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Wang L, Ren Y, Xu T, Geng J, Yang N, Wang R. Triglycerides: A Sensitizer but Not a Trigger for Hypertriglyceridemic Acute Pancreatitis. Dig Dis Sci 2024; 69:2123-2131. [PMID: 38609542 DOI: 10.1007/s10620-024-08412-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 03/25/2024] [Indexed: 04/14/2024]
Abstract
BACKGROUND The incidence of hypertriglyceridemic acute pancreatitis (HTG-AP) is increasing. Although the guideline defines the diagnostic criteria as triglyceride (TG) greater than 11.3 mmol/L, there is actually no specific threshold. Many people with hypertriglyceridemia (HTG) or obvious chyloid blood do not develop acute pancreatitis (AP). AIMS To explore the role of HTG in the pathogenesis of AP. METHODS Thirty-six male SD rats were randomly assigned into normal control, AP, HTG, HTG-AP, low-dose fenofibrate and high-dose fenofibrate groups. Serum indices and cytokine levels in serum, and pathological changes in pancreatic tissues were observed. The expression levels of TLR4 and NF-κBp65 in pancreatic tissues were detected by immunohistochemistry and Western blot. RESULTS In normal rats, HTG alone did not induce AP. However, after establishing the HTG-AP model with Poloxam 407 and L-arginine, serum-free fatty acid and TG levels were positively correlated with the levels of lipase, amylase, IL-1β, IL-6, pancreatic inflammation scores, and the expressions of TLR4 and NF-κBp65 (all P < 0.001). Expressions of TLR4 and NF-κBp65 were significantly increased in the pancreatic tissues of HTG-AP rats. Fenofibrate effectively decreased TG levels in HTG-AP rats and reduced the expression of TLR4 and NF-κBp65 (all P < 0.001). CONCLUSIONS HTG does not directly cause AP, but rather increases the susceptibility to AP or aggravates the inflammatory response. It is more like a sensitizer of inflammation rather than an activator.
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Affiliation(s)
- Lu Wang
- Clinical Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, P. R. China
| | - Yutang Ren
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Beijing, 102218, P. R. China
| | - Ting Xu
- Department of Gastroenterology, Daqing Oilfield Central Hospital, No. 9 Zhongkang Road, Daqing, 163000, Heilongjiang, P. R. China
| | - Jinting Geng
- Gastrointestinal Interal Medicine and Digestive Endoscopy Center, Second Affiliated Hospital, Jilin University, No. 4026 Yatai Street, Changchun, 130000, Jilin, P. R. China
| | - Ning Yang
- Department of Gastroenterology, Heilongjiang Provincial Hospital, 82 Zhongshan Road, Harbin, 150000, Heilongjiang, P. R. China
| | - Ruifeng Wang
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Beijing, 102218, P. R. China.
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Zhou Y, Huang X, Jin Y, Qiu M, Ambe PC, Basharat Z, Hong W. The role of mitochondrial damage-associated molecular patterns in acute pancreatitis. Biomed Pharmacother 2024; 175:116690. [PMID: 38718519 DOI: 10.1016/j.biopha.2024.116690] [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: 02/08/2024] [Revised: 04/27/2024] [Accepted: 04/29/2024] [Indexed: 06/03/2024] Open
Abstract
Acute pancreatitis (AP) is one of the most common gastrointestinal tract diseases with significant morbidity and mortality. Current treatments remain unspecific and supportive due to the severity and clinical course of AP, which can fluctuate rapidly and unpredictably. Mitochondria, cellular power plant to produce energy, are involved in a variety of physiological or pathological activities in human body. There is a growing evidence indicating that mitochondria damage-associated molecular patterns (mtDAMPs) play an important role in pathogenesis and progression of AP. With the pro-inflammatory properties, released mtDAMPs may damage pancreatic cells by binding with receptors, activating downstream molecules and releasing inflammatory factors. This review focuses on the possible interaction between AP and mtDAMPs, which include cytochrome c (Cyt c), mitochondrial transcription factor A (TFAM), mitochondrial DNA (mtDNA), cardiolipin (CL), adenosine triphosphate (ATP) and succinate, with focus on experimental research and potential therapeutic targets in clinical practice. Preventing or diminishing the release of mtDAMPs or targeting the mtDAMPs receptors might have a role in AP progression.
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Affiliation(s)
- Yan Zhou
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China; School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Xiaoyi Huang
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China; School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Yinglu Jin
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China; School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Minhao Qiu
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Peter C Ambe
- Department of General Surgery, Visceral Surgery and Coloproctology, Vinzenz-Pallotti-Hospital Bensberg, Vinzenz-Pallotti-Str. 20-24, Bensberg 51429, Germany
| | | | - Wandong Hong
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
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Eltahir HM, Elbadawy HM, Almikhlafi MA, Alalawi AM, Aldhafiri AJ, Alahmadi YM, Al thagfan SS, Albadrani M, M Eweda S, Abouzied MM. Sitagliptin ameliorates L-arginine-induced acute pancreatitis via modulating inflammatory cytokines expression and combating oxidative stress. Front Pharmacol 2024; 15:1389670. [PMID: 38910880 PMCID: PMC11190672 DOI: 10.3389/fphar.2024.1389670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 04/26/2024] [Indexed: 06/25/2024] Open
Abstract
Background Acute pancreatitis (AP) is an inflammatory condition that resolves spontaneously, but occasionally, develops into systemic inflammation, organ failure and mortality. Oxidative stress and activation of inflammatory pathways represent major players in AP pathogenesis. Current management of AP relies on attenuating injuries to the pancreas and putting the inflammatory process under control. In this study, we investigated the role of sitagliptin in modulating L-arginine-induced AP in rats. Methods Swiss rats were subdivided into a healthy control group, AP group (a single dose of L-arginine 250 mg/100 g, intraperitoneal), and sitagliptin + L-arginine-treated group (10 mg sitagliptin/kg body weight/day, orally). Sitagliptin treatment started 1 hour after L-arginine injection and continued for 3days. Biochemical and histopathological investigations were performed on serum and tissue samples collected from test animals. Results L-arginine increased pancreatic meyloperoxidase and serum amylase- and lipase activities and serum levels of TNF-α, LT-α, IFN-γ, IL-1α/β, IL-6, IL-10, IL-12, and IL-15. AP animals showed elevated MDA and NO and decreased GSH and serum calcium levels. Histopathological changes were observed by H&E staining. Sitagliptin treatment significantly ameliorated these biochemical and histological changes diminishing the signs of AP. Conclusion Sitagliptin treatment was effective in ameliorating L-arginine-induced AP which can be regarded to its anti-inflammatory and antioxidant effect.
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Affiliation(s)
- Heba M. Eltahir
- Department of Pharmacology and Toxicology (Biochemistry Subdivision), College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Hossein M. Elbadawy
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Mohannad A. Almikhlafi
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Ali M. Alalawi
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Ahmed J. Aldhafiri
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Yaser M. Alahmadi
- Department of Clinical and Hospital Pharmacy, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Sultan S. Al thagfan
- Department of Clinical and Hospital Pharmacy, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Muayad Albadrani
- Department of Family and Community Medicine, College of Medicine, Taibah University, Medina, Saudi Arabia
| | - Saber M Eweda
- 5Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Mekky M. Abouzied
- Department of Pharmacology and Toxicology (Biochemistry Subdivision), College of Pharmacy, Taibah University, Medina, Saudi Arabia
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, Egypt
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Mattke J, Darden CM, Lawrence MC, Kuncha J, Shah YA, Kane RR, Naziruddin B. Toll-like receptor 4 in pancreatic damage and immune infiltration in acute pancreatitis. Front Immunol 2024; 15:1362727. [PMID: 38585277 PMCID: PMC10995222 DOI: 10.3389/fimmu.2024.1362727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 03/11/2024] [Indexed: 04/09/2024] Open
Abstract
Acute pancreatitis is a complex inflammatory disease resulting in extreme pain and can result in significant morbidity and mortality. It can be caused by several factors ranging from genetics, alcohol use, gall stones, and ductal obstruction caused by calcification or neutrophil extracellular traps. Acute pancreatitis is also characterized by immune cell infiltration of neutrophils and M1 macrophages. Toll-like receptor 4 (TLR4) is a pattern recognition receptor that has been noted to respond to endogenous ligands such as high mobility group box 1 (HMGB1) protein and or exogenous ligands such as lipopolysaccharide both of which can be present during the progression of acute pancreatitis. This receptor can be found on a variety of cell types from endothelial cells to resident and infiltrating immune cells leading to production of pro-inflammatory cytokines as well as immune cell activation and maturation resulting in the furthering of pancreatic damage during acute pancreatitis. In this review we will address the various mechanisms mediated by TLR4 in the advancement of acute pancreatitis and how targeting this receptor could lead to improved outcomes for patients suffering from this condition.
