of reactive oxygen species in pancreatitis-associated multiple organ dysfunction. Pancreatology 2005; 5:492-500. [PMID: 16020935 DOI: 10.1159/000087063] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Severe acute pancreatitis is still associated with substantial morbidity and mortality. Experimental and clinical studies have demonstrated that reactive oxygen species (ROS) represent early occurring inflammatory mediators contributing to cell dysfunction, both locally in the pancreas and remote organs. METHOD A systematic literature review was conducted to investigate the potential roles of intra- and intercellular, as well as interorgan signaling of ROS in the development of pancreatitis-associated multiple organ dysfunction syndrome (MODS). A text word search of the Medline, PubMed and Cochrane databases, and a manual search of the citations from these references, was performed. RESULTS ROS directly compromise cellular damage and regulate intercellular signals in pancreatitis-associated MODS. ROS are involved in leukocyte activation, production of cytokines, endothelial barrier dysfunction, and microcirculatory barrier dysfunction in acute pancreatitis. Beside effects on intercellular signaling, ROS also affect intracellular events and activate the transcription factor nuclear factor kappa B that regulates inflammatory cytokine expression. CONCLUSION ROS is a critical factor responsible for the development of pancreatitis-induced remote organ dysfunction via intercellular and interorgan signaling. The role of antioxidant treatment, included as a part of multimodal management, remains to be investigated.
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Affiliation(s)
- Changbin Shi
- Department of Surgery, Lund University Hospital, Lund, Sweden
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Cuzzocrea S, Di Paola R, Mazzon E, Genovese T, Muià C, Centorrino T, Caputi AP. Role of endogenous and exogenous ligands for the peroxisome proliferators activated receptors alpha (PPAR-alpha) in the development of inflammatory bowel disease in mice. J Transl Med 2004; 84:1643-54. [PMID: 15492755 DOI: 10.1038/labinvest.3700185] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid and thyroid hormone receptors. The aim of the present study was to examine the effects of endogenous and exogenous PPAR-alpha ligand on the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). When compared to DNBS-treated PPAR-alpha wild-type (WT) mice, DNBS-treated PPAR-alpha knockout mice (PPAR-alphaKO) mice experienced a higher rate of the extent and severity of the histological signs of colon injury. After administration of DNBS PPAR-alphaWT mice experienced hemorrhagic diarrhea, weight loss and large areas of necrosis in the mucosa of the colon were also observed. Neutrophil infiltration was associated with upregulation of ICAM-1. Immunohistochemistry for nitrotyrosine showed an intense staining in the inflamed colon. Absence of a functional PPAR-alpha gene in PPAR-alphaKO mice resulted in a significant augmentation of all the above-described parameters. On the contrary, the treatment of PPAR-alphaWT with Wy-14643 (1 mg/kg daily i.p) significantly reduced: (i) the degree of hemorrhagic diarrhea and weight loss, (ii) the degree of colon injury, (iii) the rise in MPO activity (mucosa), (iv) the increase in staining (immunohistochemistry) for nitrotyrosine, as well as (v) the upregulation of ICAM-1 caused by DNBS in the colon. In order to elucidate whether the protective effects of Wy-14643 is related to activation of the PPAR-alpha receptor, we also investigated the effect the of Wy-14643 treatment on PPAR-alpha-deficient mice. The absence of the PPAR-alpha receptor significantly abolished the protective effect of the PPAR-alpha agonist against DNBS-induced colitis. Thus, endogenous and exogenous PPAR-alpha ligands reduce the degree of colitis caused by DNBS. We propose that PPAR-alpha ligand may be useful in the treatment of inflammatory bowel disease.
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Affiliation(s)
- Salvatore Cuzzocrea
- Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Policlinico Universitario, Messina, Italy.
