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1
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Swetha K, Indumathi MC, Siddappa S, Chen CH, Marathe GK. Comparative Study of Non-invasive Mouse Models of Pancreatitis. Dig Dis Sci 2025; 70:233-244. [PMID: 39604666 DOI: 10.1007/s10620-024-08771-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 11/19/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND AND AIMS Although a relevant animal model is essential for studying human diseases, one has yet to be established for mouse pancreatitis. Early non-invasive models of mouse pancreatitis have serious limitations. METHODS In this study, we compared the efficiency, consistency, and reproducibility of inducing pancreatitis in 3 non-invasive mouse models of pancreatitis in Wistar albino mice: (1) L-arginine-induced model (2 intraperitoneal injections of 4 g/kg body weight of L-arginine spaced 1 h apart), (2) caerulein-induced model (6 intraperitoneal injections of 50 µg/kg body weight of caerulein at hourly intervals), and (3) caerulein + LPS (lipopolysaccharide)-induced model (6 intraperitoneal doses of 50 µg/kg body weight of caerulein at hourly intervals, along with an LPS [10 mg/kg body weight] injection immediately after the last caerulein injection). RESULTS Our findings showed that the L-arginine-induced model was inconsistent. The levels of the pancreatic enzymes, amylase and lipase, were higher in the caerulein and caerulein + LPS groups. Histological examination showed tissue destruction in the induced groups, with varying degrees of fibrosis in the caerulein + LPS group. CONCLUSIONS The caerulein + LPS model was the most reliable model in Wistar albino mice. Our findings may be useful in helping investigators choose the most appropriate animal model for pancreatitis research.
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Affiliation(s)
- Kamatam Swetha
- Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore-06, India
| | | | - Shiva Siddappa
- Division of Biochemistry, School of Life Sciences, JSS Academy of Higher Education and Research, Mysore-15, India
| | - Chu-Huang Chen
- Vascular and Medicinal Research, The Texas Heart Institute, Houston, TX, 77030, USA
| | - Gopal K Marathe
- Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore-06, India.
- Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore-06, India.
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2
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Abstract
PURPOSE OF REVIEW Acute pancreatitis is a common acute inflammatory disorder of the pancreas, and its incidence has been increasing worldwide. Approximately 10% of acute pancreatitis progresses to severe acute pancreatitis (SAP), which carries significant morbidity and mortality. Disordered immune response to pancreatic injury is regarded as a key event that mediates systemic injury in SAP. In this article, we review recent developments in immune biomarkers of SAP and future directions for research. RECENT FINDINGS Given the importance of the NLRP3-inflammasome pathway in mediating systemic inflammatory response syndrome and systemic injury, recent studies have investigated associations of SAP with systemic levels of activators of NLRP3, such as the damage associated molecular patterns (DAMPs) for the first time in human SAP. For example, circulating levels of histones, mitochondrial DNAs, and cell free DNAs have been associated with SAP. A panel of mechanistically relevant immune markers (e.g., panel of Angiopoeitin-2, hepatocyte growth factor, interleukin-8 (IL-8), resistin and sTNF-α R1) carried higher predictive accuracies than existing clinical scores and individual immune markers. Of the cytokines with established relevance to SAP pathogenesis, phase 2 trials of immunotherapies, including tumor necrosis factor (TNF)-alpha inhibition and stimulation of IL-10 production, are underway to determine if altering the immunologic response can reduce the severity of acute pancreatitis (AP). SUMMARY Circulating systemic levels of various DAMPs and a panel of immune markers that possibly reflect activities of different pathways that drive SAP appear promising as predictive biomarkers for SAP. But larger multicenter studies are needed for external validation. Studies investigating immune cellular pathways driving SAP using immunophenotyping techniques are scarce. Interdisciplinary efforts are also needed to bring some of the promising biomarkers to the bedside for validation and testing for clinical utility. Studies investigating the role of and characterization of altered gut-lymph and gut-microbiota in severe AP are needed.
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Affiliation(s)
- Peter J Lee
- Division of Gastroenterology, Hepatology, and Nutrition. Ohio State University Wexner Medical Center, Columbus, OH
| | - Georgios I Papachristou
- Division of Gastroenterology, Hepatology, and Nutrition. Ohio State University Wexner Medical Center, Columbus, OH
| | - Cate Speake
- Center for Interventional Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Washington
| | - Adam Lacy-Hulbert
- Center for Systems Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Washington
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3
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Hoferica J, Borbély RZ, Aghdam AN, Szalai EÁ, Zolcsák Á, Veres DS, Hagymási K, Erőss B, Hegyi P, Bánovčin P, Hegyi PJ. Chronic liver disease is an important risk factor for worse outcomes in acute pancreatitis: a systematic review and meta-analysis. Sci Rep 2024; 14:16723. [PMID: 39030187 PMCID: PMC11271551 DOI: 10.1038/s41598-024-66710-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 07/03/2024] [Indexed: 07/21/2024] Open
Abstract
Chronic liver diseases (CLD) affect 1.5 billion patients worldwide, with dramatically increasing incidence in recent decades. It has been hypothesized that the chronic hyperinflammation associated with CLD may increase the risk of a more severe course of acute pancreatitis (AP). This study aims to investigate the underlying impact of CLD on the outcomes of AP. A systematic search was conducted in Embase, Medline, and Central databases until October 2022. Studies investigating patients with acute pancreatitis and CLD, were included in the meta-analysis. A total of 14,963 articles were screened, of which 36 were eligible to be included. CLD was a risk factor for increased mortality with an odds ratio (OR) of 2.53 (CI 1.30 to 4.93, p = 0.01). Furthermore, renal, cardiac, and respiratory failures were more common in the CLD group, with ORs of 1.92 (CI 1.3 to 2.83, p = 0.01), 2.11 (CI 0.93 to 4.77, p = 0.062) and 1.99 (CI 1.08 to 3.65, p = 0.033), respectively. Moreover, the likelihood of developing Systemic Inflammatory Response Syndrome (SIRS) was significantly higher, with an OR of 1.95 (CI 1.03 to 3.68, p = 0.042). CLD is an important risk factor for worse outcomes in AP pancreatitis, leading to higher mortality and increased rates of local and systemic complications.
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Affiliation(s)
- Jakub Hoferica
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Clinic of Internal Medicine - Gastroenterology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia
| | - Ruben Zsolt Borbély
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Department of Medical Imaging, Bajcsy-Zsilinszky Hospital and Clinic, Budapest, Hungary
| | - Ali Nedjati Aghdam
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Eszter Ágnes Szalai
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Department of Restorative Dentistry and Endodontics, Semmelweis University, Budapest, Hungary
| | - Ádám Zolcsák
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | - Dániel Sándor Veres
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | - Krisztina Hagymási
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Bálint Erőss
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Translational Pancreatology Research Group, Interdisciplinary Centre of Excellence for Research Development and Innovation, University of Szeged, Szeged, Hungary
| | - Peter Bánovčin
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Clinic of Internal Medicine - Gastroenterology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia
| | - Péter Jenő Hegyi
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary.
- Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary.
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4
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Poulsen VV, Hadi A, Werge MP, Karstensen JG, Novovic S. Circulating Biomarkers Involved in the Development of and Progression to Chronic Pancreatitis-A Literature Review. Biomolecules 2024; 14:239. [PMID: 38397476 PMCID: PMC10887223 DOI: 10.3390/biom14020239] [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: 12/29/2023] [Revised: 02/13/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
Chronic pancreatitis (CP) is the end-stage of continuous inflammation and fibrosis in the pancreas evolving from acute- to recurrent acute-, early, and, finally, end-stage CP. Currently, prevention is the only way to reduce disease burden. In this setting, early detection is of great importance. Due to the anatomy and risks associated with direct sampling from pancreatic tissue, most of our information on the human pancreas arises from circulating biomarkers thought to be involved in pancreatic pathophysiology or injury. The present review provides the status of circulating biomarkers involved in the development of and progression to CP.
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Affiliation(s)
- Valborg Vang Poulsen
- Pancreatitis Center East, Gastrounit, Copenhagen University Hospital—Amager and Hvidovre, 2000 Copenhagen, Denmark; (V.V.P.); (A.H.); (M.P.W.); (J.G.K.)
| | - Amer Hadi
- Pancreatitis Center East, Gastrounit, Copenhagen University Hospital—Amager and Hvidovre, 2000 Copenhagen, Denmark; (V.V.P.); (A.H.); (M.P.W.); (J.G.K.)
| | - Mikkel Parsberg Werge
- Pancreatitis Center East, Gastrounit, Copenhagen University Hospital—Amager and Hvidovre, 2000 Copenhagen, Denmark; (V.V.P.); (A.H.); (M.P.W.); (J.G.K.)
| | - John Gásdal Karstensen
- Pancreatitis Center East, Gastrounit, Copenhagen University Hospital—Amager and Hvidovre, 2000 Copenhagen, Denmark; (V.V.P.); (A.H.); (M.P.W.); (J.G.K.)
- Department of Clinical Medicine, University of Copenhagen, 2000 Copenhagen, Denmark
| | - Srdan Novovic
- Pancreatitis Center East, Gastrounit, Copenhagen University Hospital—Amager and Hvidovre, 2000 Copenhagen, Denmark; (V.V.P.); (A.H.); (M.P.W.); (J.G.K.)
- Department of Clinical Medicine, University of Copenhagen, 2000 Copenhagen, Denmark
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5
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Wu L, Hu J, Yi X, Lv J, Yao J, Tang W, Zhang S, Wan M. Gut microbiota interacts with inflammatory responses in acute pancreatitis. Therap Adv Gastroenterol 2023; 16:17562848231202133. [PMID: 37829561 PMCID: PMC10566291 DOI: 10.1177/17562848231202133] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 09/01/2023] [Indexed: 10/14/2023] Open
Abstract
Acute pancreatitis (AP) is one of the most common acute abdominal conditions, and its incidence has been increasing for years. Approximately 15-20% of patients develop severe AP (SAP), which is complicated by critical inflammatory injury and intestinal dysfunction. AP-associated inflammation can lead to the gut barrier and function damage, causing dysbacteriosis and facilitating intestinal microbiota migration. Pancreatic exocrine deficiency and decreased levels of antimicrobial peptides in AP can also lead to abnormal growth of intestinal bacteria. Meanwhile, intestinal microbiota migration influences the pancreatic microenvironment and affects the severity of AP, which, in turn, exacerbates the systemic inflammatory response. Thus, the interaction between the gut microbiota (GM) and the inflammatory response may be a key pathogenic feature of SAP. Treating either of these factors or breaking their interaction may offer some benefits for SAP treatment. In this review, we discuss the mechanisms of interaction of the GM and inflammation in AP and factors that can deteriorate or even cure both, including some traditional Chinese medicine treatments, to provide new methods for studying AP pathogenesis and developing therapies.