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Affiliation(s)
- Jordan Mattke
- Baylor University, Institute of Biomedical Studies, Waco, TX, United States
| | - Carly M. Darden
- Baylor University Medical Center, Annette C. and Harold C. Simmons Transplant Institute, Dallas, TX, United States
| | - Michael C. Lawrence
- Islet Cell Laboratory, Baylor Scott and White Research Institute, Dallas, TX, United States
| | - Jayachandra Kuncha
- Islet Cell Laboratory, Baylor Scott and White Research Institute, Dallas, TX, United States
| | - Yumna Ali Shah
- Islet Cell Laboratory, Baylor Scott and White Research Institute, Dallas, TX, United States
| | - Robert R. Kane
- Baylor University, Institute of Biomedical Studies, Waco, TX, United States
| | - Bashoo Naziruddin
- Baylor University Medical Center, Annette C. and Harold C. Simmons Transplant Institute, Dallas, TX, United States
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Gitto SB, Nakkina SP, Beardsley JM, Parikh JG, Altomare DA. Induction of pancreatitis in mice with susceptibility to pancreatic cancer. Methods Cell Biol 2022; 168:139-159. [PMID: 35366980 DOI: 10.1016/bs.mcb.2021.12.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Chronic inflammation is known to be associated with pancreatic cancer, however a complete picture regarding how these pathologies intersect is still being characterized. In vivo model systems are critical for the study of mechanisms underlying how inflammation accelerates neoplasia. Repeat injection of cerulein, a cholecystokinin (CCK) analog, is widely used to experimentally induce acute and chronic pancreatitis in vivo. Chronic cerulein administration into genetically engineered mouse models (GEMMs) with predisposition to pancreatic cancer can induce a pro-inflammatory immune response, pancreatic acinar cell damage, pancreatic stellate cell activation, and accelerate the onset of neoplasia. Here we provide a detailed protocol and insights into using cerulein to induce pancreatitis in GEMMs, and methods to experimentally assess inflammation and pancreatic neoplasia.
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Affiliation(s)
- Sarah B Gitto
- Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, United States; Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Sai Preethi Nakkina
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Jordan M Beardsley
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Jignesh G Parikh
- Department of Pathology, Orlando VA Medical Center, Orlando, FL, United States
| | - Deborah A Altomare
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States.
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6
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Khamaysi I, Hamo-Giladi DB, Abassi Z. Heparanase in Acute Pancreatitis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1221:703-719. [PMID: 32274733 DOI: 10.1007/978-3-030-34521-1_29] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Acute pancreatitis (AP) is one of the most common diseases in gastroenterology, affecting 2% of all hospitalized patients. Nevertheless, neither the etiology nor the pathophysiology of the disease is fully characterized, and no specific or effective treatment has been developed. Heparanase (Hpa) is an endoglycosidase that cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPGs) into shorter oligosaccharides, activity that is highly implicated in cell invasion associated with cancer metastasis and inflammation. Given that AP is a typical inflammatory disease, we investigated whether Hpa plays a role in AP. Our results provide keen evidence that Hpa expression and activity are significantly increased following cerulein-induced AP in wild type mice. In parallel to the classic manifestations of AP, namely elevation of amylase and lipase levels, pancreas edema and inflammation as well as induction of cytokines and signaling molecules, have been detected in this experimental model of the disease. Noteworthy, these features were far more profound in transgenic mice overexpressing heparanase (Hpa-Tg), suggesting that these mice can be utilized as a model system to reveal the molecular mechanism by which Hpa functions in AP. Further support for the involvement of Hpa in the pathogenesis of AP emerged from our observation that treatment of experimental AP with PG545 or SST0001(= Ronepastat), two potent Hpa inhibitors, markedly attenuated the biochemical, histological and immunological manifestations of the disease. Hpa, therefore, emerges as a potential new target in AP, and Hpa inhibitors are hoped to prove beneficial in AP along with their promising efficacy as anti-cancer compounds.
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Affiliation(s)
- Iyad Khamaysi
- Department of Gastroenterology, Advanced Endoscopy Procedures Unit, Rambam Health Care Campus, Haifa, Israel.
| | | | - Zaid Abassi
- Laboratory Medicine, Rambam Health Care Campus, Haifa, Israel
- Department of Physiology, The Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
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7
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Animal models to study the role of pulmonary intravascular macrophages in spontaneous and induced acute pancreatitis. Cell Tissue Res 2020; 380:207-222. [DOI: 10.1007/s00441-020-03211-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 03/30/2020] [Indexed: 12/14/2022]
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Inhibition of macrophage migration inhibitory factor attenuates inflammation and fetal kidney injury in a rat model of acute pancreatitis in pregnancy. Int Immunopharmacol 2019; 68:106-114. [PMID: 30622028 DOI: 10.1016/j.intimp.2018.12.068] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/27/2018] [Accepted: 12/31/2018] [Indexed: 12/14/2022]
Abstract
Acute pancreatitis in pregnancy (APIP) is a severe disease during pregnancy that mostly occurs during the third trimester. It can lead to additional complications including preterm delivery and high fetal mortality. In this study, we investigated the protective effects of (S, R)-3-(4-hydroxyphenyl)-4, 5dihydro-5-isoxazole acetic methyl ester (ISO-1), an inhibitor of macrophage migration inhibitory factor (MIF), on fetal kidney injury associated with the maternal acute necrotizing pancreatitis (ANP) and its potential mechanisms in a rat model. The APIP rat model was induced by retrograde infusion of sodium taurocholate saline solution into biliopancreatic duct. ISO-1 was given by intraperitoneally injection 30 min before the model was induced. The levels of maternal serum amylase, lipase, tumor necrosis factor-α (TNF-α) and interleukins (IL)-1β were measured. Maternal pancreas and fetal kidney injury were evaluated, and the expressions of MIF, phospho-p38MAPK (p-p38), nuclear factor-κB (NF-κB), TNF-α, IL-1β in fetal kidneys were detected. The results showed that fetal rats exhibited obvious acute kidney injury during APIP, and pregnant rats pretreated with ISO-1 notably attenuated the lesions. ISO-1 also significantly reduced the expression of MIF and the activations of p38MAPK, NF-κB, as well as the levels of TNF-α and IL-1β. These results indicated that ISO-1 could attenuate fetal kidney injury in pregnant rats with ANP by inhibiting MIF mediated p38MAPK/NF-κB signal pathways to reduce inflammatory response.
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9
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Huang HL, Tang GD, Liang ZH, Qin MB, Wang XM, Chang RJ, Qin HP. Role of Wnt/β-catenin pathway agonist SKL2001 in Caerulein-induced acute pancreatitis. Can J Physiol Pharmacol 2018; 97:15-22. [PMID: 30326193 DOI: 10.1139/cjpp-2018-0226] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The goal of this study was to clarify the protective role of the Wnt/β-catenin pathway agonist SKL2001 in a rat model of Caerulein-induced acute pancreatitis. AR42J cells and rats were divided into 4 groups: control, Caerulein, SKL2001 + Caerulein, and SKL2001 + control. Cell apoptosis was examined using flow cytometry. Hematoxylin-eosin staining was performed to observe pathological changes in pancreatic and small intestinal tissues. Inflammatory cytokines were detected by enzyme-linked immunosorbent assay (ELISA), while genes related to the Wnt/β-catenin pathway were quantified using quantitative real-time PCR. In vitro results showed that Caerulein promoted cell necrosis, inhibited the Wnt/β-catenin pathway, and increased the level of inflammatory cytokines. However, SKL2001 reduced cell necrosis and inflammatory cytokines and activated the Wnt/β-catenin pathway. Additionally, in vivo results demonstrated the accumulation of fluid (i.e., edema), hemorrhage, inflammation and necrosis of the pancreatic acini occurred 6 h after the final Caerulein induction, with the damage reaching a maximal level 12 h after the final Caerulein induction; meanwhile, the Wnt/β-catenin pathway was evidently inhibited with an enhanced level of inflammatory cytokines. The aforementioned damage was further aggravated 12 h later. Nevertheless, the pancreatic and small intestinal tissue damages were alleviated in Caerulein-induced rats treated with SKL2001. In conclusion, activation of the Wnt/β-catenin pathway could inhibit Caerulein-induced cell apoptosis and inflammatory cytokine release, thus improving pancreatic and intestinal damage in rats with acute pancreatitis.
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Affiliation(s)
- Hua-Li Huang
- a Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guo-Du Tang
- a Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhi-Hai Liang
- a Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Meng-Bin Qin
- b Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Xian-Mo Wang
- c Department of Clinical Laboratory, The First People's Hospital of Jingzhou City, Jingzhou, Jingzhou 434000, Hubei, China
| | - Ren-Jie Chang
- a Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - He-Ping Qin
- a Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Plavsic I, Žitinić I, Mikolasevic I, Poropat G, Hauser G. Endoscopic retrograde cholangiopancreatography-induced and non-endoscopic retrograde cholangiopancreatography-induced acute pancreatitis: Two distinct clinical and immunological entities? World J Gastrointest Endosc 2018; 10:259-266. [PMID: 30364685 PMCID: PMC6198307 DOI: 10.4253/wjge.v10.i10.259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 06/10/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is common gastrointestinal disease of varied aetiology. The most common cause of AP is gallstones, followed by alcohol abuse as an independent risk factor. With the increased need for invasive techniques to treat pancreatic and bile duct pathologies such as endoscopic retrograde cholangiopancreatography (ERCP), AP has emerged as the most frequent complication. While severe AP following ERCP is rare (0.5%), if it does develop it has a greater severity index compared to non-ERCP AP. Development of a mild form of AP after ERCP is not considered a clinically relevant condition. Differences in the clinical presentation and prognosis of the mild and severe forms have been found between non-ERCP AP and post-endoscopic pancreatitis (PEP). It has been proposed that AP and PEP may also have different immunological responses to the initial injury. In this review, we summarise the literature on clinical and inflammatory processes in PEP vs non-ERCP AP.
