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Upton JEM, Grunebaum E, Sussman G, Vadas P. Platelet Activating Factor (PAF): A Mediator of Inflammation. Biofactors 2022; 48:1189-1202. [PMID: 36029481 DOI: 10.1002/biof.1883] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/21/2022] [Indexed: 12/24/2022]
Abstract
Platelet-activating factor (PAF) is a phospholipid-derived mediator with an established role in multiple inflammatory states. PAF is synthesized and secreted by multiple cell types and is then rapidly hydrolyzed and degraded to an inactive metabolite, lyso-PAF, by the enzyme PAF acetylhydrolase. In addition to its role in platelet aggregation and activation, PAF contributes to allergic and nonallergic inflammatory diseases such as anaphylaxis, sepsis, cardiovascular disease, neurological disease, and malignancy as demonstrated in multiple animal models and, increasingly, in human disease states. Recent research has demonstrated the importance of the PAF pathway in multiple conditions including the prediction of severe pediatric anaphylaxis, effects on blood-brain barrier permeability, effects on reproduction, ocular diseases, and further understanding of its role in cardiovascular risk. Investigation of PAF as both a biomarker and a therapeutic target continues because of the need for directed management of inflammation. Collectively, studies have shown that therapies focused on the PAF pathway have the potential to provide targeted and effective treatments for multiple inflammatory conditions.
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Affiliation(s)
- Julia E M Upton
- Division of Immunology and Allergy, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Eyal Grunebaum
- Division of Immunology and Allergy, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Gordon Sussman
- Division of Clinical Immunology and Allergy, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Peter Vadas
- Division of Clinical Immunology and Allergy, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
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Ke L, Zhou J, Mao W, Chen T, Zhu Y, Pan X, Mei H, Singh V, Buxbaum J, Doig G, He C, Gu W, Lu W, Tu S, Ni H, Zhang G, Zhao X, Sun J, Chen W, Song J, Shao M, Tu J, Xia L, He W, Zhu Q, Li K, Yao H, Wu J, Fu L, Jiang W, Zhang H, Lin J, Li B, Tong Z, Windsor J, Liu Y, Li W. Immune enhancement in patients with predicted severe acute necrotising pancreatitis: a multicentre double-blind randomised controlled trial. Intensive Care Med 2022; 48:899-909. [PMID: 35713670 PMCID: PMC9205279 DOI: 10.1007/s00134-022-06745-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/16/2022] [Indexed: 12/24/2022]
Abstract
PURPOSE Infected pancreatic necrosis (IPN) is a highly morbid complication of acute necrotising pancreatitis (ANP). Since there is evidence of early-onset immunosuppression in acute pancreatitis, immune enhancement may be a therapeutic option. This trial aimed to evaluate whether early immune-enhancing Thymosin alpha 1 (Tα1) treatment reduces the incidence of IPN in patients with predicted severe ANP. METHODS We conducted a multicentre, double-blind, randomised, placebo-controlled trial involving ANP patients with an Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥ 8 and a computed tomography (CT) severity score ≥ 5 admitted within 7 days of the advent of symptoms. Enrolled patients were assigned to receive a subcutaneous injection of Tα1 1.6 mg every 12 h for the first 7 days and 1.6 mg once a day for the subsequent 7 days or matching placebos (normal saline). The primary outcome was the development of IPN during the index admission. RESULTS A total of 508 patients were randomised, of whom 254 were assigned to receive Tα1 and 254 placebo. The vast majority of the participants required admission to the intensive care unit (ICU) (479/508, 94.3%). During the index admission, 40/254(15.7%) patients in the Tα1 group developed IPN compared with 46/254 patients (18.1%) in the placebo group (difference -2.4% [95% CI - 7.4 to 5.1%]; p = 0.48). The results were similar across four predefined subgroups. There was no difference in other major complications, including new-onset organ failure (10.6% vs. 15%), bleeding (6.3% vs. 3.5%), and gastrointestinal fistula (2% vs. 2.4%). CONCLUSION The immune-enhancing Tα1 treatment of patients with predicted severe ANP did not reduce the incidence of IPN during the index admission.