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von Dobschuetz E, Bleiziffer O, Pahernik S, Dellian M, Hoffmann T, Messmer K. Soluble complement receptor 1 preserves endothelial barrier function and microcirculation in postischemic pancreatitis in the rat. Am J Physiol Gastrointest Liver Physiol 2004; 286:G791-6. [PMID: 14693506 DOI: 10.1152/ajpgi.00407.2003] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Components of the activated complement cascade are considered to play a pivotal role in ischemia-reperfusion-induced organ injury. With the use of intravital epifluorescence microscopy, we investigated the effect of complement inhibition by the recombinant soluble complement receptor 1 (sCR1; TP10) on the effect of macromolecular microvascular permeability, functional capillary perfusion, and leukocyte endothelium interaction in postischemic pancreatitis. Anaesthetized Sprague-Dawley rats were subjected to 60 min of normothermic pancreatic ischemia induced by microclipping of the blood-supplying arteries of the organ. Rats who received sCR1 (15 mg/kg body wt iv; n = 7) during reperfusion showed a significant reduction of permeability (1.77 +/- 1.34 x 10(-8) cm/s; n = 7) of tetramethylrhodamine isothiocyanate-labeled albumin injected 90 min after the onset of reperfusion compared with vehicle-treated animals (6.95 +/- 1.56 x 10(-8) cm/s; n = 7). At 120 min after the onset of reperfusion, the length of red blood cell-perfused capillaries (functional capillary density) was significantly improved (from 279 +/- 15.7 to 330 +/- 3.7 cm(-1); n = 7) and the number of leukocytes adherent to postcapillary venules was significantly reduced (from 314 +/- 87 to 163 +/- 71 mm(-2); n = 7) by sCR1 compared with vehicle treatment. Complement inhibition by sCR1 effectively ameliorates pancreatic ischemia-reperfusion-induced microcirculatory disturbances and might be considered for treatment of postischemic pancreatitis.
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Affiliation(s)
- E von Dobschuetz
- Dept. of General and Visceral Surgery, Albert Ludwigs Univ., Hugstetter Str. 55, 79106 Freiburg, Germany.
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Tan ZR, Tang GD, Jiang HX, Deng DH, Yuan HF. Effects of antioxidant on NF-κB and iNOS in rats with acute necrotizing pancreatitis. Shijie Huaren Xiaohua Zazhi 2004; 12:711-713. [DOI: 10.11569/wcjd.v12.i3.711] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the influence of antioxidant N-acetylcysteine (NAC) on nuclear factor-kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) in pancreatic tissue of rats with acute necrotizing pancreatitis (ANP).
METHODS: A total of 95 Spraque-Dawley (SD) male rats were randomly divided into control group (group C, n = 25), acute pancreatitis group (group A, n = 35) and NAC intervention group (group N, n = 35). In group A, SD rats were injected twice intraperitoneally with 8 g/L L-arginine (2×1.2 mg/g) in an interval of 1 hour for ANP. In group C, SD rats received the same amount of saline at the same time. In group N, 0.5 mol/L NAC (0.05 mg/g) was administered intraperitoneally 1 hour before the start of L-arginine injection. Animals were killed at 6, 12, 24, 36, and 48 hours after the first L-arginine injection. The concentration of NF-κB and the activity of iNOS in rat's pancreatic tissue of each group were assayed.
RESULTS: The concentration of NF-κB in pancreatic tissue in group N significantly decreased in earlier period than that in group A (10.4±2.3 vs 89.7±6.4, 6.8±3.2 vs 21.5±3.5, 7.9±3.4 vs 32.5±4.5, 5.4±2.7 vs 14.7±5.2, and 5.0±3.7 vs 11.1±2.3, P < 0.05 or P < 0.01). iNOS activity increased in group A, whereas it significantly decreased in group N (15.2± 4.0 vs 24.2±3.8, 28.3±8.0 vs 36.8±6.0, 25.2±3.8 vs 30.5±3.5 , 21.2±3.7 vs 28.7±7.2, and 18.8±5.5 vs 28.2±4.2, P < 0.05 or P < 0.01).
CONCLUSION: Antioxidants may decrease the activity of iNOS through the inhibition of NF-κB activation.