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Affiliation(s)
- Ivana Plavsic
- Department of Anesthesiology and Critical care medicine, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Ivana Žitinić
- Department of Emergency Medicine, Clinical Hospital Centre, Rijeka 51000, Croatia
| | - Ivana Mikolasevic
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Poropat
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Hauser
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, Faculty of health Studies, University of Rijeka, Rijeka 51000, Croatia
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11
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Lee H, Cheong KA, Kim JY, Kim NH, Noh M, Lee AY. IL-1 Receptor Antagonist Reduced Chemical-Induced Keratinocyte Apoptosis through Antagonism to IL-1α/IL-1β. Biomol Ther (Seoul) 2018; 26:417-423. [PMID: 29310426 PMCID: PMC6029682 DOI: 10.4062/biomolther.2017.167] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 10/12/2017] [Accepted: 10/17/2017] [Indexed: 01/04/2023] Open
Abstract
Extracellular interleukin 1 alpha (IL-1α) released from keratinocytes is one of the endpoints for in vitro assessments of skin irritancy. Although cells dying via primary skin irritation undergo apoptosis as well as necrosis, IL-1α is not released in apoptotic cells. On the other hand, active secretion has been identified in interleukin-1 receptor antagonist (IL-1ra), which was discovered to be a common, upregulated, differentially-expressed gene in a microarray analysis performed with keratinocytes treated using cytotoxic doses of chemicals. This study examined whether and how IL-1ra, particularly extracellularly released IL-1ra, was involved in chemically-induced keratinocyte cytotoxicity and skin irritation. Primary cultured normal adult skin keratinocytes were treated with cytotoxic doses of chemicals (hydroquinone, retinoic acid, sodium lauryl sulfate, or urshiol) with or without recombinant IL-1ra treatment. Mouse skin was administered irritant concentrations of hydroquinone or retinoic acid. IL-1ra (mRNA and/or intracellular/extracellularly released protein) levels increased in the chemically treated cultured keratinocytes with IL-1α and IL-1β mRNAs and in the chemically exposed epidermis of the mouse skin. Recombinant IL-1ra treatment significantly reduced the chemically-induced apoptotic death and intracellular/extracellularly released IL-1α and IL-1β in keratinocytes. Collectively, extracellular IL-1ra released from keratinocytes could be a compensatory mechanism to reduce the chemically-induced keratinocyte apoptosis by antagonism to IL-1α and IL-1β, suggesting potential applications to predict skin irritation.
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Affiliation(s)
- Hyejin Lee
- Department of Dermatology, Dongguk University Seoul, Graduate School of Medicine, Goyang 10326, Republic of Korea
| | - Kyung Ah Cheong
- Department of Dermatology, Dongguk University Seoul, Graduate School of Medicine, Goyang 10326, Republic of Korea
| | - Ji-Young Kim
- Department of Dermatology, Dongguk University Seoul, Graduate School of Medicine, Goyang 10326, Republic of Korea
| | - Nan-Hyung Kim
- Department of Dermatology, Dongguk University Seoul, Graduate School of Medicine, Goyang 10326, Republic of Korea
| | - Minsoo Noh
- Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Ai-Young Lee
- Department of Dermatology, Dongguk University Seoul, Graduate School of Medicine, Goyang 10326, Republic of Korea
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12
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Jeong YK, Kim H. A Mini-Review on the Effect of Docosahexaenoic Acid (DHA) on Cerulein-Induced and Hypertriglyceridemic Acute Pancreatitis. Int J Mol Sci 2017; 18:ijms18112239. [PMID: 29068376 PMCID: PMC5713209 DOI: 10.3390/ijms18112239] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 10/21/2017] [Accepted: 10/23/2017] [Indexed: 12/17/2022] Open
Abstract
Acute pancreatitis refers to the sudden inflammation of the pancreas. It is associated with premature activation and release of digestive enzymes into the pancreatic interstitium and systemic circulation, resulting in pancreatic tissue autodigestion and multiple organ dysfunction, as well as with increased cytokine production, ultimately leading to deleterious local and systemic effects. Although mechanisms involved in pathogenesis of acute pancreatitis have not been completely elucidated, oxidative stress is regarded as a major risk factor. In human acute pancreatitis, lipid peroxide levels in pancreatic tissues increase. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (C22:6n-3), exerts anti-inflammatory and antioxidant effects on various cells. Previous studies have shown that DHA activates peroxisome proliferator-activated receptor-γ and induces catalase, which inhibits oxidative stress-mediated inflammatory signaling required for cytokine expression in experimental acute pancreatitis using cerulein. Cerulein, a cholecystokinin analog, induces intra-acinar activation of trypsinogen in the pancreas, which results in human acute pancreatitis-like symptoms. Therefore, DHA supplementation may be beneficial for preventing or inhibiting acute pancreatitis development. Since DHA reduces serum triglyceride levels, addition of DHA to lipid-lowering drugs like statins has been investigated to reduce hypertriglyceridemic acute pancreatitis. However, high DHA concentrations increase cytosolic Ca2+, which activates protein kinase C and may induce hyperlipidemic acute pancreatitis. In this review, effect of DHA on cerulein-induced and hypertriglyceridemic acute pancreatitis has been discussed. The relation of high concentration of DHA to hyperlipidemic acute pancreatitis has been included.
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Affiliation(s)
- Yoo Kyung Jeong
- Department of Food and Nutrition, Brian Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| | - Hyeyoung Kim
- Department of Food and Nutrition, Brian Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
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Chen QJ, Yang ZY, Wang CY, Dong LM, Zhang YS, Xie C, Chen CZ, Zhu SK, Yang HJ, Wu HS, Yang C. Hydroxyethyl starch resuscitation downregulate pro-inflammatory cytokines in the early phase of severe acute pancreatitis: A retrospective study. Exp Ther Med 2016; 12:3213-3220. [PMID: 27882140 PMCID: PMC5103769 DOI: 10.3892/etm.2016.3744] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 09/22/2016] [Indexed: 12/13/2022] Open
Abstract
In the present study, we investigated the effects of hydroxyethyl starch (HES) 130/0.4 on serum pro-inflammatory variables, immunologic variables, fluid balance (FB)-negative(-) rate and renal function in severe acute pancreatitis (SAP) patients. From October, 2007 to November, 2008, a total of 120 SAP patients were enrolled in this retrospective study. Fifty-nine patients in the HES group received 6% HES 130/0.4 combined with crystalloid solution for fluid resuscitation (HES group). In the control group, 61 patients received only crystalloid solution after admission. Interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF)-α levels in serum were measured on days 1, 2, 4 and 8. The peripheral blood CD4+CD8+ T lymphocyte rates, serum BUN and Cr values were also measured on days 1, 4 and 8. Patients with FB(-) rates were recorded from day 1 to 8. Interaction term analysis (hospital stay and fluid resuscitation methods) based on mixed-effects regression model revealed significantly lower levels of IL-1 and TNF-α in the HES group compared with the control group. The difference in curve's risk ratio was not significant for IL-6, CD4+CD8+ T lymphocyte rate, BUN and Cr values (P>0.05). In the HES group, we detected a significantly higher rate of patients with FB(-) from day 4 to 8 (P<0.05). Thus, HES 130/0.4 resuscitation could decrease the IL-1 and IL-8 levels, shorten the duration of positive FB, and preserve the patient's immune status as well as renal function during the early phase of SAP.
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Affiliation(s)
- Qi-Jun Chen
- Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Zhi-Yong Yang
- Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Chun-You Wang
- Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Li-Ming Dong
- Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yu-Shun Zhang
- Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Chao Xie
- Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Chang-Zhong Chen
- Microarray Core Facility, Dana-Farber Cancer Institute, Boston, MA 02138, USA
| | - Shi-Kai Zhu
- Organ Transplantation Center, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - Hong-Ji Yang
- Organ Transplantation Center, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - He-Shui Wu
- Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Chong Yang
- Organ Transplantation Center, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
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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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Miller KJ, Raulefs S, Kong B, Steiger K, Regel I, Gewies A, Kleeff J, Michalski CW. Loss of Ifnar1 in Pancreatic Acinar Cells Ameliorates the Disease Course of Acute Pancreatitis. PLoS One 2015; 10:e0143735. [PMID: 26618925 PMCID: PMC4664425 DOI: 10.1371/journal.pone.0143735] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 11/08/2015] [Indexed: 01/09/2023] Open
Abstract
Type I interferon constitutes an essential component of the combinational therapy against viral disease. Acute pancreatitis is one side effect of type I interferon-based therapy, implying that activation of type I interferon signaling affects the homeostasis and integrity of pancreatic acinar cells. Here, we investigated the role of type I interferon signaling in pancreatic acinar cells using a caerulein-induced murine model of acute pancreatitis. Pancreas-specific ablation of interferon (alpha and beta) receptor 1 (Ifnar1) partially protected animals from caerulein-induced pancreatitis, as demonstrated by reduced tissue damage. Profiling of infiltrating immune cells revealed that this dampened tissue damage response correlated with the number of macrophages in the pancreas. Pharmacologic depletion of macrophages reversed the protective effect of Ifnar1 deficiency. Furthermore, expression of chemokine (C-C motif) ligand 2 (Ccl2), a potent factor for macrophage recruitment, was significantly increased in the Ifnar1-deficient pancreas. Thus, type I interferon signaling in pancreatic acinar cells controls pancreatic homeostasis by affecting the macrophage-mediated inflammatory response in the pancreas.