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Affiliation(s)
- Linjun Wu
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Hospital of Chinese Traditional Medicine of Leshan, Leshan, China
| | - Jing Hu
- Department of Integrated Traditional Chinese and Western Medicine, West China
- Hospital, Sichuan University, Chengdu, China
- Hospital of Chinese Traditional Medicine of Leshan, Leshan, China
| | - Xiaolin Yi
- Department of Integrated Traditional Chinese and Western Medicine, West China
- Hospital, Sichuan University, Chengdu, China
- Intensive Care Unit, Suining Municipal Hospital of TCM, Suining, China
| | - Jianqin Lv
- Department of Integrated Traditional Chinese and Western Medicine, West China
- Hospital, Sichuan University, Chengdu, China
| | - Jiaqi Yao
- Department of Integrated Traditional Chinese and Western Medicine, West China
- Hospital, Sichuan University, Chengdu, China
| | - Wenfu Tang
- Department of Integrated Traditional Chinese and Western Medicine, West China
- Hospital, Sichuan University, Chengdu, China
| | - Shu Zhang
- Department of Emergency Medicine, Emergency Medical Laboratory, West China
- Hospital, Sichuan University, Guo Xue Road 37, Chengdu 610041, Sichuan, China
| | - Meihua Wan
- Department of Integrated Traditional Chinese and Western Medicine, West China
- Hospital, Sichuan University, Guo Xue Road 37, Chengdu 610041, China
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6
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Kiss L, Fűr G, Pisipati S, Rajalingamgari P, Ewald N, Singh V, Rakonczay Z. Mechanisms linking hypertriglyceridemia to acute pancreatitis. Acta Physiol (Oxf) 2023; 237:e13916. [PMID: 36599412 DOI: 10.1111/apha.13916] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 11/25/2022] [Accepted: 01/02/2023] [Indexed: 01/06/2023]
Abstract
Hypertriglyceridemia (HTG) is a metabolic disorder, defined when serum or plasma triglyceride concentration (seTG) is >1.7 mM. HTG can be categorized as mild to very severe groups based on the seTG value. The risk of acute pancreatitis (AP), a serious disease with high mortality and without specific therapy, increases with the degree of HTG. Furthermore, even mild or moderate HTG aggravates AP initiated by other important etiological factors, including alcohol or bile stone. This review briefly summarizes the pathophysiology of HTG, the epidemiology of HTG-induced AP and the clinically observed effects of HTG on the outcomes of AP. Our main focus is to discuss the pathophysiological mechanisms linking HTG to AP. HTG is accompanied by an increased serum fatty acid (FA) concentration, and experimental results have demonstrated that these FAs have the most prominent role in causing the consequences of HTG during AP. FAs inhibit mitochondrial complexes in pancreatic acinar cells, induce pathological elevation of intracellular Ca2+ concentration, cytokine release and tissue injury, and reduce the function of pancreatic ducts. Furthermore, high FA concentrations can induce respiratory, kidney, and cardiovascular failure in AP. All these effects may contribute to the observed increased AP severity and frequent organ failure in patients. Importantly, experimental results suggest that the reduction of FA production by lipase inhibitors can open up new therapeutic options of AP. Overall, investigating the pathophysiology of HTG-induced AP or AP in the presence of HTG and determining possible treatments are needed.
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Affiliation(s)
- Lóránd Kiss
- Department of Pathophysiology, University of Szeged, Szeged, Hungary
| | - Gabriella Fűr
- Department of Pathophysiology, University of Szeged, Szeged, Hungary
| | - Sailaja Pisipati
- Department of Medicine, Mayo Clinic, Scottsdale, Arizona, USA.,Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Prasad Rajalingamgari
- Department of Medicine, Mayo Clinic, Scottsdale, Arizona, USA.,Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Nils Ewald
- Institute for Endocrinology, Diabetology and Metabolism, University Hospital Minden, Minden, Germany.,Justus-Liebig-Universität Giessen, Giessen, Germany
| | - Vijay Singh
- Department of Medicine, Mayo Clinic, Scottsdale, Arizona, USA.,Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Zoltán Rakonczay
- Department of Pathophysiology, University of Szeged, Szeged, Hungary
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7
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Venkatesh K, Glenn H, Delaney A, Andersen CR, Sasson SC. Fire in the belly: A scoping review of the immunopathological mechanisms of acute pancreatitis. Front Immunol 2023; 13:1077414. [PMID: 36713404 PMCID: PMC9874226 DOI: 10.3389/fimmu.2022.1077414] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 12/21/2022] [Indexed: 01/13/2023] Open
Abstract
Introduction Acute pancreatitis (AP) is characterised by an inflammatory response that in its most severe form can cause a systemic dysregulated immune response and progression to acute multi-organ dysfunction. The pathobiology of the disease is unclear and as a result no targeted, disease-modifying therapies exist. We performed a scoping review of data pertaining to the human immunology of AP to summarise the current field and to identify future research opportunities. Methods A scoping review of all clinical studies of AP immunology was performed across multiple databases. Studies were included if they were human studies of AP with an immunological outcome or intervention. Results 205 studies met the inclusion criteria for the review. Severe AP is characterised by significant immune dysregulation compared to the milder form of the disease. Broadly, this immune dysfunction was categorised into: innate immune responses (including profound release of damage-associated molecular patterns and heightened activity of pattern recognition receptors), cytokine profile dysregulation (particularly IL-1, 6, 10 and TNF-α), lymphocyte abnormalities, paradoxical immunosuppression (including HLA-DR suppression and increased co-inhibitory molecule expression), and failure of the intestinal barrier function. Studies including interventions were also included. Several limitations in the existing literature have been identified; consolidation and consistency across studies is required if progress is to be made in our understanding of this disease. Conclusions AP, particularly the more severe spectrum of the disease, is characterised by a multifaceted immune response that drives tissue injury and contributes to the associated morbidity and mortality. Significant work is required to develop our understanding of the immunopathology of this disease if disease-modifying therapies are to be established.
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Affiliation(s)
- Karthik Venkatesh
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
| | - Hannah Glenn
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Anthony Delaney
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- Division of Critical Care, The George Institute for Global Health, Newtown, NSW, Australia
| | - Christopher R. Andersen
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
- Division of Critical Care, The George Institute for Global Health, Newtown, NSW, Australia
| | - Sarah C. Sasson
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
- Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW, Australia
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8
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Weber AL, Pape T, Zender S, Seeliger B, Schmidt JJ, Busch M, Rath AK, Schneider A, Schmidt BMW, Fuge J, Wedemeyer H, David S, Stahl K. Therapeutic plasma exchange in patients with acute pancreatitis associated refractory shock and multi-organ failure. J Crit Care 2022; 72:154139. [PMID: 36027817 DOI: 10.1016/j.jcrc.2022.154139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/02/2022] [Accepted: 08/11/2022] [Indexed: 12/15/2022]
Affiliation(s)
- Anna-Lena Weber
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Thorben Pape
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Steffen Zender
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Benjamin Seeliger
- Department of Respiratory Medicine and German Centre of Lung Research (DZL), Hannover Medical School, Hannover, Germany.
| | - Julius J Schmidt
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
| | - Markus Busch
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Ann-Kathrin Rath
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Andrea Schneider
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Bernhard M W Schmidt
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
| | - Jan Fuge
- Department of Respiratory Medicine and German Centre of Lung Research (DZL), Hannover Medical School, Hannover, Germany.
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Sascha David
- Institute of Intensive Care Medicine, University Hospital Zurich, Zurich, Switzerland.
| | - Klaus Stahl
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
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9
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Hong XX, Wang HY, Yang JM, Lin BF, Min QQ, Liang YZ, Huang PD, Zhong ZY, Guo SJ, Huang B, Xu YF. Systemic injury caused by taurocholate-induced severe acute pancreatitis in rats. Exp Ther Med 2022; 24:468. [PMID: 35747153 PMCID: PMC9204573 DOI: 10.3892/etm.2022.11395] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 05/13/2022] [Indexed: 11/06/2022] Open
Abstract
Systemic injury plays a central role in severe acute pancreatitis (SAP). Retrograde biliopancreatic duct infusion of sodium taurocholate (NaT) is commonly used to establish SAP animal models. To better characterize the systemic injury in this model, SAP was induced in Sprague-Dawley rats by NaT administration (3.5 or 5%), followed by sacrifice at 3, 6, 9, 12, 24, 48 and 72 h. Normal saline was used as a control in Sham-operated rats. The mortality rate, ascites volume, and serum and ascitic fluid amylase and lipase activities were assessed. Multiple organ dysfunction, including dysfunction of the pancreas, lung, ileum, liver, and kidney, was investigated using hematoxylin and eosin staining. The interleukin (IL)-1β, IL-6, and tumor necrosis factor-α levels in the ascitic fluid, serum, and ileum tissues were evaluated using an enzyme-linked immunosorbent assay (ELISA). Tight junction proteins, zonula occludens-1 (ZO-1) and occludin, in ileum tissues were studied using immunofluorescence. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine (CRE) and urea levels were measured using an automatic biochemical analyzer. The results of the present study indicated that both 3.5 and 5% NaT could induce a stable elevation of pancreatitis indices, with histopathological injury of the pancreas, lungs and ileum (5% NaT). The ascitic fluid levels of IL-6 and IL-1β were increased in the 5% NaT group. ALT and AST levels increased temporarily and recovered in 72 h, without a significant increase in CRE and urea levels or apparent hepatic and renal pathological injury. In conclusion, rats with NaT-induced SAP have characteristics of necrotizing hemorrhagic pancreatitis with multiple organ injuries, including inflammatory lung injury, ischemic intestinal injury and slight liver and kidney injuries.
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Affiliation(s)
- Xin-Xin Hong
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Hong-Yan Wang
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Jiong-Ming Yang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Bao-Fu Lin
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Qin-Qin Min
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Yi-Zhong Liang
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Pei-Di Huang
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Zi-You Zhong
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Shao-Ju Guo
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Bin Huang
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Yi-Fei Xu
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
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10
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Srinivasan MP, Bhopale KK, Caracheo AA, Kaphalia L, Gong B, Popov VL, Boor PJ, Shakeel Ansari GA, Kaphalia BS. Exposure to binge ethanol and fatty acid ethyl esters exacerbates chronic ethanol-induced pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice. Am J Physiol Gastrointest Liver Physiol 2022; 322:G327-G345. [PMID: 34984929 PMCID: PMC8816639 DOI: 10.1152/ajpgi.00263.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Alcoholic chronic pancreatitis (ACP) is a fibroinflammatory disease of the pancreas. However, metabolic basis of ACP is not clearly understood. In this study, we evaluated differential pancreatic injury in hepatic alcohol dehydrogenase-deficient (ADH-) deer mice fed chronic ethanol (EtOH), chronic plus binge EtOH, and chronic plus binge EtOH and fatty acid ethyl esters (FAEEs, nonoxidative metabolites of EtOH) to understand the metabolic basis of ACP. Hepatic ADH- and ADH normal (ADH+) deer mice were fed Lieber-DeCarli liquid diet containing 3% (wt/vol) EtOH for 3 mo. One week before the euthanization, chronic EtOH-fed mice were further administered with an oral gavage of binge EtOH with/without FAEEs. Blood alcohol concentration (BAC), pancreatic injury, and inflammatory markers were measured. Pancreatic morphology, ultrastructural changes, and endoplasmic reticulum (ER)/oxidative stress were examined using H&E staining, electron microscopy, immunostaining, and/or Western blot, respectively. Overall, BAC was substantially increased in chronic EtOH-fed groups of ADH- versus ADH+ deer mice. A significant change in pancreatic acinar cell morphology, with mild to moderate fibrosis and ultrastructural changes evident by dilatations and disruption of ER cisternae, ER/oxidative stress along with increased levels of inflammatory markers were observed in the pancreas of chronic EtOH-fed groups of ADH- versus ADH+ deer mice. Furthermore, chronic plus binge EtOH and FAEEs exposure elevated BAC, enhanced ER/oxidative stress, and exacerbated chronic EtOH-induced pancreatic injury in ADH- deer mice suggesting a role of increased body burden of EtOH and its metabolism under reduced hepatic ADH in initiation and progression of ACP.NEW & NOTEWORTHY We established a chronic EtOH feeding model of hepatic alcohol dehydrogenase-deficient (ADH-) deer mice, which mimics several fibroinflammatory features of human alcoholic chronic pancreatitis (ACP). The fibroinflammatory and morphological features exacerbated by chronic plus binge EtOH and FAEEs exposure provide a strong case for metabolic basis of ACP. Most importantly, several pathological and molecular targets identified in this study provide a much broader understanding of the mechanism and avenues to develop therapeutics for ACP.