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Keck T, Werner J, Banafsche R, Stalmann A, Schneider L, Gebhard MM, Herfarth C, Klar E. Oxygen radicals promote ICAM-1 expression and microcirculatory disturbances in experimental acute pancreatitis. Pancreatology 2003; 3:156-63. [PMID: 12748425 DOI: 10.1159/000070085] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2002] [Accepted: 08/26/2002] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS The course of pancreatitis is paralleled by a drastic reduction in organ perfusion and increased ICAM-1-mediated leukocyte-endothelial interaction. We aimed to evaluate the effect of oxygen radicals on ICAM-1 expression and the microcirculation in severe acute pancreatitis using the oxygen radical scavenger dimethylsulfoxide (DMSO). MATERIALS AND METHODS Severe pancreatitis was induced in rats (n = 32) who were randomly assigned to one of two groups: either 4 ml/kg 50% DMSO/saline (v/v) started 3 h after induction of pancreatitis or 4 ml/kg saline (control). Microcirculation was evaluated by intermittent intravital microscopy. Serum amylase and lipase, histomorphometric changes, immunohistochemistry for ICAM-1 expression and 24-hour survival were investigated. RESULTS Leukocyte adherence was significantly reduced (4.4 +/- 0.47 vs. 5.58 +/- 0.69 sticker/100 micro m, p < 0.05), and mean capillary (0.96 +/- 0.06 vs. 0.45 +/- 0.13 mm/s; p < 0.01) and venous erythrocyte velocity (1.16 +/- 0.12 vs. 0.58 +/- 0.16 mm/s, p < 0.01) were significantly increased by DMSO treatment. Microcirculatory disturbances were paralleled by an increase in endothelial ICAM-1 expression, whereas DMSO reduced ICAM-1 expression. CONCLUSION DMSO improves pancreatic microcirculation and reduces ICAM-1 expression and subsequent leukocyte adhesion, suggesting an important role of oxygen free radicals in the pathway of endothelial ICAM-1 expression and microcirculatory disturbances in acute pancreatitis.
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Affiliation(s)
- Tobias Keck
- Department of Surgery, University of Freiburg, Germany
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Cuzzocrea S, Pisano B, Dugo L, Ianaro A, Patel NSA, Paola RD, Genovese T, Chatterjee PK, Rosa MD, Caputi AP, Thiemermann C. Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, ligands of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), reduce ischaemia/reperfusion injury of the gut. Br J Pharmacol 2003; 140:366-76. [PMID: 12970094 PMCID: PMC1574022 DOI: 10.1038/sj.bjp.0705419] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2003] [Accepted: 06/16/2003] [Indexed: 11/08/2022] Open
Abstract
1. The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid and thyroid hormone receptors. The thiazolidinedione rosiglitazone and the endogenous cyclopentenone prostaglandin (PG)D2 metabolite, 15-deoxy-Delta12,14-PGJ2 (15d-PGJ2), are two PPAR-gamma ligands, which modulate the transcription of target genes. 2. The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ2 on the tissue injury caused by ischaemia/reperfusion (I/R) of the gut. 3. I/R injury of the intestine was caused by clamping both the superior mesenteric artery and the coeliac trunk for 45 min, followed by release of the clamp allowing reperfusion for 2 or 4 h. This procedure results in splanchnic artery occlusion (SAO) shock. 4. Rats subjected to SAO developed a significant fall in mean arterial blood pressure, and only 10% of the animals survived for the entire 4 h reperfusion period. Surviving animals were killed for histological examination and biochemical studies. Rats subjected to SAO displayed a significant increase in tissue myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels, significant increases in plasma tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels and marked injury to the distal ileum. 5. Increased immunoreactivity to nitrotyrosine was observed in the ileum of rats subjected to SAO. Staining of sections of the ileum obtained from SAO rats with anti-intercellular adhesion molecule (ICAM-1) antibody resulted in diffuse staining. 6. Administration at 30 min prior to the onset of gut ischaemia of the two PPAR-gamma agonists (rosiglitazone (0.3 mg kg-1 i.v.) and 15d-PGJ2 (0.3 mg kg-1 i.v.)) significantly reduced the (i) fall in mean arterial blood pressure, (ii) mortality rate, (iii) infiltration of the reperfused intestine with polymorphonuclear neutrophils (MPO activity), (iv) lipid peroxidation (MDA levels), (v) production of proinflammatory cytokines (TNF-alpha and IL-1beta) and (vi) histological evidence of gut injury. Administration of rosiglitazone and 15d-PGJ2 also markedly reduced the nitrotyrosine formation and the upregulation of ICAM-1 during reperfusion. 7. In order to elucidate whether the protective effects of rosiglitazone and 15d-PGJ2 are related to the activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, bisphenol A diglycidyl ether (BADGE), on the protective effects of rosiglitazone and 15d-PGJ2. BADGE (1 mg kg-1 administered i.v. 30 min prior to the treatment of rosiglitazone or 15d-PGJ2) significantly antagonised the effect of the two PPAR-gamma agonists and thus abolished the protective effect against gut I/R. 8. These results demonstrate that the two PPAR-gamma agonists, rosiglitazone and 15d-PGJ2, significantly reduce I/R injury of the intestine.