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Affiliation(s)
| | - Susanne Raulefs
- Department of Surgery, Technische Universität München, Munich, Germany
| | - Bo Kong
- Department of Surgery, Technische Universität München, Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Ivonne Regel
- Department of Surgery, Technische Universität München, Munich, Germany
| | - Andreas Gewies
- Institute für Klinische Chemie und Pathobiochemie, Technische Universität München, Munich, Germany
| | - Jörg Kleeff
- Department of Surgery, Technische Universität München, Munich, Germany
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16
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Kim DG, Bae GS, Choi SB, Jo IJ, Shin JY, Lee SK, Kim MJ, Kim MJ, Jeong HW, Choi CM, Seo SH, Choo GC, Seo SW, Song HJ, Park SJ. Guggulsterone attenuates cerulein-induced acute pancreatitis via inhibition of ERK and JNK activation. Int Immunopharmacol 2015; 26:194-202. [PMID: 25843255 DOI: 10.1016/j.intimp.2015.03.030] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Revised: 02/23/2015] [Accepted: 03/17/2015] [Indexed: 02/07/2023]
Abstract
Guggulsterone (GS), a plant steroid and a compound found at high levels in Commiphora myrrha, exhibits anti-inflammatory, anti-cancer, and cholesterol-lowering effects. However, the potential of GS to ameliorate acute pancreatitis (AP) is unknown. The aim of this study was to evaluate the effects of GS on cerulein-induced AP. AP was induced by intraperitoneally injecting supramaximal concentrations of the stable cholecystokinin analog cerulein (50 μg/kg) hourly for 6 h. In the GS-treated group, GS was administered intraperitoneally (10, 25, or 50mg/kg) 1 h before the first cerulein injection. Mice were sacrificed 6 h after the final cerulein injection. Blood samples were collected to measure serum lipase levels and evaluate cytokine production. The pancreas and lung were rapidly removed for morphologic and histological examinations, flow cytometry analysis, myeloperoxidase (MPO) assay, and real-time reverse transcription-polymerase chain reaction analysis. Pre-treatment with GS attenuated cerulein-induced histological damage, reduced pancreas weight/body weight ratio, decreased serum lipase levels, inhibited infiltrations of macrophages and neutrophils, and suppressed cytokine production. Additionally, GS treatment suppressed the activation of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) in the pancreas in cerulein-induced pancreatitis. In conclusion, our results suggest that GS attenuates AP via deactivation of ERK and JNK.
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Affiliation(s)
- Dong-Goo Kim
- BK21 Plus Team, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea; Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea
| | - Gi-Sang Bae
- Hanbang Body Fluid Research Center, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea
| | - Sun-Bok Choi
- BK21 Plus Team, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea; Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea
| | - Il-Joo Jo
- BK21 Plus Team, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea; Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea
| | - Joon-Yeon Shin
- BK21 Plus Team, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea; Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea
| | - Sung-Kon Lee
- BK21 Plus Team, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea; Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea
| | - Myoung-Jin Kim
- BK21 Plus Team, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea; Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea
| | - Min-Jun Kim
- BK21 Plus Team, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea; Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea
| | - Hyun-Woo Jeong
- Department of Pathology, College of Korean Medicine, Dongshin University, Naju, Jeonnam 520-714, South Korea
| | - Chang-Min Choi
- Department of Obstetrics and Gynecology, College of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, South Korea
| | - Seung-Hee Seo
- Department of Cosmetology, Dongshin University, Naju, Jeonnam 520-714, South Korea
| | - Gab-Chul Choo
- Department of Forest Resources, Gyeongnam National University of Science and Technology, Jinju, Gyeongnam 660-758, South Korea
| | - Sang-Wan Seo
- Department of Oriental Medicine Industry, Honam University, Gwangju 506-714, South Korea
| | - Ho-Joon Song
- BK21 Plus Team, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea; Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea
| | - Sung-Joo Park
- BK21 Plus Team, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea; Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea; Hanbang Body Fluid Research Center, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea.
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17
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Paek J, Kang JH, Kim HS, Lee I, Seo KW, Yang MP. Serum adipokine concentrations in dogs with acute pancreatitis. J Vet Intern Med 2014; 28:1760-9. [PMID: 25312217 PMCID: PMC4895644 DOI: 10.1111/jvim.12437] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 06/11/2014] [Accepted: 07/23/2014] [Indexed: 01/15/2023] Open
Abstract
Background Limited information is available about the role of adipokines in the development and progression of acute pancreatitis (AP) in dogs. Objectives To determine whether the circulating concentrations of adipokines differed between healthy dogs and dogs with AP, and whether the circulating concentrations differed between AP survivors and AP nonsurvivors. Animals Twenty‐eight healthy dogs and 25 client‐owned dogs with AP. Methods Prospective observational cohort study of 25 client‐owned dogs with newly diagnosed AP and 28 otherwise healthy dogs with similar body condition scores. The serum concentrations of leptin, adiponectin, resistin, visfatin, interleukin (IL)‐1β, IL‐6, IL‐10, IL‐18, and tumor necrosis factor (TNF)‐α were measured. Results The serum concentrations of leptin (P = .0021), resistin (P = .0010), visfatin (P < .0001), IL‐1β (P < .0001), IL‐6 (P = .0002), IL‐10 (P < .0001), and IL‐18 (P < .0001) were significantly higher in dogs with AP than healthy dogs, whereas the adiponectin concentration (P = .0011) was significantly lower. There were significant differences in the serum concentrations of leptin (P = .028) and adiponectin (P = .046) in survivors and nonsurvivors. After the disappearance of clinical signs, the concentrations of resistin (P = .037) and IL‐1β (P = .027) decreased significantly, whereas the serum concentrations of leptin (P > .999), adiponectin (P = .11), visfatin (P = .83), IL‐6 (P = .82), IL‐10 (P = .82), IL‐18 (P = .56), and TNF‐α (P = .94) did not differ significantly. Conclusion and Clinical Importance This study showed that dysregulation of adipokines might be involved in the pathogenesis of AP. In addition, leptin and adiponectin are likely to be associated with mortality rate in AP.
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Affiliation(s)
- J Paek
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea
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18
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Proteomic analysis of pancreas in miniature pigs according to developmental stages using two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Lab Anim Res 2014; 30:1-7. [PMID: 24707298 PMCID: PMC3973805 DOI: 10.5625/lar.2014.30.1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2013] [Revised: 01/11/2014] [Accepted: 01/21/2014] [Indexed: 11/21/2022] Open
Abstract
Organ transplantation is limited by the shortage of human organs. Many studies have sought to overcome this hurdle by using animal organs. Porcine organs, especially from miniature pigs, have been used for organ xenotransplantation rather than nonhuman primates. While the molecular profiling for transplantation is well known in humans and rodents, the situation for pigs is almost completely unknown. The present study examined protein regulation of the developing stages of the pancreatic proteome (4 day-old miniature neonate, 19 day-old miniature piglet, and 14 month-old miniature adult pigs) using two-dimensional gel electrophoresis and matrix assisted laser desorption/ionization-time of flight mass spectrometry. Thirteen different expressed spots were observed and nine were identified. The data presented within this study provides critical direction relating to the development of pancreas of miniature pigs, which will assist future proteome analysis of the pancreas, and advance our understanding of the hurdles facing xenotransplantation.
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Akyazi I, Eraslan E, Gülçubuk A, Ekiz EE, Çırakli ZL, Haktanir D, Bala DA, Özkurt M, Matur E, Özcan M. Long-term aspirin pretreatment in the prevention of cerulein-induced acute pancreatitis in rats. World J Gastroenterol 2013; 19:2894-2903. [PMID: 23704822 PMCID: PMC3660814 DOI: 10.3748/wjg.v19.i19.2894] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 01/15/2013] [Accepted: 02/06/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of long term pretreatment with low-, medium- and high-dose aspirin (acetylsalicylic acid, ASA) on a model of acute pancreatitis (AP) induced in rats.
METHODS: Forty male Wistar rats were used. Three experimental groups, each consisting of eight animals, received low- (5 mg/kg per day), medium- (150 mg/kg per day) and high-dose (350 mg/kg per day) ASA in supplemented pellet chow for 100 d. Eight animals, serving as the AP-control group, and another eight, serving as reference value (RV) group, were fed with standard pellet chow for the same period. After pretreatment, AP was induced in the experimental animals by intraperitoneal administration of cerulein (2 × 50 μg/kg), while the RV group received saline in the same way. Twelve hours after the second injection, the animals were sacrificed. Pancreatic tissue and plasma samples were collected. One part of the collected pancreatic tissues was used for histopathological evaluation, and the remaining portion was homogenized. Cytokine levels [tumor necrosis factor, interleukin (IL)-1β, IL-6], hemogram parameters, biochemical parameters (amylase and lipase), nuclear factor-κB, aspirin triggered lipoxins and parameters related to the antioxidant system (malondialdehyde, nitric oxide, hemeoxygenase-1, catalase and superoxide dismutase) were measured.