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Affiliation(s)
- Lu Ke
- Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210000, Jiangsu, China
- National Institute of Healthcare Data Science, Nanjing University, Nanjing, 210010, Jiangsu, China
| | - Jing Zhou
- Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210000, Jiangsu, China
- Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, 210010, Jiangsu, China
| | - Wenjian Mao
- Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, 210010, Jiangsu, China
| | - Tao Chen
- Department of Public Health, Policy and Systems, Institute of Population Health, Whelan Building, Quadrangle, The University of Liverpool, Liverpool, L69 3GB, UK
| | - Yin Zhu
- Pancreatic Disease Centre, Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Xinting Pan
- Department of Emergency Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Hong Mei
- Department of Critical Care Medicine, The Affiliated Hospital of Zunyi Medical University, Zunyi, 536000, Guizhou, China
| | - Vikesh Singh
- Pancreatitis Centre, Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - James Buxbaum
- Division of Gastroenterology, Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, USA
| | - Gordon Doig
- Northern Clinical School, Royal, North Shore Hospital, University of Sydney, Sydney, Australia
| | - Chengjian He
- Department of Critical Care Medicine, the Affiliated Nanhua Hospital, University of South China, Hengyang, 421002, Hunan, China
| | - Weili Gu
- Department of Critical Care Medicine, Affiliated Hospital 2 of Nantong University, Nantong, 226000, Jiangsu, China
| | - Weihua Lu
- Department of Intensive Care Unit, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, Anhui, China
| | - Shumin Tu
- Department of Emergency Medicine, Shangqiu First People's Hospital, Shangqiu, 476000, Henan, China
| | - Haibin Ni
- Department of Emergency Medicine, Jiangsu Provincial Hospital of Integrated Chinese and Western Medicine, Nanjing, 210010, Jiangsu, China
| | - Guoxiu Zhang
- Department of Emergency Medicine, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, Henan, China
| | - Xiangyang Zhao
- Department of Intensive Care Unit, Qilu Hospital of Shandong University, Qingdao, 266000, Shandong, China
| | - Junli Sun
- Department of Intensive Care Unit, Luoyang Central Hospital, Zhengzhou University, Luoyang, 471100, Henan, China
| | - Weiwei Chen
- Department of Gastroenterology, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China
| | - Jingchun Song
- Department of Critical Care Medicine, 94Th Hospital of PLA, Nanchang, 330006, Jiangxi, China
| | - Min Shao
- Department of Intensive Care Unit, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Jianfeng Tu
- Department of Emergency Medicine, Zhejiang Provincial People's Hospital, Hangzhou, 310014, Zhejiang, China
| | - Liang Xia
- Pancreatic Disease Centre, Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Wenhua He
- Pancreatic Disease Centre, Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Qingyun Zhu
- Department of Emergency Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Kang Li
- Department of Critical Care Medicine, The Affiliated Hospital of Zunyi Medical University, Zunyi, 536000, Guizhou, China
| | - Hongyi Yao
- Department of Critical Care Medicine, the Affiliated Nanhua Hospital, University of South China, Hengyang, 421002, Hunan, China
| | - Jingyi Wu
- Department of Intensive Care Unit, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, Anhui, China
| | - Long Fu
- Department of Emergency Medicine, Shangqiu First People's Hospital, Shangqiu, 476000, Henan, China
| | - Wendi Jiang
- Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210000, Jiangsu, China
| | - He Zhang
- Department of Critical Care Medicine, Jinling Hospital, Medical School of Southeast University, Nanjing, 210002, Jiangsu, China
| | - Jiajia Lin
- Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210000, Jiangsu, China
| | - Baiqiang Li
- Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210000, Jiangsu, China
| | - Zhihui Tong
- Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210000, Jiangsu, China.
| | - John Windsor
- Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1142, New Zealand
| | - Yuxiu Liu
- Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210000, Jiangsu, China
- Department of Medical Statistics, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China
| | - Weiqin Li
- Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210000, Jiangsu, China.
- Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, 210010, Jiangsu, China.
- National Institute of Healthcare Data Science, Nanjing University, Nanjing, 210010, Jiangsu, China.
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Gao L, Chong E, Pendharkar S, Hong J, Windsor JA, Ke L, Li W, Phillips A. The Effects of NLRP3 Inflammasome Inhibition in Experimental Acute Pancreatitis: A Systematic Review and Meta-Analysis. Pancreas 2022; 51:13-24. [PMID: 35195590 DOI: 10.1097/mpa.0000000000001971] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
ABSTRACT Acute pancreatitis (AP) is an inflammatory disease, and NLRP3 inflammasome activation is involved in the pathogenesis of AP. Previous research showed that inhibition of NLRP3 inflammasome may exert protective effects on animal models of AP and reduces disease severity. The aim of this systematic review and meta-analysis is to evaluate the effects of drug treatment of NLRP3 inflammasome on the outcomes of experimental AP. PubMed, Embase, Medline, and Web of Science databases were searched for relevant articles without language restrictions. The main outcomes for this study included local pancreatic injury, the incidence of systemic inflammatory responses, and the incidence of organ failure. Twenty-eight animal studies including 556 animals with AP were included in the meta-analysis. Compared with controls, inhibition of NLRP3 inflammasome significantly reduced the pancreatic histopathological scores, serum amylase, and lipase levels. In addition, inhibition of NLRP3 inflammasome reduced the levels of circulating inflammatory cytokines, as well as mitigating severity of AP-associated acute lung injury and acute intestinal injury. To conclude, inhibition of NLRP3 inflammasome has protective effects on AP by mitigating organ injury and systemic inflammation in animal studies, indicating that NLRP3 inflammasome holds promise as a target for specific AP therapy.