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Affiliation(s)
- Mukund P. Srinivasan
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Kamlesh K. Bhopale
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Anna A. Caracheo
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Lata Kaphalia
- 2Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas
| | - Bin Gong
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Vsevolod L. Popov
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Paul J. Boor
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - G. A. Shakeel Ansari
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
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11
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Liu W, Du JJ, Li ZH, Zhang XY, Zuo HD. Liver injury associated with acute pancreatitis: The current status of clinical evaluation and involved mechanisms. World J Clin Cases 2021; 9:10418-10429. [PMID: 35004974 PMCID: PMC8686151 DOI: 10.12998/wjcc.v9.i34.10418] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/16/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is a very common acute disease, and the mortality rate of severe AP (SAP) is between 15% and 35%. The main causes of death are multiple organ dysfunction syndrome and infections. The mortality rate of patients with SAP related to liver failure is as high as 83%, and approximately 5% of the SAP patients have fulminant liver failure. Liver function is closely related to the progression and prognosis of AP. In this review, we aim to elaborate on the clinical manifestations and mechanism of liver injury in patients with AP.
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Affiliation(s)
- Wei Liu
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Juan-Juan Du
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Zeng-Hui Li
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xin-Yu Zhang
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Hou-Dong Zuo
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
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12
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Jabłońska B, Mrowiec S. Nutritional Support in Patients with Severe Acute Pancreatitis-Current Standards. Nutrients 2021; 13:1498. [PMID: 33925138 PMCID: PMC8145288 DOI: 10.3390/nu13051498] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/20/2021] [Accepted: 04/25/2021] [Indexed: 12/14/2022] Open
Abstract
Severe acute pancreatitis (SAP) leads to numerous inflammatory and nutritional disturbances. All SAP patients are at a high nutritional risk. It has been proven that proper nutrition significantly reduces mortality rate and the incidence of the infectious complications in SAP patients. According to the literature, early (started within 24-48 h) enteral nutrition (EN) is optimal in most patients. EN protects gut barrier function because it decreases gastrointestinal dysmotility secondary to pancreatic inflammation. Currently, the role of parenteral nutrition (PN) in SAP patients is limited to patients in whom EN is not possible or contraindicated. Early versus delayed EN, nasogastric versus nasojejunal tube for EN, EN versus PN in SAP patients and the role of immunonutrition (IN) in SAP patients are discussed in this review.
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Affiliation(s)
- Beata Jabłońska
- Department of Digestive Tract Surgery, Medical University of Silesia, Medyków 14 St., 40752 Katowice, Poland;
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13
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Da Cheng Qi Decoction Alleviates Cerulein-Stimulated AR42J Pancreatic Acinar Cell Injury via the JAK2/STAT3 Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6657036. [PMID: 33927777 PMCID: PMC8053057 DOI: 10.1155/2021/6657036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 03/08/2021] [Accepted: 03/27/2021] [Indexed: 12/22/2022]
Abstract
Background Acute pancreatitis (AP) is a common acute abdomen inflammation, characterized by the dysregulation of digestive enzyme production and secretion. Many studies have shown that Da Cheng Qi Decoction (DCQD) is a secure, effective prescription on AP. In this study, cerulein-stimulated AR42J cells damage model was established to further explore the feasibility and underlying mechanism of DCQD as a potential inhibitor of JAK2/STAT3 pathway for the treatment of AP. Methods Cell viability of DCQD was measured using a cell counting Kit-8 assay. Pancreatic biochemical markers such as amylase, lipase, and C-reactive protein production were measured by assay kits, respectively. Cytokines (TNF-α, IL-6, IL-10, and IL-1β) were assayed by ELISA. Protein location and protein expression were detected by immunofluorescence staining and Western blotting, respectively. Gene expression was assessed by real-time PCR. For mechanistic analysis of the effect of DCQD on JAK2/STAT3 signaling pathway, selective JAK2 inhibitor (Fedratinib) and STAT3 inhibitor (Stattic) as well as STAT3 activator (Garcinone D) were used. Results DCQD protected cells by regulating cerulein-induced inflammation and reducing the secretion of pancreatic biochemical markers. Moreover, DCQD could not only inhibit the nuclear translocation of p-STAT3, but also decrease the mRNA expression of JAK2 and STAT3 as well as the ratio of p-JAK2/JAK2 and p-STAT3/STAT3 in protein level. Additionally, DCQD could regulate the mRNA and protein expression of JAK2/STAT3 downstream effectors, Bax and Bcl-XL. The activated effect of cerulein on JAK2/STAT3 pathway was also reversed by JAK2 inhibitor Fedratinib or STAT3 inhibitor Stattic. And the overexpression of JAK2/STAT3 pathway, via STAT3 activator Garcinone D, did exert damage on cells, which bore a resemblance to cerulein. Conclusion The activation of JAK2/STAT3 pathway may play a key role in the pathogenesis of cerulein-stimulated AR42J pancreatic acinar cell injury. DCQD could improve inflammatory cytokines and cell injury, which might be mediated by suppressing the activation of JAK2/STAT3 signaling pathway.
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14
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Srinivasan MP, Bhopale KK, Caracheo AA, Kaphalia L, Loganathan G, Balamurugan AN, Rastellini C, Kaphalia BS. Differential cytotoxicity, ER/oxidative stress, dysregulated AMPKα signaling, and mitochondrial stress by ethanol and its metabolites in human pancreatic acinar cells. Alcohol Clin Exp Res 2021; 45:961-978. [PMID: 33690904 DOI: 10.1111/acer.14595] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 02/24/2021] [Accepted: 03/01/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Alcoholic chronic pancreatitis (ACP) is a serious inflammatory disorder of the exocrine pancreatic gland. A previous study from this laboratory showed that ethanol (EtOH) causes cytotoxicity, dysregulates AMPKα and ER/oxidative stress signaling, and induces inflammatory responses in primary human pancreatic acinar cells (hPACs). Here we examined the differential cytotoxicity of EtOH and its oxidative (acetaldehyde) and nonoxidative (fatty acid ethyl esters; FAEEs) metabolites in hPACs was examined to understand the metabolic basis and mechanism of ACP. METHODS We evaluated concentration-dependent cytotoxicity, AMPKα inactivation, ER/oxidative stress, and inflammatory responses in hPACs by incubating them for 6 h with EtOH, acetaldehyde, or FAEEs at clinically relevant concentrations reported in alcoholic subjects using conventional methods. Cellular bioenergetics (mitochondrial stress and a real-time ATP production rate) were determined using Seahorse XFp Extracellular Flux Analyzer in AR42J cells treated with acetaldehyde or FAEEs. RESULTS We observed concentration-dependent increases in LDH release, inactivation of AMPKα along with upregulation of ACC1 and FAS (key lipogenic proteins), downregulation of p-LKB1 (an oxidative stress-sensitive upstream kinase regulating AMPKα) and CPT1A (involved in β-oxidation of fatty acids) in hPACs treated with EtOH, acetaldehyde, or FAEEs. Concentration-dependent increases in oxidative stress and ER stress as measured by GRP78, unspliced XBP1, p-eIF2α, and CHOP along with activation of p-JNK1/2, p-ERK1/2, and p-P38MAPK were present in cells treated with EtOH, acetaldehyde, or FAEEs, respectively. Furthermore, a significant decrease was observed in the total ATP production rate with subsequent mitochondrial stress in AR42J cells treated with acetaldehyde and FAEEs. CONCLUSIONS EtOH and its metabolites, acetaldehyde and FAEEs, caused cytotoxicity, ER/oxidative and mitochondrial stress, and dysregulated AMPKα signaling, suggesting a key role of EtOH metabolism in the etiopathogenesis of ACP. Because oxidative EtOH metabolism is negligible in the exocrine pancreas, the pathogenesis of ACP could be attributable to the formation of FAEEs and related pancreatic acinar cell injury.
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Affiliation(s)
- Mukund P Srinivasan
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Kamlesh K Bhopale
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Anna A Caracheo
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Lata Kaphalia
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX, USA
| | | | - Appakalai N Balamurugan
- Department of Surgery, University of Louisville, Louisville, KY, USA.,Islet Biology Laboratory, Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Department of Surgery, University of Cincinnati, Cincinnati, OH, USA
| | - Cristiana Rastellini
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX, USA.,Department of Neuroscience & Cell Biology, The University of Texas Medical Branch, Galveston, TX, USA.,Department of Microbiology & Immunology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Bhupendra S Kaphalia
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA
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15
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Pitchumoni CS. Acute Pancreatitis. GERIATRIC GASTROENTEROLOGY 2021:1449-1481. [DOI: 10.1007/978-3-030-30192-7_55] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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16
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Ahmad I, Valverde A, Naqvi RA, Naqvi AR. Long Non-coding RNAs RN7SK and GAS5 Regulate Macrophage Polarization and Innate Immune Responses. Front Immunol 2020; 11:604981. [PMID: 33362791 PMCID: PMC7757381 DOI: 10.3389/fimmu.2020.604981] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 11/06/2020] [Indexed: 12/11/2022] Open
Abstract
Macrophages (Mφ) are immune cells that exhibit remarkable functional plasticity. Identification of novel endogenous factors that can regulate plasticity and innate immune functions of Mφ will unravel new strategies to curb immune-related diseases. Long non-coding RNAs (lncRNAs) are a class of endogenous, non-protein coding, regulatory RNAs that are increasingly being associated with various cellular functions and diseases. Despite their ubiquity and abundance, lncRNA-mediated epigenetic regulation of Mφ polarization and innate immune functions is poorly studied. This study elucidates the regulatory role of lncRNAs in monocyte to Mφ differentiation, M1/M2 dichotomy and innate immune responses. Expression profiling of eighty-eight lncRNAs in monocytes and in vitro differentiated M2 Mφ identified seventeen differentially expressed lncRNAs. Based on fold-change and significance, we selected four differentially expressed lncRNAs viz., RN7SK, GAS5, IPW, and ZFAS1 to evaluate their functional impact. LncRNA knockdown was performed on day 3 M2 Mφ and the impact on polarization was assessed on day 7 by surface marker analysis. Knockdown of RN7SK and GAS5 showed downregulation of M2 surface markers (CD163, CD206, or Dectin) and concomitant increase in M1 markers (MHC II or CD23). RN7SK or GAS5 knockdown showed no significant impact on CD163, CD206, or CD23 transcripts. M1/M2 markers were not impacted by IPW or ZFAS1 knockdown. Functional regulation of antigen uptake/processing and phagocytosis, two central innate immune pathways, by candidate lncRNA was assessed in M1/M2 Mφ. Compared to scramble, enhanced antigen uptake and processing were observed in both M1/M2 Mφ transfected with siRNA targeting GAS5 and RN7SK but not IPW and ZFAS1. In addition, knockdown of RN7SK significantly augmented uptake of labelled E. coli in vitro by M1/M2 Mφ, while no significant difference was in GAS5 silencing cells. Together, our results highlight the instrumental role of lncRNA (RN7SK and GAS5)-mediated epigenetic regulation of macrophage differentiation, polarization, and innate immune functions.