RESULTS: Cerulein administration induced mild pancreatitis, characterized by interstitial edema (total histopathological score of 5.88 ± 0.44 vs 0.25 ± 0.16, P < 0.001). Subsequent pancreatic tissue damage resulted in an increase in amylase (2829.71 ± 772.48 vs 984.57 ± 49.22 U/L, P = 0.001) and lipase (110.14 ± 75.84 U/L vs 4.71 ± 0.78 U/L, P < 0.001) in plasma, and leucocytes (6.89 ± 0.48 vs 4.36 ± 0.23, P = 0.001) in peripheral blood. Cytokines, IL-1β (18.81 ± 2.55 pg/μg vs 6.65 ± 0.24 pg/μg, P = 0.002) and IL-6 (14.62 ± 1.98 pg/μg vs 9.09 ± 1.36 pg/μg, P = 0.04) in pancreatic tissue also increased. Aspirin pretreatment reduced the increase in the aforementioned parameters to a certain degree and partially improved the histopathological alterations caused by cerulein. No evidence of side effects related to chronic ASA administration (e.g., inflammation or bleeding) was observed in the gastrointestinal tract in macroscopic and histopathological examination.
CONCLUSION: Long term ASA pretreatment could prevent and/or ameliorate certain hematological, serological and histological alterations caused by cerulein-induced AP.
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Jo IJ, Bae GS, Park KC, Choi SB, Jung WS, Jung SY, Cho JH, Choi MO, Song HJ, Park SJ. Scolopendra subspinipes mutilans protected the cerulein-induced acute pancreatitis by inhibiting high-mobility group box protein-1. World J Gastroenterol 2013; 19:1551-1562. [PMID: 23539679 PMCID: PMC3602472 DOI: 10.3748/wjg.v19.i10.1551] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Revised: 10/15/2012] [Accepted: 10/30/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the inhibitory effects of Scolopendra subspinipes mutilans (SSM) on cerulein-induced acute pancreatitis (AP) in a mouse model.
METHODS: SSM water extract (0.1, 0.5, or 1 g/kg) was administrated intraperitoneally 1 h prior to the first injection of cerulein. Once AP developed, the stable cholecystokinin analogue, cerulein was injected hourly, over a 6 h period. Blood samples were taken 6 h later to determine serum amylase, lipase, and cytokine levels. The pancreas and lungs were rapidly removed for morphological examination, myeloperoxidase assay, and real-time reverse transcription polymerase chain reaction. To specify the role of SSM in pancreatitis, the pancreatic acinar cells were isolated using collagenase method. Then the cells were pre-treated with SSM, then stimulated with cerulein. The cell viability, cytokine productions and high-mobility group box protein-1 (HMGB-1) were measured. Furthermore, the regulating mechanisms of SSM action were evaluated.
RESULTS: The administration of SSM significantly attenuated the severity of pancreatitis and pancreatitis associated lung injury, as was shown by the reduction in pancreatic edema, neutrophil infiltration, vacuolization and necrosis. SSM treatment also reduced pancreatic weight/body weight ratio, serum amylase, lipase and cytokine levels, and mRNA expression of multiple inflammatory mediators such as tumor necrosis factor-α and interleukin-1β. In addition, treatment with SSM inhibited HMGB-1 expression in the pancreas during AP. In accordance with in vivo data, SSM inhibited the cerulein-induced acinar cell death, cytokine, and HMGB-1 release. SSM also inhibited the activation of c-Jun NH2-terminal kinase, p38 and nuclear factor (NF)-κB.
CONCLUSION: These results suggest that SSM plays a protective role during the development of AP and pancreatitis associated lung injury via deactivating c-Jun NH2-terminal kinase, p38 and NF-κB.
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Abstract
OBJECTIVES Pancreatic cancer is the fourth leading cause of cancer-related death. Cryosurgery has emerged as a promising new technique for treatment. Although 80% of pancreatic cancers are located in the pancreatic head, no research has been conducted on the safety and efficacy of cryosurgery for these tumors. METHODS Two groups of Tibetan miniature pigs (n = 4 per group) underwent cryosurgery to the pancreatic head with either the deep freezing protocol (100% argon output) or shallow freezing protocol (10% argon output), and compared to sham-operated pigs. RESULTS Serum inflammatory factors and amylase increased during the 5 days after cryoablation in both groups but acute pancreatitis did not occur. Adhesions were observed between the pancreatic head and adjacent organs, and only minor trauma was caused to the stomach, duodenum, small intestine, and liver. Ice balls with a radius of 0.5 cm beyond the tumor edge were sufficient to cause complete necrosis of the pancreatic tissue, and decreased the degree of cold injury to surrounding tissues. CONCLUSIONS Shallow freezing protocol seemed to be safer than, and just as effective as, the deep freezing protocol. This preliminary study suggests that cryosurgery could potentially be an effective treatment of cancer of the pancreatic head.
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22
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Mansfield C. Pathophysiology of acute pancreatitis: potential application from experimental models and human medicine to dogs. J Vet Intern Med 2012; 26:875-87. [PMID: 22676262 DOI: 10.1111/j.1939-1676.2012.00949.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Revised: 04/05/2012] [Accepted: 04/24/2012] [Indexed: 12/18/2022] Open
Abstract
The cellular events leading to pancreatitis have been studied extensively in experimental models. Understanding the cellular events and inciting causes of the multisystem inflammatory cascades that are activated with this disease is of vital importance to advance diagnosis and treatment of this condition. Unfortunately, the pathophysiology of pancreatitis in dogs is not well understood, and extrapolation from experimental and human medicine is necessary. The interplay of the inflammatory cascades (kinin, complement, cytokine) is extremely complex in both initiating leukocyte migration and perpetuating disease. Recently, nitric oxide (NO) and altered microcirculation of the pancreas have been proposed as major initiators of inflammation. In addition, the role of the gut is becoming increasingly explored as a cause of oxidative stress and potentiation of systemic inflammation in pancreatitis.
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Affiliation(s)
- Caroline Mansfield
- Faculty of Veterinary Science, The University of Melbourne, Werribee, Vic., Australia.
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23
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Abstract
The initial injury in acute pancreatitis is characteristically sterile and results in acinar cells necrosis. Intracellular contents released from damaged cells into the extracellular space serve as damage-associated molecular patterns (DAMPs) that trigger inflammation. There is increasing evidence that this sterile inflammatory response mediated through DAMPs released from necrotic acinar cells is a key determinant of further pancreatic injury, remote organ injury, and disease resolution in experimental models. A number of DAMPS, including high-mobility group box protein 1, DNA, adenosine triphosphate and heat shock protein 70, have been shown to have a role in experimental pancreatitis. Many of these DAMPs are also detectable in the human pancreatitis. Genetic deletion and pharmacologic antagonism demonstrate that specific DAMP receptors, including Toll-like receptor (TLR) 4, TLR9, and P2X7, are also required for inflammation in experimental acute pancreatitis. Downstream DAMP-sensing components include nod-like receptor protein 3, caspase 1, interleukin-1β (IL-1), IL-18, and IL-1 receptor, and also are required for full experimental pancreatitis. These DAMP-mediated pathways provide novel therapeutic targets using antagonists of TLRs and other receptors.
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Affiliation(s)
- Rafaz Hoque
- Section of Digestive Diseases, Yale University, New Haven, CT, USA
| | - Ahsan Malik
- Section of Digestive Diseases, Yale University, New Haven, CT, USA
| | - Fred Gorelick
- Section of Digestive Diseases, Yale University, New Haven, CT, USA
| | - Wajahat Mehal
- Section of Digestive Diseases, Yale University, New Haven, CT, USA
- Department of Immunobiology, Yale University, New Haven, CT, USA
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Romac JMJ, Shahid RA, Choi SS, Karaca GF, Westphalen CB, Wang TC, Liddle RA. Pancreatic secretory trypsin inhibitor I reduces the severity of chronic pancreatitis in mice overexpressing interleukin-1β in the pancreas. Am J Physiol Gastrointest Liver Physiol 2012; 302:G535-41. [PMID: 22173919 PMCID: PMC3311433 DOI: 10.1152/ajpgi.00287.2011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2011] [Accepted: 12/13/2011] [Indexed: 01/31/2023]
Abstract
IL-1β is believed to play a pathogenic role in the development of pancreatitis. Expression of human IL-1β in pancreatic acinar cells produces chronic pancreatitis, characterized by extensive intrapancreatic inflammation, atrophy, and fibrosis. To determine if activation of trypsinogen is important in the pathogenesis of chronic pancreatitis in this model, we crossed IL-1β transgenic [Tg(IL1β)] mice with mice expressing a trypsin inhibitor that is normally produced in rat pancreatic acinar cells [pancreatic secretory trypsin inhibitor (PTSI) I]. We previously demonstrated that transgenic expression of PSTI-I [Tg(Psti1)] increased pancreatic trypsin inhibitor activity by 190%. Tg(IL1β) mice were found to have marked pancreatic inflammation, characterized by histological changes, including acinar cell loss, inflammatory cell infiltration, and fibrosis, as well as elevated myeloperoxidase activity and elevated pancreatic trypsin activity, as early as 6 wk of age. In contrast to Tg(IL1β) mice, pancreatitis was significantly less severe in dual-transgenic [Tg(IL1β)-Tg(Psti1)] mice expressing IL-1β and PSTI-I in pancreatic acinar cells. These findings indicate that overexpression of PSTI-I reduces the severity of pancreatitis and that pancreatic trypsin activity contributes to the pathogenesis of an inflammatory model of chronic pancreatitis.