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Affiliation(s)
| | - Eric Chong
- Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, School of Medicine, University of Auckland, Auckland, New Zealand
| | - Sayali Pendharkar
- Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, School of Medicine, University of Auckland, Auckland, New Zealand
| | | | | | - Lu Ke
- From the Center of Severe Acute Pancreatitis, Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Weiqin Li
- From the Center of Severe Acute Pancreatitis, Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
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Malla RR, Kumari S, Amajala KC, Deepak KGK, Gugalavath S, Rokkam P. Methods and Models in Exploring Pancreatic Functions. EXPLORING PANCREATIC METABOLISM AND MALIGNANCY 2019:253-268. [DOI: 10.1007/978-981-32-9393-9_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Sarr MG. Minimal access necrosectomy: the newest advance of many in the treatment of necrotising pancreatitis. Gut 2018; 67:599-600. [PMID: 28798041 DOI: 10.1136/gutjnl-2017-314660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 06/08/2017] [Accepted: 07/25/2017] [Indexed: 12/08/2022]
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Akinosoglou K, Gogos C. Immune-modulating therapy in acute pancreatitis: Fact or fiction. World J Gastroenterol 2014; 20:15200-15215. [PMID: 25386069 PMCID: PMC4223254 DOI: 10.3748/wjg.v20.i41.15200] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Revised: 05/21/2014] [Accepted: 06/17/2014] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is one of the most common diseases of the gastrointestinal tract, bearing significant morbidity and mortality worldwide. Current treatment of AP remains unspecific and supportive and is mainly targeted to aggressively prevent systemic complications and organ failure by intensive care. As acute pancreatitis shares an indistinguishable profile of inflammation with sepsis, therapeutic approaches have turned towards modulating the systemic inflammatory response. Targets, among others, have included pro- and anti-inflammatory modulators, cytokines, chemokines, immune cells, adhesive molecules and platelets. Even though, initial results in experimental models have been encouraging, clinical implementation of immune-regulating therapies in acute pancreatitis has had a slow progress. Main reasons include difficulty in clinical translation of experimental data, poor understanding of inflammatory response time-course, flaws in experimental designs, need for multimodal approaches and commercial drawbacks. Whether immune-modulation in acute pancreatitis remains a fact or just fiction remains to be seen in the future.
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Saluja AK, Dudeja V. Relevance of animal models of pancreatic cancer and pancreatitis to human disease. Gastroenterology 2013; 144:1194-8. [PMID: 23622128 PMCID: PMC5724756 DOI: 10.1053/j.gastro.2013.01.070] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 01/19/2013] [Accepted: 01/22/2013] [Indexed: 02/07/2023]
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Singh P, Singh IN, Mondal SC, Singh L, Garg VK. Platelet-activating factor (PAF)-antagonists of natural origin. Fitoterapia 2012; 84:180-201. [PMID: 23160091 DOI: 10.1016/j.fitote.2012.11.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Revised: 10/30/2012] [Accepted: 11/04/2012] [Indexed: 01/06/2023]
Abstract
Presently herbal medicines are being used by about 80% of the world population for primary health care as they stood the test of time for their safety, efficacy, cultural acceptability and lesser side effects. The discovery of platelet activating factor antagonists (PAF antagonists) during these decades are going on with different framework, but the researchers led their efficiency in studying in vitro test models. Since it is assumed that PAF play a central role in etiology of many diseases in humans such as asthma, neuronal damage, migraine, cardiac diseases, inflammatory, headache etc. Present days instinctively occurring PAF antagonist exists as a specific grade of therapeutic agents for the humans against these and different diseases either laid hold of immunological or non-immunological types. Ginkgolide, cedrol and many other natural PAF antagonists such as andrographolide, α-bulnesene, cinchonine, piperine, kadsurenone, different Piper species' natural products and marine origin plants extracts or even crude drugs having PAF antagonist properties are being used currently against different inflammatory pathologies. This review is an attempt to summarize the data on PAF and action of natural PAF antagonists on it, which were evaluated by in vivo and in vitro assays.
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Affiliation(s)
- Preeti Singh
- Department of Pharmacology, R.V.N.I. Dadri, Greater Noida, 201301, Uttar Pradesh, India.
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Abstract
There is an ongoing effort to revise the 1992 Atlanta classification of acute pancreatitis in the light of emerging evidence. The categorization of the severity of acute pancreatitis is one of the key elements of the classification. This paper aims to define the optimal number of categories and provide their definitions on sound clinical grounds.