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Affiliation(s)
- Salvatore Cuzzocrea
- Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy
| | - Barbara Pisano
- Department of Experimental Pharmacology, University of Naples Federico II, Italy
| | - Laura Dugo
- Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy
| | - Angela Ianaro
- Department of Experimental Pharmacology, University of Naples Federico II, Italy
| | - Nimesh S A Patel
- Department of Experimental Medicine & Nephrology, The William Harvey Research Institute, St Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ
| | - Rosanna Di Paola
- Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy
| | - Tiziana Genovese
- Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy
| | - Prabal K Chatterjee
- Department of Experimental Medicine & Nephrology, The William Harvey Research Institute, St Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ
| | - Massimo Di Rosa
- Department of Experimental Pharmacology, University of Naples Federico II, Italy
| | - Achille P Caputi
- Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy
| | - Christoph Thiemermann
- Department of Experimental Medicine & Nephrology, The William Harvey Research Institute, St Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ
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Li YY, Li XL, Yang CX, Zhong H, Yao H, Zhu L. Effects of tetrandrine and QYT on ICAM-1 and SOD gene expression in pancreas and liver of rats with acute pancreatitis. World J Gastroenterol 2003; 9:155-9. [PMID: 12508373 PMCID: PMC4728232 DOI: 10.3748/wjg.v9.i1.155] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: Available experimental evidence from both clinical and animal models shows that both Chinese medicines tetrandine (Tet) and Qing Yi Tong (QYT) have positive treatment effects on acute pancreatitis (AP). This investigation was conducted to explore the treatment mechanisms of Tet and QYT on AP at the molecular level and thereby explain their therapeutic affects. It included an investigation of the effects of these drugs on gene expression of both intercellular adhesion molecule 1 (ICAM-1) and superoxide dismutase (Mn-SOD and Cu, Zn-SOD) in a rat model with AP.
METHODS: AP in the test rats was induced by subjecting them to laparotomy followed by a retrograde injection of 4% sodium taurocholate into the bilio-pancreatic duct. The test rats with AP were divided into three groups. One was treated with Tet, one with QYT, and one with normal saline solution. The sham-operated control group (SO) rats were only subjected to laparotomy. They were given no further treatment. For the Tet group, Tet was injected intraperitoneally, and for the QYT group, QYT was given with a nose-gastric catheter. These procedures were done at both 10 min and 5 h after AP induction. The levels of ICAM-1 mRNA expression and of SOD (Mn-SOD and Cu, Zn-SOD) mRNA expression in the pancreas and liver tissues were measured by RT-PCR at 1, 5, and 10 h after AP induction.
RESULTS: When compared with the SO group during the observation time, rats with AP showed a higher expression of ICAM and a lower expression of Mn-SOD in both pancreas and liver tissues, and a lower expression of Cu, Zn-SOD in the pancreas. Tet treatment attenuated changes in the expression of both ICAM-1, and SOD (Mn-SOD and Cu, Zn-SOD) to a significant degree. A similar effect on the expression of SOD (Mn-SOD and Cu, Zn-SOD) was also found in the QYT group, but no obvious suppressive effect on ICAM-1 expression was observed.
CONCLUSION: The results of this study suggest that one of the main mechanisms of Tet and QYT in treating AP is to enhance anti-oxidation of the body. The results also suggest that the anti-inflammatory effect of Tet is involved in the reduction of ICAM-1 expression. This explains why Tet and QYT are beneficial in treating AP.
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Affiliation(s)
- Yong-Yu Li
- Department of Pathophysiology, Medical College of Tongji University, Shanghai 200331, China.