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Affiliation(s)
- Joelle M-J Romac
- Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, North Carolina 27710, USA
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Xiping Z, Yan P, Xinmei H, Guanghua F, Meili M, Jie N, Fangjie Z. Effects of dexamethasone and Salvia miltiorrhizae on the small intestine and immune organs of rats with severe acute pancreatitis. Inflammation 2010; 33:259-66. [PMID: 20127399 DOI: 10.1007/s10753-010-9180-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
To observe the protecting effects and mechanisms of Dexamethasone and Salviae miltiorrhizae on intestinal mucosa and immune organs (spleen, thymus and lymph node) in rats with severe acute pancreatitis (SAP). The rats were randomly divided into sham-operated, model control, Dexamethasone treated group and Salviae miltiorrhizae treated group. At 3, 6 and 12 h after operation, the mortality rate, pathological changes of intestinal mucosa and immune organs as well as the contents of serum PAF, IL-1 beta and sIL-2R were observed, respectively. The mortality rate and the contents of PAF (at 3 and 6 h), IL-1 beta (at all time points) and sIL-2R (at 3 and 6 h) as well as the pathological scores of thymus (at all time points) and spleen (at 3 h) in Dexamethasone treated group were significantly lower than those in model control groups (P < 0.05). The contents of PAF (at 3 and 12 h), IL-1 beta (at 6 and 12 h) and sIL-2R (at 3 and 6 h) as well as the pathological scores of thymus (at all time points) and spleen (at 3 and 12 h) in Salviae miltiorrhizae treated group were markedly lower than those in model control groups (P < 0.05). Since both Dexamethasone and Salvia miltiorrhizae can reduce the contents of serum PAF, sIL-2R and IL-1 beta, mitigate the pathological changes in the small intestine, spleen and thymus and reduce the mortality rate of SAP rats, they show good therapeutic effects on SAP rats.
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Affiliation(s)
- Zhang Xiping
- Department of General Surgery, Hangzhou First People's Hospital, Hangzhou, 310006, Zhejiang Province, China
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De Campos T, Deree J, Coimbra R. From acute pancreatitis to end-organ injury: mechanisms of acute lung injury. Surg Infect (Larchmt) 2007; 8:107-20. [PMID: 17381402 DOI: 10.1089/sur.2006.011] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Multi-organ dysfunction, and in particular lung injury, is often responsible for the unfavorable outcome of patients with severe acute pancreatitis. Understanding of the mechanisms by which local inflammation in the pancreas leads to end-organ injury is crucial for the development of new therapeutic strategies. METHODS A MEDLINE search was performed with the terms "acute pancreatitis," "lung injury," "inflammatory response," "SIRS," and "multi-organ dysfunction." Pertinent articles were selected for analysis. RESULTS Modulation of the inflammatory response using a combination of immunomodulatory agents may decrease the incidence of severe pancreatitis-related acute lung injury and acute respiratory distress syndrome. CONCLUSION Clinical trials are of utmost importance to establish the validity of such strategies.
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Affiliation(s)
- Tercio De Campos
- Division of Trauma, University of California-San Diego, 200 W. Arbor Drive, San Diego, CA 92103, USA
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27
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An HJ, Lee JH, Lee HJ, Yang WM, Park SK, Hong SH, Kim HM, Um JY. Electroacupuncture protects against CCK-induced acute pancreatitis in rats. Neuroimmunomodulation 2007; 14:112-8. [PMID: 17804915 DOI: 10.1159/000107793] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2007] [Accepted: 06/26/2007] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Electroacupuncture (EA) has been used to treat myalgia, adiposis and gastroenteropathy in Korea. EA as a complementary and alternative medicine has been accepted worldwide mainly for the treatment acute and chronic pain and inflammation. The aim of this study was to investigate the effects of EA on acute pancreatitis induced by cholecystokinin octapeptide (CCK) in rats. METHODS Animals were divided into four groups: (1) a normal group; (2) a CCK-induced acute pancreatitis group; (3) a CCK-induced acute pancreatitis group treated with 100-Hz EA, and (4) a CCK-induced acute pancreatitis group treated with 2-Hz EA. High-frequency (100-Hz) and low-frequency EA (2-Hz) stimulations were applied to an acupoint equivalent to Zusanli (ST36) in rats, followed by 75 microg/kg CCK subcutaneously three times, after 1, 3 and 5 h. The entire procedure was repeated over 5 days. Repeated CCK treatment resulted in typical laboratory and morphological changes in experimentally induced pancreatitis. RESULTS EA significantly decreased the pancreatic weight/body weight ratio in CCK-induced acute pancreatitis, increased the pancreatic levels of HSP60 and HSP72, and decreased the beta-amylase and lipase levels associated with CCK-induced acute pancreatitis. Furthermore, the release of ACTH was increased in the blood serum of the EA-treated group. CONCLUSION EA may have protective effects against CCK-induced acute pancreatitis through the release of ACTH.
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Affiliation(s)
- Hyo-Jin An
- Department of Pharmacology, College of Oriental Medicine, Oriental Medical Science, Institute of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
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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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Reddymasu S, Banks DE, Jordan PA. Acute pancreatitis in a patient with malnutrition due to major depressive disorder. Am J Med 2006; 119:179-80. [PMID: 16443432 DOI: 10.1016/j.amjmed.2005.09.023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2005] [Revised: 09/08/2005] [Accepted: 09/09/2005] [Indexed: 12/22/2022]
Affiliation(s)
- Savio Reddymasu
- Department of Medicine, Louisiana State University Health Sciences Center, Shreveport, La 71115, USA.
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30
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Abstract
Acute pancreatitis is a common clinical condition. It is a disease of variable severity in which some patients experience mild, self-limited attacks while others manifest a severe, highly morbid, and frequently lethal attack. The exact mechanisms by which diverse etiological factors induce an attack are still unclear. It is generally believed that the earliest events in acute pancreatitis occur within acinar cells. Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction. If this inflammatory reaction is marked, it leads to a systemic inflammatory response syndrome (SIRS). An excessive SIRS leads to distant organ damage and multiple organ dysfunction syndrome (MODS). MODS associated with acute pancreatitis is the primary cause of morbidity and mortality in this condition. Recent studies have established the role played by inflammatory mediators in the pathogenesis of acute pancreatitis and the resultant MODS. At the same time, recent research has demonstrated the importance of acinar cell death in the form of apoptosis and necrosis as a determinant of pancreatitis severity. In this review, we will discuss about our current understanding of the pathophysiology of acute pancreatitis.
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Affiliation(s)
- Madhav Bhatia
- Department of Pharmacology, National University of Singapore, Singapore.
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Denham W, Norman J. Potential new therapies for the treatment of acute pancreatitis. Expert Opin Investig Drugs 2005; 8:973-82. [PMID: 15992099 DOI: 10.1517/13543784.8.7.973] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The treatment of acute pancreatitis has remained virtually unchanged for the past 50 years, in large part due to a poor understanding of the initial intracellular events. Furthermore, there is a lack of knowledge regarding the mediator(s) responsible for the progression of the disease from local pancreatic inflammation to a systemic inflammatory disease, as well as the mediator(s) responsible for distant organ dysfunction and failure. With recent advances in the pathophysiology of pancreatitis, in particular the role of the inflammatory mediators interleukin-1 beta, tumour necrosis factor alpha and platelet-activating factor, the potential for new effective therapies has been realised. At present, a number of inflammatory mediator antagonists are being tested in humans, with the hope that we may soon develop a specific treatment for a disease, which thus far, has none.
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Affiliation(s)
- W Denham
- Department of Surgery, MDC 16, University of South Florida, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA.
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32
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Abstract
Acute pancreatitis is an inflammatory disorder, and inflammation not only affects the pathogenesis but also the course of the disease. Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction; if marked this leads to a systemic inflammatory response syndrome (SIRS). An excessive SIRS leads to distant organ damage and multiple organ dysfunction syndrome (MODS). MODS associated with acute pancreatitis is the primary cause of morbidity and mortality in this condition. Recent studies by us and other investigators have established the critical role played by inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, IL-8, CINC/GRO-alpha, MCP-1, PAF, IL-10, CD40L, C5a, ICAM-1, MIP1-alpha, RANTES, substance P, and hydrogen sulfide in acute pancreatitis and the resultant MODS. This review intends to present an overview of the inflammatory response that takes place following pancreatic acinar cell injury.