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Xu Z, Smith JS, Tian J, Byrnes AP. Induction of shock after intravenous injection of adenovirus vectors: a critical role for platelet-activating factor. Mol Ther 2009; 18:609-16. [PMID: 19953082 DOI: 10.1038/mt.2009.279] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Innate immune responses are a major barrier to safe systemic gene therapy with adenovirus (Ad) vectors. We show that intravenous (IV) injection of rats with Ad5 vectors causes a novel rapid shock reaction that involves hypotension, hemoconcentration, tissue edema, and vasocongestion, with notable pathology in the pancreas and the gastrointestinal system. We show for the first time that this reaction is dependent on platelet-activating factor (PAF), a lipid signaling molecule that is a known shock inducer. Ad upregulated PAF within 5 minutes in vivo, and antagonists of the PAF receptor were able to prevent Ad-induced shock. Ad upregulated PAF via the reticuloendothelial system (RES), because splenectomy or depletion of phagocytes blocked the ability of Ad to induce both PAF and shock. Rats were considerably more sensitive to Ad-induced shock than were mice, but PAF mediated shock in both species. Other Ad-induced innate immune responses such as cytokine induction and thrombocytopenia were not mediated by PAF. In summary, systemic IV injection of Ad stimulates the RES to upregulate PAF within a matter of minutes, which results in shock. The identification of this novel pathway suggests strategies to improve the safety of systemic gene therapy with Ad vectors.
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Affiliation(s)
- Zhili Xu
- Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA
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Protection of Salvia miltiorrhizae to the spleen and thymus of rats with severe acute pancreatitis or obstructive jaundice. Mediators Inflamm 2009; 2009:186136. [PMID: 20016826 PMCID: PMC2790077 DOI: 10.1155/2009/186136] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2009] [Accepted: 08/31/2009] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE To investigate the therapeutic effects and mechanism of Salvia miltiorrhizae in the treatment of SAP and OJ. METHODS A total of 288 rats were used for SAP- and OJ-associated experiments. The rats were randomly divided into sham-operated group, model control group and treated group. The mortality rates of rats, contents of endotoxin and PLA(2) in blood, pathological changes of different indexes in spleen and thymus were observed. RESULTS The contents of endotoxin and PLA2 in treated group were significantly lower than those in model control group.The pathological severity scores of spleen and thymus of SAP rats as well as that of spleen of OJ rats in treated groups were significantly lower than those in model control groups (P < .05). The staining intensity as well as the product of the staining intensity and positive rate of Bax protein of spleen in model control group were significantly higher than those in treated groups (P < .01) , and the apoptosis index of spleen in treated group was significantly lower than that in model control group (P < .01). CONCLUSION Salvia miltiorrhizae exerts protective effects on the spleen and thymus of SAP rats and spleen of OJ rats.
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Zhang X, Chen L, Zhang J, Tian H, Zhang X, Zhou Y, Wang Z, Wang K. Effect of salvia miltiorrhizae on apoptosis and NF-kappaB p65 expression in the liver of rats with severe acute pancreatitis or obstructive jaundice. J Gastroenterol Hepatol 2009; 24:841-52. [PMID: 19067778 DOI: 10.1111/j.1440-1746.2008.05692.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
OBJECTIVE To investigate the therapeutic effects and mechanism of salvia miltiorrhizae in the treatment of severe acute pancreatitis (SAP) or obstructive jaundice (OJ). METHODS SAP rat models were prepared and randomly divided into the model control group and treated group. The sham-operated group was also set. At 3 h, 6 h and 12 h after operation, the mortality rate, the pathological changes in the liver, the contents of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, the expression levels of Bax and NF-kappaB p65 proteins in the liver, and the apoptosis index of hepatic cells in SAP rats in each group were observed. On days 7, 14, 21 and 28 after operation, the above parameters and the contents of TBILI (total billirubin), DBILI (direct bilirubin) and r-GT (r-glutamyl transpeptidase) in serum in OJ rats were observed. RESULTS The contents of serum ALT (at 6 h and 12 h after operation) and AST (at 3 h and 12 h after operation) as well as the staining intensity of NF-kappaB p65 protein (at 12 h after operation) in the liver of SAP rats in the treated group were significantly lower than those in model control group (all P < 0.01). The pathological severity scores (on 21 d and 28 d after operation) in the liver, the contents of serum ALT (on 14 d and 21 d after operation), AST (on 21 d after operation), TBILI (on 21 d and 28 d after operation), DBILI (on 28 d after operation) and r-GT (on 21 d after operation), and the apoptosis index of hepatic cells in OJ rats in treated group were significantly lower than those in model control group (all P < 0.05). The positive rates of Bax protein (on 28 d after operation) in treated group was significantly lower than model control group (P < 0.05). CONCLUSIONS Salvia miltiorrhizae is able to improve the liver function of SAP or OJ rats, suppress the expression of NF-kappaB p65 protein in the liver of SAP rats, and inhibit apoptosis in OJ rats, thereby showing some protective effects on the liver of SAP or OJ rats.