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17
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Srinivasan MP, Bhopale KK, Caracheo AA, Amer SM, Khan S, Kaphalia L, Loganathan G, Balamurugan AN, Kaphalia BS. Activation of AMP-activated protein kinase attenuates ethanol-induced ER/oxidative stress and lipid phenotype in human pancreatic acinar cells. Biochem Pharmacol 2020; 180:114174. [PMID: 32717227 DOI: 10.1016/j.bcp.2020.114174] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/20/2020] [Accepted: 07/22/2020] [Indexed: 12/18/2022]
Abstract
Primary toxicity targets of alcohol and its metabolites in the pancreas are cellular energetics and endoplasmic reticulum (ER). Therefore, the role of AMP-Activated Protein Kinase (AMPKα) in amelioration of ethanol (EtOH)-induced pancreatic acinar cell injury including ER/oxidative stress, inflammatory responses, the formation of fatty acid ethyl esters (FAEEs) and mitochondrial bioenergetics were determined in human pancreatic acinar cells (hPACs) and AR42J cells incubated with/without AMPKα activator [5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)]. EtOH treated hPACs showed concentration and time-dependent increases for FAEEs and inactivation of AMPKα, along with the upregulation of ACC1 and FAS (key lipogenic proteins) and downregulation of CPT1A (involved β-oxidation of fatty acids). These cells also showed significant ER stress as evidenced by the increased expression for GRP78, IRE1α, and PERK/CHOP arm of unfolded protein response promoting apoptosis and activating p-JNK1/2 and p-ERK1/2 with increased secretion of cytokines. AR42J cells treated with EtOH showed increased oxidative stress, impaired mitochondrial biogenesis, and decreased ATP production rate. However, AMPKα activation by AICAR attenuated EtOH-induced ER/oxidative stress, lipogenesis, and inflammatory responses as well as the formation of FAEEs and restored mitochondrial function in hPACs as well as AR42J cells. Therefore, it is likely that EtOH-induced inactivation of AMPKα plays a crucial role in acinar cell injury leading to pancreatitis. Findings from this study also suggest that EtOH-induced inactivation of AMPKα is closely related to ER/oxidative stress and synthesis of FAEEs, as activation of AMPKα by AICAR attenuates formation of FAEEs, ER/oxidative stress and lipogenesis, and improves inflammatory responses and mitochondrial bioenergetics.
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Affiliation(s)
- Mukund P Srinivasan
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Kamlesh K Bhopale
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Anna A Caracheo
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Samir M Amer
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Department of Forensic Medicine and Clinical Toxicology, Tanta University, Tanta, Egypt
| | - Shamis Khan
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Lata Kaphalia
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | | | - Appakalai N Balamurugan
- Department of Surgery, University of Louisville, Louisville, KY 40202, USA; Islet Biology Laboratory, Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Department of Surgery, University of Cincinnati, Cincinnati, OH 45229, USA
| | - Bhupendra S Kaphalia
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA.
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18
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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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van den Berg FF, Kempeneers MA, van Santvoort HC, Zwinderman AH, Issa Y, Boermeester MA. Meta-analysis and field synopsis of genetic variants associated with the risk and severity of acute pancreatitis. BJS Open 2019; 4:3-15. [PMID: 32011822 PMCID: PMC6996643 DOI: 10.1002/bjs5.50231] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 09/11/2019] [Indexed: 12/17/2022] Open
Abstract
Background Genetic risk factors can provide insight into susceptibility for acute pancreatitis (AP) and disease progression towards (infected) necrotizing pancreatitis and persistent organ failure. The aim of the study was to undertake a systematic review of the genetic evidence for AP. Methods Online databases (MEDLINE, Embase, BIOSIS, Web of Science, Cochrane Library) were searched to 8 February 2018. Studies that reported on genetic associations with AP susceptibility, severity and/or complications were eligible for inclusion. Meta‐analyses were performed of variants that were reported by at least two data sources. Venice criteria and Bayesian false‐discovery probability were applied to assess credibility. Results Ninety‐six studies reporting on 181 variants in 79 genes were identified. In agreement with previous meta‐analyses, credible associations were established for SPINK1 (odds ratio (OR) 2·87, 95 per cent c.i. 1·89 to 4·34), IL1B (OR 1·23, 1·06 to 1·42) and IL6 (OR 1·64, 1·15 to 2·32) and disease risk. In addition, two novel credible single‐nucleotide polymorphisms were identified in Asian populations: ALDH2 (OR 0·48, 0·36 to 0·64) and IL18 (OR 1·47, 1·18 to 1·82). Associations of variants in TNF, GSTP1 and CXCL8 genes with disease severity were identified, but were of low credibility. Conclusion Genetic risk factors in genes related to trypsin activation and innate immunity appear to be associated with susceptibility to and severity of AP.
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Affiliation(s)
- F F van den Berg
- Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - M A Kempeneers
- Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - H C van Santvoort
- Department of Surgery, St Antonius Hospital, Nieuwegein, the Netherlands.,Department of Surgery, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - A H Zwinderman
- Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Y Issa
- Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - M A Boermeester
- Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
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20
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Wang L, Zhao X, Wang Y. The pivotal role and mechanism of long non-coding RNA B3GALT5-AS1 in the diagnosis of acute pancreatitis. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:2307-2315. [PMID: 31177837 DOI: 10.1080/21691401.2019.1623231] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The present study planned to dig the potential impacts of long non-coding RNA B3GALT5-AS1 in acute pancreatitis (AP). A total of 66 patients who were diagnosed with AP using ultrasonic imaging were enrolled in the study. Expression levels of B3GALT5-AS1 in the serum of AP patients were determined. Afterwards, rat pancreatic AR42J acinar cells were disposed with caerulein to produce AP-like injury. The role and molecular mechanisms of B3GALT5-AS1 in AP were explored through in vitro cell experiments. The levels of lncRNA B3GALT5-AS1 were observed to be lessened in patients with AP relative to healthy controls. In addition, caerulein was observed to induce injuries in the AR42J cells (depressed cell viability, enhanced cell apoptosis, cytokines production, and levels of amylase). Overexpression of B3GALT5-AS1 alleviated the caerulein-produced injury in the AR42J cells. Moreover, it was determined that miR-203 showed a downside expression by B3GALT5-AS1 regulation, and the overexpression of B3GALT5-AS1 retrained caerulein-produced injury through the suppression of miR-203. In addition, it was observed that miR-203 lessened the level of nuclear factor interleukin-3 (NFIL3) and that NFIL3 was targeted by miR-203. Lastly, the impacts of B3GALT5-AS1 on caerulein-induced cell injury were manifested through the NF-κB signalling pathway. The data from the present study revealed that in patients with AP, B3GALT5-AS1 is expressed in reduced amounts. Overexpression of B3GALT5-AS1 may alleviate caerulein-induced cell injury in AR42J cells through the regulation of miR-203/NFIL3 axis and by inhibiting the activation of the NF-κB signals.
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Affiliation(s)
- Linlin Wang
- a Department of Ultrasound, China-Japan Union Hospital, Jilin University , Changchun , Jilin , China
| | - Xiaonan Zhao
- b Infectious Department of China-Japan Union Hospital, Jilin University , Changchun , China
| | - Ye Wang
- c Department of Pediatrics, China-Japan Union Hospital, Jilin University , Changchun , Jilin , China
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21
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Jain D, Bhaduri G, Jain P. DIFFERENT SCORING SYSTEMS IN ACUTE ALCOHOLIC PANCREATITIS: WHICH ONE TO FOLLOW? AN ONGOING DILEMA. ARQUIVOS DE GASTROENTEROLOGIA 2019; 56:280-285. [PMID: 31633726 DOI: 10.1590/s0004-2803.201900000-53] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 07/19/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Acute pancreatitis is a common disorder in medical practice. In recent times, management has changed drastically with majority of decisions like intravenous antibiotics, negative suction with Ryle's tube and surgical interventions like necrosectomy etc based on severity of the disease. There are different scores in use to assess severity of disease but the relative efficacy has remained a debatable subject. OBJECTIVE The present study was thus done to investigate the predictive accuracy of different scoring systems in acute pancreatitis. METHODS Fifty patients of acute pancreatitis admitted in medicine ward of Pt. B.D. Sharma PGIMS, Rohtak, India, were taken for study after fulfilling eligibility criteria. These patients were investigated at admission and followed up prospectively. The severity of pancreatitis was classified for each of these patients as per Revised Atlanta System of Classification. Commonly used scoring systems pertaining to acute pancreatitis, viz, BISAP, Ranson, APACHE II and modified computed tomography severity index (CTSI) were calculated. Subsequently these scores were then correlated with severity, presence of organ failure, occurrence of local complications and final outcome of the patients. RESULTS Out of 50 patients, etiology was chronic alcohol intake in all but one with idiopathic pancreatitis. The mean age of the study population was 42.06±13.27 years. 32% of these patients had pancreatic necrosis, 40% had peripancreatic collections. 56% of them had mild acute pancreatitis, 24% had moderately severe acute pancreatitis, while 20% had severe acute pancreatitis. APACHE II had the highest accuracy in predicting severity, organ failure and fatal outcomes. As far as these parameters were concerned, the negative predictive values of BISAP score were also considerable. Modified CTSI score was accurate in predicting local complications but had limited accuracy in other predictions. CONCLUSION APACHE II emerged as most reliable scoring system followed by BISAP and Ranson in management of the patients with acute pancreatitis. But in constraints of time and resources, even BISAP score with its significant negative predictive values served as a valuable tool for assessing and managing these patients.