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Affiliation(s)
- M Bhatia
- Department of Pharmacology, National University of Singapore, Faculty of Medicine, Singapore.
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33
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Kimura Y, Hirota M, Okabe A, Inoue K, Kuwata K, Ohmuraya M, Ogawa M. Dynamic aspects of granulocyte activation in rat severe acute pancreatitis. Pancreas 2003; 27:127-32. [PMID: 12883260 DOI: 10.1097/00006676-200308000-00004] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We demonstrated dynamic aspects of granulocyte activation in rat severe acute pancreatitis, which was induced by cerulein and aggravated following lipopolysaccharide (LPS) injection. Pancreatitis induced by cerulein increased intracellular elastase activity of granulocytes in the blood. However, significant systemic cytokinemia was not provoked under such conditions. After induction of severe pancreatitis by LPS, intracellular elastase activity of circulating granulocytes decreased markedly and immediately. This decrease occurred simultaneous to induction of systemic hypercytokinemia and granulocyte migration into the lung. Overall results imply that: (1) circulating granulocytes are activated by induction of mild pancreatitis; (2) activation of granulocytes is mediated by factors other than systemic cytokinemia, such as locally produced cytokines; (3) those priming granulocytes immediately and significantly migrate from the circulation into the extravascular space by induction of endotoxemia; and (4) migration of granulocytes, in turn, may be mediated by systemic cytokinemia.
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Affiliation(s)
- Yu Kimura
- Department of Surgery II, Kumamoto University Medical School, 1-1-1 Honjo, Kumamoto-city, Kumamoto 860-8556, Japan
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Abstract
INTRODUCTION The pathogenesis of acute pancreatitis remains elusive. Sepsis and multiple organ failure continue to cause death (overall mortality rate, approximately 10%) despite immense improvements in supportive, radiologic, and surgical therapy. The gut appears to play a key role in the development of these complications. AIM To critically review the evidence implicating the gut in the pathogenesis of acute pancreatitis. METHODS Relevant English-language literature or abstracts cited in the MEDLINE database were reviewed. RESULTS AND CONCLUSION Gram-negative enteric organisms account for most infections of pancreatic necrosis and subsequent sepsis, which suggests the gut as a source. Intestinal permeability is increased early in patients with severe acute pancreatitis and correlates with endotoxemia, which suggests translocation as a possible mechanism. The pathogenesis of the deranged function of the gut mucosal barrier and the possible sites of increase in intestinal permeability are discussed. The gut also plays a role in priming neutrophils and the release of inflammatory cytokines, which initiate and propagate nearly all the detrimental consequences of severe inflammation and sepsis. Future research avenues and potential therapeutic measures that may restore and preserve gut barrier function are explored.
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Affiliation(s)
- Basil J Ammori
- Division of Surgery, The University of Leeds, and the Center for Digestive Diseases, The General Infirmary, Leeds, United Kingdom.
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36
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Ethridge RT, Hashimoto K, Chung DH, Ehlers RA, Rajaraman S, Evers BM. Selective inhibition of NF-kappaB attenuates the severity of cerulein-induced acute pancreatitis. J Am Coll Surg 2002; 195:497-505. [PMID: 12375755 DOI: 10.1016/s1072-7515(02)01222-x] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Acute pancreatitis (AP) is associated with increased cytokine production, which can ultimately produce deleterious local and systemic effects. The transcription factor NF-kappaB is activated by degradation of its inhibitory factor, IkappaB, and can stimulate various cytokines. The purpose of this study was to determine whether the inhibition of NF-kappaB binding activity with a novel peptide that binds to the NF-kappaB essential modifier binding domain (NBD) could attenuate the severity of AP. STUDY DESIGN AP was induced in Swiss Webster mice by hourly injections of the cholecystokinin analogue cerulein (50 microg/kg). Mice were injected with either the wild-type or control (mutated) NBD peptide at the time of the first cerulein injection; they were then sacrificed over a time course, and pancreata and lungs were harvested for histologic analysis and scoring. Myeloperoxidase activity was measured to assess neutrophil sequestration as an indicator of inflammation. NF-kappaB binding activity and steady-state levels of IkappaB and NF-kappaB subunits were determined by gel shift and Western blot, respectively. RESULTS AP resulted in increased NF-kappaB DNA-binding activity and decreased steady-state levels of IkappaB. Treatment with NBD peptide decreased inflammation in the pancreas, decreased hemorrhage in the lungs, and decreased myeloperoxidase activity in both pancreas and lung. CONCLUSIONS The marked induction of NF-kappaB binding activity suggests a role for this transcription factor in the early inflammatory changes associated with AP. Treatment with the NBD peptide attenuated the severity of injury associated with AP. Novel compounds that selectively target NF-kappaB may prove to be useful treatment of AP and AP-associated lung injury.
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Affiliation(s)
- Richard T Ethridge
- Departments of Surgery, The University of Texas Medical Branch, Galveston 77555-0533, USA
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37
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Bruno MJ. Current insights into the pathogenesis of acute and chronic pancreatitis. SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY. SUPPLEMENT 2002:103-8. [PMID: 11768555 DOI: 10.1080/003655201753265532] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
Abstract
For a long time the pathogenesis of pancreatitis has remained enigmatic. Recent developments in cellular and molecular biology, however, have provided a tremendous research impetus and some of its mysteries are finally being disclosed. This review discusses the implications of the discovery of the disease gene in hereditary pancreatitis and outlines recent advances in our understanding of the mechanism and site of trypsinogen activation and the role of immunocytes and cytokines in acute pancreatitis. With respect to chronic pancreatitis, this review focuses on its association with mutations in the cystic fibrosis conductance regulator gene and the mechanisms of pancreatic fibrosis. These advances in our knowledge of the pathogenesis of the disease, together with emerging biotechnological techniques, will boost the development of future therapies aimed at strategically targeting key pathophysiological processes involved in acute and chronic pancreatitis.
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Affiliation(s)
- M J Bruno
- Division of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
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38
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Pin CL, Rukstalis JM, Johnson C, Konieczny SF. The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity. J Cell Biol 2001; 155:519-30. [PMID: 11696558 PMCID: PMC2198859 DOI: 10.1083/jcb.200105060] [Citation(s) in RCA: 212] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The pancreas is a complex organ that consists of separate endocrine and exocrine cell compartments. Although great strides have been made in identifying regulatory factors responsible for endocrine pancreas formation, the molecular regulatory circuits that control exocrine pancreas properties are just beginning to be elucidated. In an effort to identify genes involved in exocrine pancreas function, we have examined Mist1, a basic helix-loop-helix transcription factor expressed in pancreatic acinar cells. Mist1-null (Mist1(KO)) mice exhibit extensive disorganization of exocrine tissue and intracellular enzyme activation. The exocrine disorganization is accompanied by increases in p8, RegI/PSP, and PAP1/RegIII gene expression, mimicking the molecular changes observed in pancreatic injury. By 12 m, Mist1(KO) mice develop lesions that contain cells coexpressing acinar and duct cell markers. Analysis of the factors involved in cholecystokinin (CCK) signaling reveal inappropriate levels of the CCK receptor A and the inositol-1,4,5-trisphosphate receptor 3, suggesting that a functional defect exists in the regulated exocytosis pathway of Mist1(KO) mice. Based on these observations, we propose that Mist1(KO) mice represent a new genetic model for chronic pancreas injury and that the Mist1 protein serves as a key regulator of acinar cell function, stability, and identity.
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Affiliation(s)
- C L Pin
- Department of Paediatrics, Child Health Research Institute, University of Western Ontario, London, Ontario N6C 2V5, Canada
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Vaquero E, Gukovsky I, Zaninovic V, Gukovskaya AS, Pandol SJ. Localized pancreatic NF-kappaB activation and inflammatory response in taurocholate-induced pancreatitis. Am J Physiol Gastrointest Liver Physiol 2001; 280:G1197-208. [PMID: 11352813 DOI: 10.1152/ajpgi.2001.280.6.g1197] [Citation(s) in RCA: 116] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Transcription factor nuclear factor-kappaB (NF-kappaB) is activated in cerulein pancreatitis and mediates cytokine expression. The role of transcription factor activation in other models of pancreatitis has not been established. Here we report upregulation of NF-kappaB and inflammatory molecules, and their correlation with local pancreatic injury, in a model of severe pancreatitis. Rats received intraductal infusion of taurocholate or saline, and the pancreatic head and tail were analyzed separately. NF-kappaB and activator protein-1 (AP-1) activation were assessed by gel shift assay, and mRNA expression of interleukin-6, tumor necrosis factor-alpha, KC, monocyte chemoattractant protein-1, and inducible nitric oxide synthase was assessed by semiquantitative RT-PCR. Morphological damage and trypsin activation were much greater in the pancreatic head than tail, in parallel with a stronger activation of NF-kappaB and cytokine mRNA. Saline infusion mildly affected these parameters. AP-1 was strongly activated in both pancreatic segments after either taurocholate or saline infusion. NF-kappaB inhibition with N-acetylcysteine ameliorated the local inflammatory response. Correlation between localized NF-kappaB activation, cytokine upregulation, and tissue damage suggests a key role for NF-kappaB in the development of the inflammatory response of acute pancreatitis.