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Affiliation(s)
- Xiping Zhang
- Department of General Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
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Chen C, Xia SH, Chen H, Li XH. Therapy for acute pancreatitis with platelet-activating factor receptor antagonists. World J Gastroenterol 2008; 14:4735-8. [PMID: 18720532 PMCID: PMC2739333 DOI: 10.3748/wjg.14.4735] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [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
Acute pancreatitis (AP) causes release of platelet-activating factor (PAF), which induces systemic effects that contribute to circulatory disturbances and multiple organ failure. PAF is a cell surface secretion of bioactive lipid, which could produce physiological and pathological effects by binding to its cell surface receptor called platelet-activating factor receptor (PAF-R). Studies showed that PAF participates in the occurrence and development of AP and administration of platelet-activating factor receptor antagonists (PAF-RAs) could significantly reduce local and systemic events after AP. PAF has also been implicated as a key mediator in the progression of severe AP, which can lead to complications and unacceptably high mortality rates. Several classes of PAF-RA show PAF-RAs significant local and systemic effects on reducing inflammatory changes. As a preventive treatment, PAF-RA could block a series of PAF-mediated inflammatory injury and thus improve the prognosis of AP. This review introduces the important role of PAF-RA in the treatment of AP.
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The protecting effects and mechanisms of Baicalin and Octreotide on heart injury in rats with SAP. Mediators Inflamm 2008; 2007:19469. [PMID: 18274634 PMCID: PMC2220025 DOI: 10.1155/2007/19469] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2007] [Accepted: 10/24/2007] [Indexed: 12/13/2022] Open
Abstract
Purpose. To observe the protecting effects and mechanisms
of Baicalin and Octreotide on heart injury in rats with severe
acute pancreatitis (SAP).
Methods. The SAP rat models were randomly divided into
the model group, Baicalin-treated group, Octreotide treated group,
and sham operation group. The contents of some inflammatory
indexes in blood were determined. The rat mortality, pathological
changes of heart, the changes of NF-κB,
P-Selectin, Bax, Bcl-2, and Caspase-3 protein
expression levels as well as apoptotic index were observed in all
groups, respectively, at 3 hours, 6 hours, and 12 hours after
operation.
Results. The survival rate of model group was less
than treated groups at 12 hours, difference was significant. The
contents of some inflammatory indexes of the treated groups were
lower than those of the model group to various degrees at
different time points. The pathological myocardial changes under
light microscope were milder in treated groups than in model
group. The changes of
NF-κB,
P-Selectin, Bax, Bcl-2, and Caspase-3 protein expression levels in
all groups were different. There was only a case of myocardial
cell apoptosis in an Octreotide-treated group at 6 hours.
Conclusion. Baicalin and Octreotide have protecting
effects on heart injury of rats with SAP.
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Abstract
The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may be useful as prophylaxis against Post Endoscopic retrograde cholangiopancreatography Pancreatitis (PEP). The protease inhibitor Gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL) is a nitrogen oxide (NO) donor, which relaxes the sphincter of Oddi. Studies show conflicting results when applied prior to ERCP and a large multicenter randomized study is warranted. Steroids administered as prophylaxis against PEP has been validated without effect in several randomized trials. The non-steroidal anti-inflammatory drugs (NSAID) indomethacin and diclofenac have in randomized studies showed potential as prophylaxis against PEP. Interleukin 10 (IL-10) is a cytokine with anti-inflammatory properties but two trials testing IL-10 as prophylaxis to PEP have returned conflicting results. Antibodies against tumor necrosis factor-alpha (TNF-α) have a potential as rescue therapy but no clinical trials are currently being conducted. The antibiotics beta-lactams and quinolones reduce mortality when necrosis is present in pancreas and may also reduce incidence of infected necrosis. Evidence based pharmacological treatment of AP is limited and studies on the effect of potent anti-inflammatory drugs are warranted.
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Zhang XP, Wang L, Zhou YF. The pathogenic mechanism of severe acute pancreatitis complicated with renal injury: a review of current knowledge. Dig Dis Sci 2008; 53:297-306. [PMID: 17597411 DOI: 10.1007/s10620-007-9866-5] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2006] [Accepted: 06/04/2006] [Indexed: 01/30/2023]
Abstract
The onset of severe acute pancreatitis (SAP) is clinically harmful as it may rapidly progress from a local pancreatic inflammation into proemial systemic inflammatory reactions. Patients with SAP have a high mortality, with most cases of death resulting from complications involving the failure of organs other than the pancreas. The distinctive feature of SAP is that once it starts, it may aggrevate the clinical condition of the patient continuously, so that the levels of injury to the other organs surpass the severity of the pancreatic lesion, even causing multiple organ failure and, ultimately, death. In clinical practice, the main complications in terms of organ dysfunctions are shock, acute respiratory failure, acute renal failure, among others. The acute renal injury caused by SAP is not only able to aggravate the state of pancreatitis, but it also develops into renal failure and elevates patients' mortality. Studies have found that the injury due to massive inflammatory mediators, microcirculation changes and apoptosis, among others, may play important roles in the pathogenic mechanism of acute renal injury.
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Affiliation(s)
- Xi Ping Zhang
- Department of General Surgery, Hangzhou First People's Hospital, Hangzhou, Zhejiang Province 310006, China.