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Affiliation(s)
- Deepak Jain
- Pt B D Sharma University of Health Sciences Rohtak, Department of Medicine, Haryana, India
| | - Gourab Bhaduri
- Pt B D Sharma University of Health Sciences Rohtak, Department of Medicine, Haryana, India
| | - Promil Jain
- Pt B D Sharma University of Health Sciences Rohtak, Department of Pathology, Haryana, India
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Mallick B, Tomer S, Arora SK, Lal A, Dhaka N, Samanta J, Sinha SK, Gupta V, Yadav TD, Kochhar R. Change in serum levels of inflammatory markers reflects response of percutaneous catheter drainage in symptomatic fluid collections in patients with acute pancreatitis. JGH Open 2019; 3:295-301. [PMID: 31406922 PMCID: PMC6684513 DOI: 10.1002/jgh3.12158] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Accepted: 01/18/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Percutaneous catheter drainage (PCD) is used as the first step in the management of symptomatic fluid collections in patients with acute pancreatitis (AP). There are limited data on the effect of PCD on inflammatory markers. AIM To study the effects of PCD on serum levels of C-reactive protein (CRP), IL-6, and IL-10 and its correlation with the outcome. METHODS Consecutive patients of AP with symptomatic fluid collections undergoing PCD were evaluated for serum levels of CRP, IL-6, and IL-10 before PCD and at 3 and 7 days after PCD. Resolution of organ failure (OF), sepsis, and pressure symptoms was considered to demonstrate the success of PCD. Changes in levels following PCD were correlated with outcome. RESULTS Indications of PCD in 59 patients (age 38.9 ± 13.17 years, 49 male) were suspected/documented infected pancreatic necrosis (n = 45), persistent OF (n = 40), and pressure symptoms (n = 7). A total of 49 (83.1%) patients improved with PCD, five patients required surgery, and six died. A significant difference was noted between baseline levels of CRP (P = 0.026) and IL-6 (P = 0.013) among patients who improved compared to those who worsened following PCD. Significant decrease (P < 0.01) of all three markers on day 3 of PCD insertion, with further decrease (P < 0.01) on day 7, was noted. The percentage of the decrease of IL-6 levels on day 3 and of CRP on day 7 correlated with the outcome. CONCLUSION PCD is associated with a significant decrease in CRP, IL-6, and IL-10 levels. Percentage decrease in IL-6 on day 3 and CRP on day 7 correlated with the outcome of patients managed with PCD.
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Affiliation(s)
- Bipadabhanjan Mallick
- Department of GastroenterologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Shallu Tomer
- Department of ImmunopathologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Sunil K Arora
- Department of ImmunopathologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Anupam Lal
- Department of RadiodiagnosisPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Narendra Dhaka
- Department of GastroenterologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Jayanta Samanta
- Department of GastroenterologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Saroj K Sinha
- Department of GastroenterologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Vikas Gupta
- Department of General SurgeryPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Thakur Deen Yadav
- Department of General SurgeryPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Rakesh Kochhar
- Department of GastroenterologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
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Garg PK, Singh VP. Organ Failure Due to Systemic Injury in Acute Pancreatitis. Gastroenterology 2019; 156:2008-2023. [PMID: 30768987 PMCID: PMC6486861 DOI: 10.1053/j.gastro.2018.12.041] [Citation(s) in RCA: 356] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/07/2018] [Accepted: 12/29/2018] [Indexed: 02/07/2023]
Abstract
Acute pancreatitis may be associated with both local and systemic complications. Systemic injury manifests in the form of organ failure, which is seen in approximately 20% of all cases of acute pancreatitis and defines "severe acute pancreatitis." Organ failure typically develops early in the course of acute pancreatitis, but also may develop later due to infected pancreatic necrosis-induced sepsis. Organ failure is the most important determinant of outcome in acute pancreatitis. We review here the current understanding of the risk factors, pathophysiology, timing, impact on outcome, and therapy of organ failure in acute pancreatitis. As we discuss the pathophysiology of severe systemic injury, the distinctions between markers and mediators of severity are highlighted based on evidence supporting their causality in organ failure. Emphasis is placed on clinically relevant end points of organ failure and the mechanisms underlying the pathophysiological perturbations, which offer insight into potential therapeutic targets to treat.
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Plavsic I, Zitinic I, Tulic V, Poropat G, Marusic M, Hauser G. Early immune response in post endoscopic retrograde cholangiopancreatography pancreatitis as a model for acute pancreatitis. World J Meta-Anal 2019; 7:96-100. [DOI: 10.13105/wjma.v7.i3.96] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 03/27/2019] [Accepted: 03/28/2019] [Indexed: 02/06/2023] Open
Abstract
This opinion review summarizes comparison of clinical presentation and immunology of post-endoscopic pancreatitis and acute pancreatitis (AP) of other etiology. The rationale for this topic was found in studies that mention differences in clinical presentation between these entities, stating that severe form of AP after endoscopic retrograde cholangiopancreatography was more severe than AP of other etiology. Found difference in clinical presentation may have a background in different immunology that needs to be further investigated.
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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 Zitinic
- Department of Emergency Medicine, Clinical Hospital Centre, Rijeka 51000, Croatia
| | - Vera Tulic
- Department of Anesthesiology and Critical care medicine, 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, Medical Faculty Rijeka, University of Rijeka, Rijeka 51000, Croatia
| | - Marinko Marusic
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Sv. Duh, Zagreb, Faculty of Health Studies, University of Rijeka, Rijeka 51000, Croatia
- Medical Faculty Osijek, University of J.J. Stossmayer, Osijek 31000, 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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de Oliveira C, Khatua B, Bag A, El-Kurdi B, Patel K, Mishra V, Navina S, Singh VP. Multimodal Transgastric Local Pancreatic Hypothermia Reduces Severity of Acute Pancreatitis in Rats and Increases Survival. Gastroenterology 2019; 156:735-747.e10. [PMID: 30518512 PMCID: PMC6368865 DOI: 10.1053/j.gastro.2018.10.034] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 10/11/2018] [Accepted: 10/20/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Acute pancreatitis (AP) of different etiologies is associated with the activation of different signaling pathways in pancreatic cells, posing challenges to the development of targeted therapies. We investigated whether local pancreatic hypothermia, without systemic hypothermia, could lessen the severity of AP induced by different methods in rats. METHODS A urethane balloon with 2 polyurethane tubes was placed inside the stomach of rats. AP was induced in Wistar rats by the administration of cerulein or glyceryl tri-linoleate (GTL). Then, cold water was infused into the balloon to cool the pancreas. Pancreatic temperatures were selected based on those found to decrease acinar cell injury. An un-perfused balloon was used as a control. Pancreatic and rectal temperatures were monitored, and an infrared lamp or heating pad was used to avoid generalized hypothermia. We collected blood, pancreas, kidney, and lung tissues and analyzed them by histology, immunofluorescence, immunoblot, cytokine and chemokine magnetic bead, and DNA damage assays. The effect of hypothermia on signaling pathways initiated by cerulein and GTL was studied in acinar cells. RESULTS Rats with pancreatic cooling developed less severe GTL-induced AP compared with rats that received the control balloon. In acinar cells, cooling decreased the lipolysis induced by GTL, increased the micellar form of its fatty acid, lowered the increase in cytosolic calcium, prevented the loss of mitochondrial membrane potential (by 70%-80%), and resulted in a 40%-50% decrease in the uptake of a fatty acid tracer. In rats with AP, cooling decreased pancreatic necrosis by 48%, decreased serum levels of cytokines and markers of cell damage, and decreased markers of lung and renal damage. Pancreatic cooling increased the proportions of rats surviving 6 hours after induction of AP (to 90%, from <10% of rats that received the control balloon). In rats with cerulein-induced AP, pancreatic cooling decreased pancreatic markers of apoptosis and inflammation. CONCLUSIONS In rats with AP, transgastric local pancreatic hypothermia decreases pancreatic necrosis, apoptosis, inflammation, and markers of pancreatitis severity and increases survival.
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Affiliation(s)
- Cristiane de Oliveira
- Department of Medicine, Mayo Clinic, Scottsdale, AZ, University of Pittsburgh, Pittsburgh, PA
| | - Biswajit Khatua
- Department of Medicine, Mayo Clinic, Scottsdale, AZ, University of Pittsburgh, Pittsburgh, PA
| | - Arup Bag
- Department of Medicine, Mayo Clinic, Scottsdale, AZ, University of Pittsburgh, Pittsburgh, PA
| | - Bara El-Kurdi
- Department of Medicine, Mayo Clinic, Scottsdale, AZ, University of Pittsburgh, Pittsburgh, PA
| | - Krutika Patel
- Department of Medicine, Mayo Clinic, Scottsdale, AZ, University of Pittsburgh, Pittsburgh, PA
| | - Vivek Mishra
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Sarah Navina
- Pathology, University of Pittsburgh, Pittsburgh, PA
| | - Vijay P. Singh
- Department of Medicine, Mayo Clinic, Scottsdale, AZ, University of Pittsburgh, Pittsburgh, PA
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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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Rumbus Z, Toth E, Poto L, Vincze A, Veres G, Czako L, Olah E, Marta K, Miko A, Rakonczay Z, Balla Z, Kaszaki J, Foldesi I, Maleth J, Hegyi P, Garami A. Bidirectional Relationship Between Reduced Blood pH and Acute Pancreatitis: A Translational Study of Their Noxious Combination. Front Physiol 2018; 9:1360. [PMID: 30327613 PMCID: PMC6174522 DOI: 10.3389/fphys.2018.01360] [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: 04/07/2018] [Accepted: 09/07/2018] [Indexed: 12/13/2022] Open
Abstract
Acute pancreatitis (AP) is often accompanied by alterations in the acid-base balance, but how blood pH influences the outcome of AP is largely unknown. We studied the association between blood pH and the outcome of AP with meta-analysis of clinical trials, and aimed to discover the causative relationship between blood pH and AP in animal models. PubMed, EMBASE, and Cochrane Controlled Trials Registry databases were searched from inception to January 2017. Human studies reporting systemic pH status and outcomes (mortality rate, severity scores, and length of hospital stay) of patient groups with AP were included in the analyses. We developed a new mouse model of chronic metabolic acidosis (MA) and induced mild or severe AP in the mice. Besides laboratory blood testing, the extent of pancreatic edema, necrosis, and leukocyte infiltration were assessed in tissue sections of the mice. Thirteen studies reported sufficient data in patient groups with AP (n = 2,311). Meta-analysis revealed markedly higher mortality, elevated severity scores, and longer hospital stay in AP patients with lower blood pH or base excess (P < 0.001 for all studied outcomes). Meta-regression analysis showed significant negative correlation between blood pH and mortality in severe AP. In our mouse model, pre-existing MA deteriorated the pancreatic damage in mild and severe AP and, vice versa, severe AP further decreased the blood pH of mice with MA. In conclusion, MA worsens the outcome of AP, while severe AP augments the decrease of blood pH. The discovery of this vicious metabolic cycle opens up new therapeutic possibilities in AP.