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Affiliation(s)
- E Vaquero
- Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, California 90073, USA.
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40
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Okabe A, Hirota M, Nozawa F, Shibata M, Nakano S, Ogawa M. Altered cytokine response in rat acute pancreatitis complicated with endotoxemia. Pancreas 2001; 22:32-9. [PMID: 11138968 DOI: 10.1097/00006676-200101000-00006] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We demonstrated that the dynamic aspects of cytokine production in rat acute pancreatitis, which was induced by cerulein and aggravated by subsequent lipopolysaccharide (LPS) injection. A priming effect by induction of mild pancreatitis with cerulein enhanced the subsequent cytokine production by LPS injection. Alternatively, after induction of severe pancreatitis with cerulein and LPS, cytokine production was markedly suppressed for > or = 90 hours. Production of interleukin-2 (IL-2) by splenocytes decreased, and mortality rate after cecal ligation and puncture (CLP) increased significantly after induction of severe acute pancreatitis. These results suggest that the suppression of a cytokine response in severe acute pancreatitis may alter the defense system and, as a result, increase mortality after CLP.
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Affiliation(s)
- A Okabe
- Department of Surgery II, Kumamoto University Medical School, Kumamoto-city, Japan
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41
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Ulrich CD, Kopras E, Wu Y, Ward S. Hereditary pancreatitis: epidemiology, molecules, mutations, and models. THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE 2000; 136:260-74. [PMID: 11039846 DOI: 10.1067/mlc.2000.109405] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- C D Ulrich
- Department of Internal Medicine, University of Cincinnati, OH, USA
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42
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Andoh A, Takaya H, Saotome T, Shimada M, Hata K, Araki Y, Nakamura F, Shintani Y, Fujiyama Y, Bamba T. Cytokine regulation of chemokine (IL-8, MCP-1, and RANTES) gene expression in human pancreatic periacinar myofibroblasts. Gastroenterology 2000; 119:211-9. [PMID: 10889171 DOI: 10.1053/gast.2000.8538] [Citation(s) in RCA: 126] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS We have previously isolated and characterized human pancreatic periacinar myofibroblasts. In this study, to define the role of these cells in the pathogenesis of acute pancreatitis, we investigated chemokine expression in them. METHODS Secretion of chemokines (interleukin [IL]-8, monocyte chemoattractant protein [MCP]-1, RANTES, and MIP [macrophage inflammatory protein]-1alpha) was evaluated by ELISA, Northern blotting, and nuclear run-on assays. The activation of NF-kappaB and NF-IL6 was assessed by an electrophoretic gel mobility shift assay. RESULTS IL-8 and MCP-1 secretion was rapidly induced by both IL-1beta and tumor necrosis factor (TNF)-alpha. RANTES secretion was induced more slowly and was induced mainly by TNF-alpha. However, MIP-1alpha secretion was not induced by any stimuli. These responses were also observed at the messenger RNA level, and they were accompanied by an increase in transcriptional rate. The increase in transcriptional activation of chemokine genes correlated with the NF-kappaB and NF-IL6 activation. Furthermore, a blockade of NF-kappaB activation by PDTC and TPCK markedly reduced the IL-1beta- or TNF-alpha-induced chemokine gene expression. CONCLUSIONS Chemokine secretion is differentially regulated in pancreatic periacinar myofibroblasts, suggesting a role for these cells in mediating the infiltration and accumulation of inflammatory cells in the pancreas.
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Affiliation(s)
- A Andoh
- Department of Internal Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, Japan.
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43
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Abstract
Inflammatory mediators play a key role in acute pancreatitis and the resultant multiple organ dysfunction syndrome, which is the primary cause of death in this condition. Recent studies have confirmed the critical role played by inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, IL-8, PAF, IL-10, C5a, ICAM-1, and substance P. The systemic effects of acute pancreatitis have many similarities to those of other conditions such as septicaemia, severe burns, and trauma. The delay between the onset of inflammation in the pancreas and the development of the systemic response makes acute pancreatitis an ideal experimental and clinical model with which to study the role of inflammatory mediators and to test novel therapies. Elucidation of the key mediators involved in the pathogenesis of acute pancreatitis will facilitate the development of clinically effective anti-inflammatory therapy.
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Affiliation(s)
- M Bhatia
- Department of Surgery, Royal Liverpool University Hospital, University of Liverpool, Liverpool, L69 3GA, UK
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44
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Abstract
Inflammatory mediators play a key role in acute pancreatitis and the resultant multiple organ dysfunction syndrome, which is the primary cause of death in this condition. Recent studies have confirmed the critical role played by inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, IL-8, PAF, IL-10, C5a, ICAM-1, and substance P. The systemic effects of acute pancreatitis have many similarities to those of other conditions such as septicaemia, severe burns, and trauma. The delay between the onset of inflammation in the pancreas and the development of the systemic response makes acute pancreatitis an ideal experimental and clinical model with which to study the role of inflammatory mediators and to test novel therapies. Elucidation of the key mediators involved in the pathogenesis of acute pancreatitis will facilitate the development of clinically effective anti-inflammatory therapy.
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Affiliation(s)
- M Bhatia
- Department of Surgery, Royal Liverpool University Hospital, University of Liverpool, Liverpool, L69 3GA, UK
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45
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Denham W, Norman J. The potential role of therapeutic cytokine manipulation in acute pancreatitis. Surg Clin North Am 1999; 79:767-81. [PMID: 10470326 DOI: 10.1016/s0039-6109(05)70042-6] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The central, detrimental role of the inflammatory cytokines IL-1 and TNF and the biologically active phospholipid PAF in the pathogenesis of AP has been established over the past 8 years. A number of antagonists to these mediators have been used successfully in the laboratory setting and are currently being examined in prospective randomized trials. The effectiveness of any antagonist depends not only on its ability to block the effects of the inflammatory mediators but also on its administration early enough in the course of the pancreatitis before pancreatic necrosis or organ dysfunction.
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Affiliation(s)
- W Denham
- Department of Surgery, University of South Florida College of Medicine, Tampa, USA
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46
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Lukiw WJ, Martinez J, Pelaez RP, Bazan NG. The interleukin-1 type 2 receptor gene displays immediate early gene responsiveness in glucocorticoid-stimulated human epidermal keratinocytes. J Biol Chem 1999; 274:8630-8. [PMID: 10085100 DOI: 10.1074/jbc.274.13.8630] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Human epidermal keratinocytes (HEKs) in primary culture (P2-P4) were used to study glucocorticoid (GC)-mediated transcription of the genes encoding the constitutively expressed interleukin-1 type 1 receptor (IL-1R1) and the inducible interleukin-1 type 2 receptor (IL-1R2). Utilizing Northern dot blot analysis and a quantitative reverse transcription-polymerase chain reaction protocol for IL-1R1 and IL-1R2, dexamethasone and, in particular, the budesonide epimer R were shown to effectively and rapidly induce transcription from the IL-IR2 gene when compared with IL-1R1 or beta-actin RNA message levels in the same sample. Southern blot analysis of newly generated IL-1R2 reverse transcription-polymerase chain reaction products using end-labeled IL-1R2 intron probes suggested that GC enhancement of IL-1R2 expression was regulated primarily at the level of de novo transcription. GC-induced IL-1R2 gene transcription displayed features characteristic of a classical immediate early gene response, including a signal transduction function, a relatively low basal abundance, a rapid, transient induction, cycloheximide superinduction, actinomycin D suppression, and a rapid decay of IL-1R2 RNA message. Parallel time course kinetic analysis of IL-1R2 RNA message levels with Western immunoblotting revealed tight coupling of de novo IL-IR2 gene transcription with translation of the IL-1R2 RNA message; a newly synthesized ( approximately 46-kDa) IL-1R2 protein was detected in the HEK growth medium as early as 1 h after budesonide epimer R treatment. These data indicate that different GC compounds can variably up-regulate the IL-1R2 response in HEKs through transcription-mediated mechanisms and, for the first time, suggest that a gene encoding a soluble cytokine receptor can respond like an immediate early gene.
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Affiliation(s)
- W J Lukiw
- Louisiana State University Medical Center, Neuroscience Center and Department of Ophthalmology, New Orleans, Louisiana 70112-2272, USA
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Abstract
BACKGROUND The systemic manifestations of acute pancreatitis are responsible for the majority of pancreatitis-associated morbidity and mortality and are now believed to be due to the actions of specific inflammatory cytokines. This report summarizes what is known about the role of cytokines in the pathogenesis of acute pancreatitis. METHODS Comprehensive literature review of experimental pancreatitis as well as all reports of cytokine involvement during clinical pancreatitis. RESULTS Several cytokines and other noncytokine inflammatory mediators are produced rapidly during pancreatitis. These mediators arise in many tissues in a predictable fashion independent of the animal model used or the underlying etiology in human disease. Preventing the activities of these mediators has a profound beneficial effect in experimental animals. CONCLUSIONS A few recently described inflammatory mediators are believed to be primarily responsible for the systemic manifestations of acute pancreatitis and its associated distant organ dysfunction. The predictable nature in which they are produced may allow for novel approaches to treating this disease. Am J Surg.
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Affiliation(s)
- J Norman
- Department of Surgery, University of South Florida, Tampa 33601, USA
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