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17
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Zhang XP, Wu CJ, Li ZJ. Advances in research of severe acute pancreatitis complicated by lung injury. Shijie Huaren Xiaohua Zazhi 2008; 16:299-306. [DOI: 10.11569/wcjd.v16.i3.299] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [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
Lung injury is one of the most common complications of severe acute pancreatitis (SAP). At present, the pathogenesis of SAP complicated by lung injury still remains unclear. However, great attention has been paid to it at home and abroad. Many factors such as pancreatic enzyme, polymorphonuclear neutrophil, oxygen free radical, cytokine, microcirculatory disturbance, complement, kinin, NO and ET play an important role in the pathogenesis of SAP by interacting with each other. This paper reviews the advances in the pathogenesis of SAP complicated by lung injury and related studies in order to provide the theoretical basis for its effective prevention and treatment.
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Tang WF, Wan MH. Progress in evidence-based medicine for treatment of severe acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2008; 16:292-298. [DOI: 10.11569/wcjd.v16.i3.292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [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
Severe acute pancreatitis (SAP) is an abdominal catastrophe with a high morbidity and mortality. Up to now, no special drugs or therapeutic methods are available for SAP. Since evidence-based medicine came into being, much more clinical evidence has provided better choice of treatment for SAP. However, such evidence does not fit for all ASP patients based on its critical inclusion and exclusion criteria. It is, therefore, important to treat ASP patients by combining such evidence with clinical experiences.
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Zhang XP, Wang L, Zhang J. Study progress on mechanism of severe acute pancreatitis complicated with hepatic injury. J Zhejiang Univ Sci B 2007; 8:228-36. [PMID: 17444596 PMCID: PMC1838834 DOI: 10.1631/jzus.2007.b0228] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Study on the action mechanism of inflammatory mediators generated by the severe acute pancreatitis (SAP) in multiple organ injury is a hotspot in the surgical field. In clinical practice, the main complicated organ dysfunctions are shock, respiratory failure, renal failure, encephalopathy, with the rate of hepatic diseases being closely next to them. The hepatic injury caused by SAP cannot only aggravate the state of pancreatitis, but also develop into hepatic failure and cause patient death. Its complicated pathogenic mechanism is an obstacle in clinical treatment. Among many pathogenic factors, the changes of vasoactive substances, participation of inflammatory mediators as well as OFR (oxygen free radical), endotoxin, etc. may play important roles in its progression.
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Affiliation(s)
- Xi-ping Zhang
- Department of General Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China.
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21
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Abstract
Many animal models are available to investigate the pathogenesis of pancreatitis, an inflammatory disorder of the pancreas. However, the secretagogue hyperstimulation model of pancreatitis is the most commonly used. Animals infused with high doses of cholecystokinin (CCK) exhibit hyperamylasemia, pancreatic edema, and acinar cell injury, which closely mimic pancreatitis in humans. Intra-acinar zymogen activation is an essential early event in the pathogenesis of secretagogue-induced pancreatitis. Early in the course of pancreatitis, lysosomal hydrolases colocalize with digestive zymogens and activate them. These activated zymogens then cause acinar cell injury and necrosis, a characteristic of pancreatitis. Besides being the site of initiation of injury in pancreatitis, acinar cells also synthesize and release cytokines and chemokines very early in the course of pancreatitis, which then attract and activate inflammatory cells and initiate the disease's systemic phase.
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Affiliation(s)
- Ashok K Saluja
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA.
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Affiliation(s)
- Stephen J Pandol
- Department of Medicine, Department of Veterans Affairs and University of California, Los Angeles, California, USA.
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Abstract
Acute pancreatitis generates a complex cascade of immunological events that affect the pathogenesis and the progression of this disease. Several inflammatory mediators seem to play a critical role in the pathogenesis of pancreatitis and the subsequent inflammatory response. In turn, these mediators can influence hemostasis. Coagulation abnormalities occur in acute pancreatitis and are related to its severity. The contribution of blood platelets in the disturbed hemostasis in acute pancreatitis, although extensively studied, remains obscure. This article reviews the local and systemic implications of hemostatic abnormalities during acute pancreatitis. Furthermore, we discuss the prognostic value and the potential therapeutic implications of platelet activation and other hemostatic variables.