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Abstract
Laser microscopic techniques currently used in morphology and cell biology represent highly sensitive tools for detecting biomolecules within their natural environment. Use of the fluorescence-, reflectance- and transmission modes of confocal laser scanning microscopes (CLSM) equipped with He-Ne- and Ar+-ion lasers for CeIV and DAB based detection of endogenous or immunobound enzymatic activities in tissue sections (vibratome, cryostat, paraffin and semithin plastic sections) opens a wide range of interesting new possibilities in cellular and molecular biology. Increased resolution power, blur-free confocal imaging, higher sensitivity, optical sectioning capability and 3D-image analysis provide a large quantity of valuable information about biological objects specimens. The new infrared multiphoton laser scanning microscopy (NIR-LSM) is increasingly becoming the optical tool of choice for (a) fluorescence imaging of cellular and subcellular components with high spatial and temporal resolution, (b) fluorescence resonance energy transfer between physiologically relevant molecular species involving protein-protein interactions, (c) nanoprocessing within living cells and tissues, with varied applications in (d) photochemistry and (e) medical diagnostics as well. Both, CLSM and NIR-LSM as modern microscopical strategies are indispensable in basic research and will prove to be invaluable for clinical diagnostic studies and therapy in the near future.
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Affiliation(s)
- Karl-Jürgen Halbhuber
- Institute of Anatomy II, Faculty of Medicine, Friedrich Schiller University, Teichgraben 7, D-07743 Jena, Germany.
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Wayman NS, Hattori Y, McDonald MC, Mota-Filipe H, Cuzzocrea S, Pisano B, Chatterjee PK, Thiemermann C. Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J 2002; 16:1027-40. [PMID: 12087064 DOI: 10.1096/fj.01-0793com] [Citation(s) in RCA: 284] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This study was designed to investigate the effects of various chemically distinct activators of PPAR-gamma and PPAR-alpha in a rat model of acute myocardial infarction. Using Northern blot analysis and RT-PCR in samples of rat heart, we document the expression of the mRNA for PPAR-gamma (isoform 1 but not isoform 2) as well as PPAR-beta and PPAR-alpha in freshly isolated cardiac myocytes and cardiac fibroblasts and in the left and right ventricles of the heart. Using a rat model of regional myocardial ischemia and reperfusion (in vivo), we have discovered that various chemically distinct ligands of PPAR-gamma (including the TZDs rosiglitazone, ciglitazone, and pioglitazone, as well as the cyclopentanone prostaglandins 15D-PGJ2 and PGA1) cause a substantial reduction of myocardial infarct size in the rat. We demonstrate that two distinct ligands of PPAR-alpha (including clofibrate and WY 14643) also cause a substantial reduction of myocardial infarct size in the rat. The most pronounced reduction in infarct size was observed with the endogenous PPAR-gamma ligand, 15-deoxyDelta12,14-prostagalndin J2 (15D-PGJ2). The mechanisms of the cardioprotective effects of 15D-PGJ2 may include 1) activation of PPAR-alpha, 2) activation of PPAR-gamma, 3) expression of HO-1, and 4) inhibition of the activation of NF-kappaB in the ischemic-reperfused heart. Inhibition by 15D-PGJ2 of the activation of NF-kappaB in turn results in a reduction of the 1) expression of inducible nitric oxide synthase and the nitration of proteins by peroxynitrite, 2) formation of the chemokine MCP-1, and 3) expression of the adhesion molecule ICAM-1. We speculate that ligands of PPAR-gamma and PPAR-alpha may be useful in the therapy of conditions associated with ischemia-reperfusion of the heart and other organs. Our findings also imply that TZDs and fibrates may help protect the heart against ischemia-reperfusion injury. This beneficial effect of 15D-PGJ2 was associated with a reduction in the expression of the 1) adhesion molecules ICAM-1 and P-selectin, 2) chemokine macrophage chemotactic protein 1, and 3) inducible isoform of nitric oxide synthase. 15D-PGJ2 reduced the nitration of proteins (immunohistological analysis of nitrotyrosine formation) caused by ischemia-reperfusion, likely due to the generation of peroxynitrite. Not all of the effects of 15D-PGJ2, however, are due to the activation of PPAR-gamma. For instance, exposure of rat cardiac myocytes to 15D-PGJ2, but not to rosiglitazone, results in an up-regulation of the expression of the mRNA for heme-oxygenase-1 (HO-1). Taken together, these results provide convincing evidence that several, chemically distinct ligands of PPAR-gamma reduce the tissue necrosis associated with acute myocardial infarction.
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Affiliation(s)
- Nicole S Wayman
- Department of Experimental Medicine and Nephrology, William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London EC1M 6BQ, UK
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Immunomodulatory Treatment of Severe Acute Pancreatitis. Intensive Care Med 2002. [DOI: 10.1007/978-1-4757-5551-0_70] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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