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Affiliation(s)
- Zoltan Rumbus
- Institute for Translational Medicine, Medical School, University of Pecs, Pecs, Hungary
| | - Emese Toth
- Momentum Gastroenterology Multidisciplinary Research Group, Hungarian Academy of Sciences–University of Szeged, Szeged, Hungary
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Laszlo Poto
- Institute of Bioanalysis, Medical School, University of Pecs, Pecs, Hungary
| | - Aron Vincze
- Department of Gastroenterology, First Department of Medicine, University of Pecs, Pecs, Hungary
| | - Gabor Veres
- First Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Laszlo Czako
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Emoke Olah
- Institute for Translational Medicine, Medical School, University of Pecs, Pecs, Hungary
| | - Katalin Marta
- Institute for Translational Medicine, Medical School, University of Pecs, Pecs, Hungary
- Department of Translational Medicine, First Department of Medicine, University of Pecs, Pecs, Hungary
| | - Alexandra Miko
- Institute for Translational Medicine, Medical School, University of Pecs, Pecs, Hungary
- Department of Translational Medicine, First Department of Medicine, University of Pecs, Pecs, Hungary
| | - Zoltan Rakonczay
- Department of Pathophysiology, University of Szeged, Szeged, Hungary
| | - Zsolt Balla
- Department of Pathophysiology, University of Szeged, Szeged, Hungary
| | - Jozsef Kaszaki
- Institute of Surgical Research, University of Szeged, Szeged, Hungary
| | - Imre Foldesi
- Department of Laboratory Medicine, University of Szeged, Szeged, Hungary
| | - Jozsef Maleth
- First Department of Medicine, University of Szeged, Szeged, Hungary
- Momentum Epithel Cell Signaling and Secretion Research Group, Hungarian Academy of Sciences–University of Szeged, Szeged, Hungary
| | - Peter Hegyi
- Institute for Translational Medicine, Medical School, University of Pecs, Pecs, Hungary
- Momentum Gastroenterology Multidisciplinary Research Group, Hungarian Academy of Sciences–University of Szeged, Szeged, Hungary
- Department of Translational Medicine, First Department of Medicine, University of Pecs, Pecs, Hungary
| | - Andras Garami
- Institute for Translational Medicine, Medical School, University of Pecs, Pecs, Hungary
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Yuan L, Zhu L, Zhang Y, Chen H, Kang H, Li J, Zhao X, Wan M, Miao Y, Tang W. Effect of Da-Cheng-Qi decoction for treatment of acute kidney injury in rats with severe acute pancreatitis. Chin Med 2018; 13:38. [PMID: 30013616 PMCID: PMC6045888 DOI: 10.1186/s13020-018-0195-8] [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: 04/02/2018] [Accepted: 07/09/2018] [Indexed: 02/05/2023] Open
Abstract
Background The traditional Chinese formula Da-Cheng-Qi-decoction (DCQD) has been used to treat acute pancreatitis for decades. DCQD could ameliorate the disease severity and the complications of organ injuries, including those of the liver and lungs. However, the pharmacological effects in the kidney, a target organ, are still unclear. This study aimed to investigate the herbal tissue pharmacology of DCQD for acute kidney injury (AKI) in rats with severe acute pancreatitis (SAP). Methods Rats were randomly divided into the sham-operation group (SG), the model group (MG) and the low-, medium- and high-dose treatment groups (LDG, MDG, and HDG, respectively). Sodium taurocholate (3.5%) was retrogradely perfused into the biliopancreatic duct to establish the model of SAP in rats. Different doses of DCQD were administered to the treatment groups 2 h after the induction of SAP. The major components of DCQD in kidney tissues were detected by HPLC–MS/MS. Inflammatory mediators in the kidney tissues, as well as serum creatinine (Scr), blood urea nitrogen (BUN) and pathologic scores, were also evaluated. Results Ten components of DCQD were detected in the kidneys of the treatment groups, and their concentrations increased dose-dependently. Compared with the SG, the levels of inflammatory mediators, Scr, BUN and pathological scores in the MG were obviously increased (p < 0.05). The high dose of DCQD showed a maximal effect in downregulating the pro-inflammatory mediators interleukin-6 (IL)-6 and tumour necrosis factor-α (TNF-α), upregulating anti-inflammatory mediators IL-4 and IL-10 in the kidney and alleviating the pathological damages. DCQD decreased the pancreas and kidney pathological scores of rats with SAP, especially in the HDG (p < 0.05). Compared with the MG, the level of Scr in the HDG was significantly decreased (p < 0.05). Conclusions DCQD ameliorated AKI in rats with SAP via regulating the inflammatory response, which might be closely related to the distribution of its components in the kidney. Electronic supplementary material The online version of this article (10.1186/s13020-018-0195-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ling Yuan
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan People's Republic of China
| | - Lv Zhu
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan People's Republic of China
| | - Yumei Zhang
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan People's Republic of China
| | - Huan Chen
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan People's Republic of China
| | - Hongxin Kang
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan People's Republic of China
| | - Juan Li
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan People's Republic of China
| | - Xianlin Zhao
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan People's Republic of China
| | - Meihua Wan
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan People's Republic of China
| | - Yifan Miao
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan People's Republic of China
| | - Wenfu Tang
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan People's Republic of China
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Abstract
PURPOSE OF REVIEW The obesity pandemic poses a unique set of problems for acute pancreatitis - both by increasing acute pancreatitis incidence, and worsening acute pancreatitis severity. This review explores these associations, underlying mechanisms, and potential therapies. RECENT FINDINGS We review how the obesity associated increase in gallstones, surgical, and endoscopic interventions for obesity management, diabetes, and related medications such as incretin-based therapies and hypertriglyceridemia may increase the incidence of acute pancreatitis. The mechanism of how obesity may increase acute pancreatitis severity are discussed with a focus on cytokines, adipokines, damage-associated molecular patterns and unsaturated fatty acid-mediated lipotoxicity. The role of obesity in exacerbating pancreatic necrosis is discussed; focusing on obesity-associated pancreatic steatosis. We also discuss how peripancreatic fat necrosis worsens organ failure independent of pancreatic necrosis. Last, we discuss emerging therapies including choice of intravenous fluids and the use of lipase inhibitors which have shown promise during severe acute pancreatitis. SUMMARY We discuss how obesity may contribute to increasing acute pancreatitis incidence, the role of lipolytic unsaturated fatty acid release in worsening acute pancreatitis, and potential approaches, including appropriate fluid management and lipase inhibition in improving acute pancreatitis outcomes.
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Harshit Kumar A, Singh Griwan M. A comparison of APACHE II, BISAP, Ranson's score and modified CTSI in predicting the severity of acute pancreatitis based on the 2012 revised Atlanta Classification. Gastroenterol Rep (Oxf) 2017; 6:127-131. [PMID: 29780601 PMCID: PMC5952961 DOI: 10.1093/gastro/gox029] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 06/02/2017] [Accepted: 06/06/2017] [Indexed: 12/21/2022] Open
Abstract
Objective Our aim was to prospectively compare the Accuracy of Acute Physiology and Chronic Health Evaluation (APACHE) II, Bedside Index of Severity in Acute Pancreatitis (BISAP), Ranson's score and modified Computed Tomography Severity Index (CTSI) in predicting the severity of acute pancreatitis based on Atlanta 2012 definitions in a tertiary care hospital in northern India. Methods Fifty patients with acute pancreatitis admitted to our hospital during the period of March 2015 to September 2016 were included in the study. APACHE II, BISAP and Ranson's score were calculated for all the cases. Modified CTSI was also determined based on a pancreatic protocol contrast enhanced computerized tomography (CT). Optimal cut-offs for these scoring systems and the area under the curve (AUC) were evaluated based on the receiver operating characteristics (ROC) curve and these scoring systems were compared prospectively. Results Of the 50 cases, 14 were graded as severe acute pancreatitis. Pancreatic necrosis was present in 15 patients, while 14 developed persistent organ failure and 14 needed intensive care unit (ICU) admission. The AUC for modified CTSI was consistently the highest for predicting severe acute pancreatitis (0.919), pancreatic necrosis (0.993), organ failure (0.893) and ICU admission (0.993). APACHE II was the second most accurate in predicting severe acute pancreatitis (AUC 0.834) and organ failure (0.831). APACHE II had a high sensitivity for predicting pancreatic necrosis (93.33%), organ failure (92.86%) and ICU admission (92.31%), and also had a high negative predictive value for predicting pancreatic necrosis (96.15%), organ failure (96.15%) and ICU admission (95.83%). Conclusion APACHE II is a useful prognostic scoring system for predicting the severity of acute pancreatitis and can be a crucial aid in determining the group of patients that have a high chance of need for tertiary care during the course of their illness and therefore need early resuscitation and prompt referral, especially in resource-limited developing countries.
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31
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Deng LH, Hu C, Cai WH, Chen WW, Zhang XX, Shi N, Huang W, Ma Y, Jin T, Lin ZQ, Jiang K, Guo J, Yang XN, Xia Q. Plasma cytokines can help to identify the development of severe acute pancreatitis on admission. Medicine (Baltimore) 2017; 96:e7312. [PMID: 28700471 PMCID: PMC5515743 DOI: 10.1097/md.0000000000007312] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 04/19/2017] [Accepted: 05/26/2017] [Indexed: 02/05/2023] Open
Abstract
Severe acute pancreatitis (AP) is associated with high morbidity and mortality. Early severity stratification remains a challenging issue to overcome to improve outcomes. We aim to find novel plasma cytokines for the early identification of severe AP according to the revised Atlanta criteria.In this prospective observational study, 30 cytokines, screened semiquantitatively with a human multicytokine array, were submitted to quantitative determination using either microparticle-based multiplex immunoassays analyzed on a Luminex 100 platform or enzyme-linked immunosorbent assay kits. The cytokine profiles of patients and the discriminative value of cytokines for severe AP were analyzed.Plasma samples of 70 patients with AP (20 mild, 30 moderately severe, and 20 severe) were selected in this study if they were admitted within 48 hours of the onset of symptoms. Plasma from healthy volunteers was collected as the healthy control. Growth differentiation factor-15 (GDF-15) and pentraxin 3 (PTX3) on admission were independent prognostic markers for the development of severe AP and had higher discriminative powers than conventional markers (GDF-15 vs hematocrit, P = .003; GDF-15 vs C-reactive protein, P = .037; GDF-15 vs creatinine, P = .048; GDF-15 vs Acute Physiology and Chronic Health Evaluation II, P = .007; PTX3 vs hematocrit, P = .006; PTX3 vs C-reactive protein, P = .047; PTX3 vs Acute Physiology and Chronic Health Evaluation II, P = .011; PTX3 vs Bedside Index for Severity in Acute Pancreatitis, P = .048).Plasma GDF-15 and PTX3 can help to identify the development of severe AP on admission. Future work should validate their accuracy in a larger, multicenter patient cohort.
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Affiliation(s)
- Li-Hui Deng
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
| | - Cheng Hu
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
| | - Wen-Hao Cai
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
| | - Wei-Wei Chen
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
- Department of Gastroenterology, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu Province, China
| | - Xiao-Xin Zhang
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
| | - Na Shi
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
| | - Wei Huang
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
- NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK
| | - Yun Ma
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
| | - Tao Jin
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
| | - Zi-Qi Lin
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
| | - Kun Jiang
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
| | - Jia Guo
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
| | - Xiao-Nan Yang
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
| | - Qing Xia
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province
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An Unbalanced Inflammatory Cytokine Response Is Not Associated With Mortality Following Sepsis: A Prospective Cohort Study. Crit Care Med 2017; 45:e493-e499. [PMID: 28257334 DOI: 10.1097/ccm.0000000000002292] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
OBJECTIVE The prevailing theory of host response during sepsis states that an excessive production of pro-inflammatory mediators causes early deaths, whereas a predominantly anti-inflammatory response may lead to immunosuppression, secondary infection, and late deaths. We assessed inflammatory (im)balance by measuring pro-inflammatory interleukin-6 and anti-inflammatory interleukin-10 during three distinct time periods after sepsis, and assessed its association with mortality. DESIGN Prospective observational cohort. SETTING Two tertiary mixed ICUs in The Netherlands. PATIENTS Consecutive patients presenting with severe sepsis or septic shock from 2011 to 2013. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We repeatedly measured plasma interleukin-6 and interleukin-10 concentrations using cytometric bead array. Poisson regression was used to analyze the relation between inflammatory markers measured on 1) ICU admission and day 4 mortality, 2) day 4 and day 28 mortality, and 3) ICU discharge and 1-year mortality. Secondary outcome was development of ICU-acquired infections. Among 708 patients, 86 (12%) died within 4 days, 140 (20%) died between days 4 and 28, and an additional 155 (22%) died before 1 year. Interleukin-6 and interleukin-10 levels were both independently associated with mortality, but the balance of this response as modelled by an interleukin-6 and interleukin-10 interaction term was not (relative risk, 0.99; 95% CI, 0.95-1.04 on admission; relative risk, 1.02; 95% CI, 0.98-1.06 on day 4; and relative risk, 1.12; 95% CI, 0.98-1.29 at ICU discharge). However, inflammatory imbalance on day 4 was associated with development of ICU-acquired infections (subdistribution hazard ratio, 0.87; 95% CI, 0.77-0.98). CONCLUSIONS Although both interleukin-6 and interleukin-10 productions are associated with death, the balance of these inflammatory mediators does not seem to impact either early, intermediate, or late mortality in patients presenting to the ICU with sepsis.