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Affiliation(s)
- Anna Kakafika
- Department of Clinical Biochemistry, Royal Free Hospital, Royal Free and University College School of Medicine, London, UK
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24
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Abstract
Acute pancreatitis has an incidence of approximately 40 cases per year per 100,000 adults. Although usually self-limiting, 10% to 20% of afflicted patients will progress to severe pancreatitis. The mortality rate among patients with severe pancreatitis may approach 30% when they progress to multisystem organ failure. The development of acute pancreatitis illustrates the requirement for understanding the basic mechanisms of disease progression to drive the exploration of therapeutic options. The pathogenesis of acute pancreatitis involves the interplay of local and systemic immune responses that are often difficult to characterize, particularly when results from animal models are used as a foundation for human trials. Experimental studies suggest that the prognosis for acute pancreatitis depends upon the degree of pancreatic necrosis and the intensity of multisystem organ failure generated by the systemic inflammatory response. This suggests an intricate balance between localized tissue damage with proinflammatory cytokine production and a systemic, anti-inflammatory response that restricts the inappropriate movement of proinflammatory agents into the circulation. The critical players of this interaction include the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, IL-8, and platelet activating factor (PAF). The anti-inflammatory cytokines IL-10, as well as TNF-soluble receptors and IL-1 receptor antagonist, have also been shown to be intimately involved in the inflammatory response to acute pancreatitis. Other compounds implicated in disease pathogenesis in experimental models include complement, bradykinin, nitric oxide, reactive oxygen intermediates, substance P, and higher polyamines. Several of these mediators have been documented to be present at increased concentrations in the plasma of patients with severe, acute pancreatitis. Preclinical work has shown that some of these mediators are markers for disease activity, whereas other inflammatory components may actually drive the disease process as important mediators. Implication of such mediators suggests that interruption or blunting of an inappropriate immune response has the potential to improve outcome. Although the manipulations of specific mediators in animal models may be promising, they may not transition well to the human clinical setting. However, continued reliance on experimental animal models of acute pancreatitis may be necessary to determine the underlying causes of disease. Full understanding of these basic mechanisms involves determining not only which mediators are present, but also closely documenting the kinetics of their appearance. Measurement of the inflammatory response may also serve to identify diagnostic markers for the presence of acute pancreatitis and provide insight into prognosis. Understanding the models, documenting the markers, and deciphering the mediators have the potential to improve treatment of acute pancreatitis.
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Affiliation(s)
- Jill Granger
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109-0602, USA
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25
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Fantini L, Tomassetti P, Pezzilli R. Management of acute pancreatitis: current knowledge and future perspectives. World J Emerg Surg 2006; 1:16. [PMID: 16759369 PMCID: PMC1488834 DOI: 10.1186/1749-7922-1-16] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2006] [Accepted: 05/23/2006] [Indexed: 02/06/2023] Open
Abstract
In recent years, a number of articles have been published on the treatment of acute pancreatitis in experimental models and most of them concerned animals with mild disease. However, it is difficult to translate these results into clinical practice. For example, infliximab, a monoclonal TNF antibody, was experimentally tested in rats and it was found to significantly reduce the pathologic score and serum amylase activity and also to alleviate alveolar edema and acute respiratory distress syndrome; however, no studies are available in clinical human acute pancreatitis. Another substance, such as interleukin 10, was efficacious in decreasing the severity and mortality of lethal pancreatitis in rats, but seems to have no effect on human severe acute pancreatitis. Thus, the main problem in acute pancreatitis, especially in the severe form of the disease, is the difficulty of planning clinical studies capable of giving reliable statistically significant answers regarding the benefits of the various proposed therapeutic agents previously tested in experimental settings. According to the pathophysiology of acute pancreatitis, the efficacy of the drugs already available, such as gabexate mesilate, lexipafant and somatostatin should be re-evaluated and should be probably administered in a different manner. Of course, also in this case, we need adequate studies to test this hypothesis.
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Affiliation(s)
- Lorenzo Fantini
- Department of Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Paola Tomassetti
- Department of Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Raffaele Pezzilli
- Department of Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy
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N/A, 王 蕾. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13:2364-2370. [DOI: 10.11569/wcjd.v13.i19.2364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Abstract
In acute pancreatitis the evaluation of severity is as important as the diagnosis. If there is evidence for severe pancreatitis, an immediate intensive care of all organ systems is needed, to avoid complications. Besides clinical signs, serum CRP is the most valuable parameter to define severity. According to present knowledge, a CT-scan is only needed in sepsis or multiorgan failure. Non-invasive ventilation should be started early in case of hypoxia. Up to now, no general benefit was detected for antibiotic prophylaxis or enteral nutrition. No consensus exists whether and when endoscopic interventions are superior to surgery in the treatment of infected necrosis.
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Affiliation(s)
- G Adler
- Abteilung Innere Medizin I (Gastroenterologie), Medizinische Klinik, Universitätsklinikum Ulm.
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30
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Silverman WB. Medical and Endoscopic Treatment of Acute Pancreatitis. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2003; 6:381-387. [PMID: 12954145 DOI: 10.1007/s11938-003-0041-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Accurate diagnosis of acute pancreatitis and assessment of disease severity is crucial. Multiorgan failure predicts a poorer prognosis. Treatment of acute biliary pancreatitis by endoscopic retrograde cholangiopancreatography (ERCP) may improve overall prognosis. Referral of seriously ill or unstable patients to a specialized center is recommended. Managing teams must be vigilant regarding the avoidance of iatrogenic complications, such as endoscopic misadventure or inadvertent line sepsis. Large, multicenter endoscopic outcome trials for prevention of ERCP-related pancreatitis, and to determine efficacy of treatment of acute gallstone pancreatitis, are needed.
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Affiliation(s)
- William B. Silverman
- Division of Gastroenterology/Hepatology, University of Iowa Hospitals & Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA
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31
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Sun W, Zhang JD, Zhao Y, Zhao Y, Wang Q. Expression of IL-6 and integrin family cell adhesion molecules in acute necrotizing pancreatitis complicated with multiple organ injury in rats. Shijie Huaren Xiaohua Zazhi 2003; 11:753-755. [DOI: 10.11569/wcjd.v11.i6.753] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [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 detect the expression of integrin family cellular adhesion molecules LFA-1, Mac-1 and IL-6 in acute necrotizing pancreatitis complicated with multiple organ injury.
METHODS The flow cytometer was used to detect the expression of LFA-1 and Mac-1 on leukocyte and the radio-immunity to detect the IL-6 in acute necrotizing pancreatitis of rats at different time points.
RESULTS The expression of LFA-1 and Mac-1 increased significantly in acute pancreatitis group compared with that in control group at all time points (P<0.01), i.e.: LFA-1: 1 h, 7.6±0.4 vs 22.7±1.6; 3 h, 7.9±0.5 vs 26.7±5.5; 6 h, 13.5±1.8 vs 30.3±1.6; 12 h, 9.7±0.7 vs 20.3±4.2; 24 h, 10.1±1.1 vs 15.9±0.7. Mac-1: 1 h, 6.2±1.1 vs 7.0±2.5; 3 h, 6.3±0.8 vs 36.0±1.5; 6 h, 7.9±1.2 vs 27.1±1.4; 12 h, 6.4±0.4 vs 22.5±2.1; 24 h, 7.1±0.4 vs 20.6±1.6. Expression of IL-6 increased significantly in acute pancreatitis group compared with that in control group, i.e.: 1 h, 65.6±3.2 vs 72.4±4.0 (P<0.05); 3 h, 68.2±5.5 vs 155.3±16.3 (P<0.01); 6 h, 69.3±2.6 vs 229.2±16.4 (P<0.01); 12 h, 73.4±2.6 vs 287.7±13.9 (P<0.01); 24 h, 76.9±3.3 vs 289.5±16.1 (P<0.01). Morphological examination demonstrated that inflammatory cells, insterstitial edema, interstitial hemorrhage, desquamation and disintegration occurred in the lungs and kidneys.
CONCLUSION IL-6, LFA-1 and Mac-1 may play the very active role in acute pancreatitis.
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Affiliation(s)
- Wei Sun
- Department of General Surgery, 2nd Hospital of China Medical University, Shenyang 110003, Liaoning Province, China
| | - Jun-Dong Zhang
- Department of General Surgery, The First Hospital of Daqing City, Daqing 163001, Heilongjiang Province, China
| | - Ying Zhao
- Department of General Surgery, 2nd Hospital of China Medical University, Shenyang 110003, Liaoning Province, China
| | - Yu Zhao
- Department of General Surgery, 2nd Hospital of China Medical University, Shenyang 110003, Liaoning Province, China
| | - Qiang Wang
- Department of General Surgery, 2nd Hospital of China Medical University, Shenyang 110003, Liaoning Province, China
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32
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Flint RS, Windsor JA. The role of the intestine in the pathophysiology and management of severe acute pancreatitis. HPB (Oxford) 2003; 5:69-85. [PMID: 18332961 PMCID: PMC2020573 DOI: 10.1080/13651820310001108] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The outcome of severe acute pancreatitis has scarcely improved in 10 years. Further impact will require new paradigms in pathophysiology and treatment. There is accumulating evidence to support the concept that the intestine has a key role in the pathophysiology of severe acute pancreatitis which goes beyond the notion of secondary pancreatic infection. Intestinal ischaemia and reperfusion and barrier failure are implicated in the development of multiple organ failure. DISCUSSION Conventional management of severe acute pancreatitis has tended to ignore the intestine. More recent attempts to rectify this problem have included 1) resuscitation aimed at restoring intestinal blood flow through the use of appropriate fluids and splanchnic-sparing vasoconstrictors or inotropes; 2) enteral nutrition to help maintain the integrity of the intestinal barrier; 3) selective gut decontamination and prophylactic antibiotics to reduce bacterial translocation and secondary infection. Novel therapies are being developed to limit intestinal injury, and these include antioxidants and anti-cytokine agents. This paper focuses on the role of the intestine in the pathogenesis of severe acute pancreatitis and reviews the implications for management.
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Affiliation(s)
- RS Flint
- Pancreatitis Research Group, Department of Surgery, Faculty of Medical and Health Sciences, University of AucklandAucklandNew Zealand
| | - JA Windsor
- Pancreatitis Research Group, Department of Surgery, Faculty of Medical and Health Sciences, University of AucklandAucklandNew Zealand
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