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Zhang YM, Ren HY, Zhao XL, Li J, Li JY, Wu FS, Su H, Tang WF. Pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction in the liver of rats with severe acute pancreatitis. World J Gastroenterol 2017; 23:1367-1374. [PMID: 28293083 PMCID: PMC5330821 DOI: 10.3748/wjg.v23.i8.1367] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 11/06/2016] [Accepted: 01/11/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction (DCQD) in the liver of rats with severe acute pancreatitis (SAP) based on an herbal recipe tissue pharmacology hypothesis.
METHODS Healthy male Sprague-Dawley rats were randomly divided into a sham operation group (SOG); a model group (MG); and low-, median- and high-dose treatment groups (LDG, MDG, and HDG, respectively). Different dosages (6, 12 and 24 g/kg for the LDG, MDG, and HDG, respectively) of DCQD were administered to the rats with SAP. The tissue concentrations of aloe-emodin, rhein, emodin, chrysophanol, honokiol, rheo chrysophanol, magnolol, hesperidin, naringenin and naringin in the liver of the treated rats were detected by high-performance liquid chromatography tandem mass spectrometry. Alanine transaminase (ALT) and aspartate transaminase (AST) in serum, inflammatory mediators in the liver and pathological scores were evaluated.
RESULTS The major components of DCQD were detected in the liver, and their concentrations increased dose-dependently. The high dose of DCQD showed a maximal effect in ameliorating the pathological damages, decreasing the pro-inflammatory mediators tumor necrosis factor-α and interleukin (IL)-6 and increasing anti-inflammatory mediators IL-4 and IL-10 in the liver. The pathological scores in the pancreas for the MG were significantly higher than those for the SOG (P < 0.05). DCQD could reduce the pathological scores in the pancreas and liver of the rats with SAP, especially in the HDG. Compared to the SOG, the ALT and AST levels in serum were higher in the MG (P < 0.05), while there was no statistical difference in the MG and HDG.
CONCLUSION DCQD could alleviate liver damage by altering the inflammatory response in rats with SAP based on the liver distribution of its components.
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Role of bedside pancreatic scores and C-reactive protein in predicting pancreatic fluid collections and necrosis. Indian J Gastroenterol 2017; 36:43-49. [PMID: 28181127 DOI: 10.1007/s12664-017-0728-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 01/04/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Acute pancreatitis is a disease with variable outcome; the course of the disease can be modified by early aggressive management in patients with severe pancreatitis. Easily calculable pancreatic scores and investigations can help to triage these patients. We aimed to determine the role of bedside index for severity in acute pancreatitis (BISAP), harmless acute pancreatitis score (HAPS), and systemic inflammatory response syndrome (SIRS) scores on day of admission and C-reactive protein (CRP) at 48 h for predicting the presence of pancreatic fluid collection (PFC) and necrosis on CT scans done at 72 h. METHODS Of a total of 114 consecutively seen patients of pancreatitis, 64 with acute pancreatitis were enrolled in the study. All individuals had the pancreatitis predicting scores calculated at the time of admission, CRP at 48 h, and contrast-enhanced computed tomography (CECT) abdomen at 72 h from admission. RESULTS The study population of 64 (55 male) had a mean (+SD) age of 37.7 ± 13 years. Alcohol was the most common (68.8%) etiology in these patients. Based on CECT, patients were divided into 2 groups; group 1 with 41 patients who had mild pancreatitis and group 2 with 23 patients who had pancreatic fluid collection with or without necrosis (PFCN). PFCN were seen in 19 (29.7%) of patients with 2 or more SIRS criteria, 17 (26.6%) of patients with BISAP score ≥3, and 16 patients (25.0%) with HAPS >0 respectively. All three scores were able to predict PFCN significantly. CRP >150 mg/L was noted in 23 patients and was able to predict the presence of fluid collections (p=0.0002) and pancreatic necrosis (p = 0.0004) on CT. CONCLUSION BISAP, HAPS, and SIRS scores and CRP of 150 mg/L all correlated significantly with the occurrence of fluid collections and pancreatic necrosis on CT at 72 h. None of the scores was superior to the other in this respect.
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Lempinen M, Puolakkainen P, Kemppainen E. Clinical Value of Severity Markers in Acute Pancreatitis. Scand J Surg 2016; 94:118-23. [PMID: 16111093 DOI: 10.1177/145749690509400207] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Acute pancreatitis is a common digestive disease of which the severity may vary from mild, edematous to severe, necrotizing disease. An improved outcome in the severe form of the disease is based on early identification of disease severity and subsequent focused management of these high-risk patients. However, the ability of clinicians to predict, upon presentation, which patient will have mild or severe acute pancreatitis is not accurate. Prospective systems using clinical criteria have been used to determine severity in patients with acute pancreatitis, such as the Ranson's prognostic signs, Glasgow score, and the acute physiology and chronic health evaluation II score (APACHE II). Their application in clinical practise has been limited by the time delay of at least 48 h to judge all parameters in the former two and by being cumbersome and time-consuming in the latter. Contrast-enhanced computed tomography is presently the most accurate non-invasive single method to evaluate the severity of acute pancreatitis. It cannot, however, be performed to all patients with acute pancreatitis. Therefore, considerable interest has grown in the development of reliable biochemical markers that reflect the severity of acute pancreatitis. In this article we critically appraise current and new severity markers of acute pancreatitis in their ability to distinguish between mild and severe disease and their clinical utility.
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Affiliation(s)
- M Lempinen
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland.
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Huang J, Wu Z, Lu S, Shen J, Kong X, Shen Y. Soluble B7-H2 as a novel marker in early evaluation of the severity of acute pancreatitis. Lab Med 2016; 46:109-17. [PMID: 25918189 DOI: 10.1309/lmfsrh0v82hfxppi] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The clinical usefulness of soluble B7-H2 (sB7-H2) as an early indicator of acute pancreatitis (AP) remains unclear, so we performed the present study to investigate this issue. For our cohort, we recruited 75 patients with AP, 70 patients with other abdominal sepsis, and 20 healthy control individuals. The sB7-H2 levels of AP patients or healthy control individuals were measured by enzyme-linked immunosorbent assay (ELISA). The sB7-H2 levels in patients with AP rather than other patients with abdominal sepsis were significantly higher than those in healthy controls. Hence, we selected AP to study the clinical significance of sB7-H2 in inflammatory conditions. The sB7-H2 level was positively correlated with the white blood cell (WBC) count and the lactate dehydrogenase (LDH), high-sensitivity C-reactive protein (hs-CRP), and lipopolysaccharide LPS levels (P <.05 for each). Receiver operating characteristic (ROC) analysis revealed that sB7-H2 can distinguish moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP) from mildly acute pancreatitis (MAP) with 77.8% sensitivity and 80.0% specificity; and that the levels of sB7-H2 also can distinguish SAP from MSAP and MAP with 92.0% sensitivity and 86.0% specificity. The present results indicate that sB7-H2 might be a useful marker in the clinical diagnosis of AP.
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Affiliation(s)
- Jian Huang
- Department of Emergency Internal Medicine of the First Affiliated Hospital, Suzhou University, China
| | - Zhengwang Wu
- Department of General Surgery, No. 7 Hospital of Changzhou People's Hospital, China
| | - Shiqi Lu
- Department of Emergency Internal Medicine of the First Affiliated Hospital, Suzhou University, China
| | - Jiaqing Shen
- Department of Emergency Internal Medicine of the First Affiliated Hospital, Suzhou University, China
| | - Xiaoming Kong
- Department of Emergency Internal Medicine of the First Affiliated Hospital, Suzhou University, China
| | - Yueping Shen
- School of Public Health at the Medical College of Suzhou University, China
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Gillies N, Pendharkar SA, Asrani VM, Mathew J, Windsor JA, Petrov MS. Interleukin-6 is associated with chronic hyperglycemia and insulin resistance in patients after acute pancreatitis. Pancreatology 2016; 16:748-55. [PMID: 27401909 DOI: 10.1016/j.pan.2016.06.661] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 06/17/2016] [Accepted: 06/29/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Diabetes is a pervasive disease, with a mounting prevalence and burden on health care systems. Under this collective term of diabetes falls diabetes after diseases of the exocrine pancreas, a condition which was previously under-recognised and often mislabeled as type 2 diabetes mellitus and is now increasingly acknowledged as a stand-alone entity. However, there is a paucity of clinical studies investigating the underlying pathophysiology of diabetes after acute pancreatitis, the most frequent disease of the pancreas. This study aimed to investigate the role of adipocytokines in glucose metabolism after acute pancreatitis. METHODS This was a cross-sectional follow-up study of a patient cohort diagnosed with acute pancreatitis. Fasting venous blood samples were collected to analyse markers of glucose metabolism (fasting blood glucose, haemoglobin A1c, homeostasis model assessment (HOMA-IR) as a measure of insulin resistance) and adypocytokines (adiponectin, interleukin-6, leptin, monocyte chemoattractant protein-1, retinol binding protein-4, resistin, and tumor necrosis factor-α). Participants were categorized into two groups: normoglycemia after acute pancreatitis and chronic hyperglycemia after acute pancreatitis (CHAP). Binary logistic regression and linear regression analyses were used to investigate the association between each of the adipocytokines and markers of glucose metabolism. Potential confounders were adjusted for in multivariate analyses. RESULTS A total of 83 patients with acute pancreatitis were included, of whom 19 developed CHAP. Interleukin-6 was significantly associated with CHAP in both unadjusted and adjusted models (p = 0.030 and p = 0.018, respectively). Further, it was also significantly associated with HOMA-IR in both unadjusted and adjusted models (p = 0.029 and p = 0.037, respectively). Other adipocytokines were not significantly associated with markers of glucose metabolism. CONCLUSION Interleukin-6 appears to be implicated in the development of chronic hyperglycemia and insulin resistance in patients after acute pancreatitis. It may become a potential target in the prevention and early treatment of diabetes after diseases of the exocrine pancreas.
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Affiliation(s)
- Nicola Gillies
- Department of Surgery, University of Auckland, New Zealand
| | | | | | - Juby Mathew
- Department of Surgery, University of Auckland, New Zealand
| | - John A Windsor
- Department of Surgery, University of Auckland, New Zealand
| | - Maxim S Petrov
- Department of Surgery, University of Auckland, New Zealand.
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Huang Z, Yu SH, Liang HY, Zhou J, Yan HT, Chen T, Cheng L, Ning L, Wang T, Luo ZL, Wang KY, Liu WH, Tang LJ. Outcome benefit of abdominal paracentesis drainage for severe acute pancreatitis patients with serum triglyceride elevation by decreasing serum lipid metabolites. Lipids Health Dis 2016; 15:110. [PMID: 27341816 PMCID: PMC4919836 DOI: 10.1186/s12944-016-0276-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Our previous reports demonstrated that abdominal paracentesis drainage (APD) exerts a beneficial effect on severe acute pancreatitis (SAP) patients. However, the underlying mechanisms for this effectiveness are not well understood. METHODS A retrospective cohort of 132 consecutive non-hypertriglyceridemia (HTG)-induced SAP patients with triglyceride (TG) elevation and pancreatitis-associated ascitic fluid (PAAF) was recruited from May 2010 to May 2015 and included in this study. The patients were divided into two groups: the APD group (n = 68) and the non-APD group (n = 64). The monitored parameters mainly included mortality, hospital stay, the incidence of further intervention, levels of serum lipid metabolites and inflammatory factors, parameters related to organ failure and infections, and severity scores. RESULTS The demographic data and severity scores were comparable between the two groups. Compared with the non-APD group, the primary outcomes (including mortality, hospital stay and the incidence of percutaneous catheter drainage) in the APD group were improved. The serum levels of lipid metabolites were significantly lower in the APD group after 2 weeks of treatment than in the non-APD group. Logistic regression analysis indicated that the decreased extent of free fatty acid (FFA)(odds ratio, 1.435; P = 0.015) was a predictor of clinical improvement after 2 weeks of treatment. CONCLUSION Treatment with APD benefits non-HTG-induced SAP patients with serum TG elevation by decreasing serum levels of FFA.
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Affiliation(s)
- Zhu Huang
- />Postgraduate Department, Third Military Medical University, Chongqing, China
- />General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan Province 610083 China
| | - Sun-Hong Yu
- />General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan Province 610083 China
| | - Hong-Yin Liang
- />General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan Province 610083 China
| | - Jing Zhou
- />Postgraduate Department, Third Military Medical University, Chongqing, China
- />General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan Province 610083 China
| | - Hong-Tao Yan
- />General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan Province 610083 China
| | - Tao Chen
- />General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan Province 610083 China
| | - Long Cheng
- />General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan Province 610083 China
| | - Lin Ning
- />General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan Province 610083 China
| | - Tao Wang
- />General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan Province 610083 China
| | - Zhu-Lin Luo
- />General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan Province 610083 China
| | - Kui-Ying Wang
- />General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan Province 610083 China
| | - Wei-Hui Liu
- />General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan Province 610083 China
| | - Li-Jun Tang
- />General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan Province 610083 China
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Abstract
Hypertriglyceridemic pancreatitis (HTGP) is often encountered clinically as a common form of recurrent acute pancreatitis (AP). It is important to evaluate the management of severe hypertriglyceridemia (HTG) or anti-inflammation in the prophylaxis of HTGP in the clinic. FTY720 (2-amino-2[2-(4-octylphenyl) ethyl]-1, 3-propanediol) is a new anti-inflammatory agent with low toxicity and reported to ameliorate lung injury with pancreatitis in rat. We evaluated its protective affection on AP induced by seven hourly intraperitoneal injection of cerulein in apolipoprotein CIII transgenic mice with severe HTG. FTY720 at 1.5 mg/kg was administered by gastric lavage daily for 3 days before induction of AP. The effects of FTY720 to protect against HTGP were assessed by serum amylase, pancreatic pathological scores, immunostaining, and the expression of inflammatory cytokine genes. As a result, injection of cerulein resulted in more severe pathological changes of AP and higher monocyte chemoattractant protein 1 expression in the pancreas in transgenic than in nontransgenic mice. FTY720 pretreatment improved the pathological severity of AP and decreased the expression of monocyte chemoattractant protein 1 in the pancreas significantly, especially near fourfold reduction in transgenic mice. However, FTY720 did not affect plasma triglyceride levels, and other inflammatory factors and plasma amylase were not correlated with the extent of pancreatic damage in AP with or without FTY720 administration. In summary, our study in a new model, apolipoprotein CIII transgenic mice, demonstrated that HTG mice are susceptible to induction of AP. Prophylactic treatment of FTY720 can significantly attenuate cerulein-induced AP and hence warrant further investigation of sphingosine-1-phosphate receptors agonist for potential clinical application in recurrent attacks of HTGP.
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40
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Noel P, Patel K, Durgampudi C, Trivedi RN, de Oliveira C, Crowell MD, Pannala R, Lee K, Brand R, Chennat J, Slivka A, Papachristou GI, Khalid A, Whitcomb DC, DeLany JP, Cline RA, Acharya C, Jaligama D, Murad FM, Yadav D, Navina S, Singh VP. Peripancreatic fat necrosis worsens acute pancreatitis independent of pancreatic necrosis via unsaturated fatty acids increased in human pancreatic necrosis collections. Gut 2016; 65:100-11. [PMID: 25500204 PMCID: PMC4869971 DOI: 10.1136/gutjnl-2014-308043] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 11/17/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Peripancreatic fat necrosis occurs frequently in necrotising pancreatitis. Distinguishing markers from mediators of severe acute pancreatitis (SAP) is important since targeting mediators may improve outcomes. We evaluated potential agents in human pancreatic necrotic collections (NCs), pseudocysts (PCs) and pancreatic cystic neoplasms and used pancreatic acini, peripheral blood mononuclear cells (PBMC) and an acute pancreatitis (AP) model to determine SAP mediators. METHODS We measured acinar and PBMC injury induced by agents increased in NCs and PCs. Outcomes of caerulein pancreatitis were studied in lean rats coadministered interleukin (IL)-1β and keratinocyte chemoattractant/growth-regulated oncogene, triolein alone or with the lipase inhibitor orlistat. RESULTS NCs had higher fatty acids, IL-8 and IL-1β versus other fluids. Lipolysis of unsaturated triglyceride and resulting unsaturated fatty acids (UFA) oleic and linoleic acids induced necro-apoptosis at less than half the concentration in NCs but other agents did not do so at more than two times these concentrations. Cytokine coadministration resulted in higher pancreatic and lung inflammation than caerulein alone, but only triolein coadministration caused peripancreatic fat stranding, higher cytokines, UFAs, multisystem organ failure (MSOF) and mortality in 97% animals, which were prevented by orlistat. CONCLUSIONS UFAs, IL-1β and IL-8 are elevated in NCs. However, UFAs generated via peripancreatic fat lipolysis causes worse inflammation and MSOF, converting mild AP to SAP.
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Affiliation(s)
- Pawan Noel
- Departments of Medicine, Mayo Clinic, Scottsdale, Arizona, USA
| | - Krutika Patel
- Departments of Medicine, Mayo Clinic, Scottsdale, Arizona, USA
| | - Chandra Durgampudi
- Departments of Medicine, University of Pittsburgh Medical Center, Pasavant, Pennsylvania, USA
| | - Ram N Trivedi
- Departments of Medicine, Mayo Clinic, Scottsdale, Arizona, USA
| | | | | | - Rahul Pannala
- Departments of Medicine, Mayo Clinic, Scottsdale, Arizona, USA
| | - Kenneth Lee
- Departments of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Randall Brand
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jennifer Chennat
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Adam Slivka
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | | | - Asif Khalid
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - David C Whitcomb
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - James P DeLany
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Rachel A Cline
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Chathur Acharya
- Departments of Medicine, University of Pittsburgh Medical Center, Pasavant, Pennsylvania, USA
| | - Deepthi Jaligama
- Departments of Medicine, University of Pittsburgh Medical Center, Pasavant, Pennsylvania, USA
| | - Faris M Murad
- Departments of Medicine, Washington University, Saint Louis, Missouri, USA
| | - Dhiraj Yadav
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sarah Navina
- Departments of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Vijay P Singh
- Departments of Medicine, Mayo Clinic, Scottsdale, Arizona, USA
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Huang C, Alamili M, Nielsen CH, Rosenberg J, Gögenur I. Rapid eye movement-sleep is reduced in patients with acute uncomplicated diverticulitis-an observational study. PeerJ 2015; 3:e1146. [PMID: 26290799 PMCID: PMC4540026 DOI: 10.7717/peerj.1146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 07/11/2015] [Indexed: 12/22/2022] Open
Abstract
Introduction. Sleep disturbances are commonly found in patients in the postoperative period. Sleep disturbances may give rise to several complications including cardiopulmonary instability, transient cognitive dysfunction and prolonged convalescence. Many factors including host inflammatory responses are believed to cause postoperative sleep disturbances, as inflammatory responses can alter sleep architecture through cytokine-brain interactions. Our aim was to investigate alteration of sleep architecture during acute infection and its relationships to inflammation and clinical symptoms. Materials & Methods. In this observational study, we included patients with acute uncomplicated diverticulitis as a model to investigate the isolated effects of inflammatory responses on sleep. Eleven patients completed the study. Patients were admitted and treated with antibiotics for two nights, during which study endpoints were measured by polysomnography recordings, self-reported discomfort scores and blood samples of cytokines. One month later, the patients, who now were in complete remission, were readmitted and the endpoints were re-measured (the baseline values). Results. Total sleep time was reduced 4% and 7% the first (p = 0.006) and second (p = 0.014) nights of diverticulitis, compared to baseline, respectively. The rapid eye movement sleep was reduced 33% the first night (p = 0.016), compared to baseline. Moreover, plasma IL-6 levels were correlated to non-rapid eye movement sleep, rapid eye movement sleep and fatigue. Conclusion. Total sleep time and rapid eye movement sleep were reduced during nights with active diverticulitis and correlated with markers of inflammation.
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Affiliation(s)
- Chenxi Huang
- Department of Surgery, University of Copenhagen, Roskilde and Køge Hospitals , Køge , Denmark ; Department of Surgical Gastroenterology, University of Copenhagen, Herlev Hospital , Herlev , Denmark
| | - Mahdi Alamili
- Department of Surgery, University of Copenhagen, Roskilde and Køge Hospitals , Køge , Denmark
| | - Claus Henrik Nielsen
- Department of Infectious Diseases and Rheumatology, Institute for Inflammation Research, University Hospital of Copenhagen , Rigshospitalet, Copenhagen , Denmark
| | - Jacob Rosenberg
- Department of Surgical Gastroenterology, University of Copenhagen, Herlev Hospital , Herlev , Denmark
| | - Ismail Gögenur
- Department of Surgery, University of Copenhagen, Roskilde and Køge Hospitals , Køge , Denmark
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Urinary neutrophil gelatinase-associated lipocalin as an early predictor of disease severity and mortality in acute pancreatitis. Pancreas 2015; 44:448-52. [PMID: 25426620 DOI: 10.1097/mpa.0000000000000282] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES In reference to our earlier publication, laboratory tests that reflect severe intravascular volume depletion can be used for predicting the severity of acute pancreatitis (AP). The aim of the study was to assess whether urinary level of neutrophil gelatinase-associated lipocalin (NGAL) could represent a useful marker of AP severity. METHODS We observed a cohort of 104 prospectively enrolled patients. The patients were classified into 3 groups: mild AP, moderately severe AP, and severe AP. Urine samples were collected on admission (NGAL-as) and during the first 24 hours (NGAL-first day) for examination of urinary level of NGAL concentrations from the first day. RESULTS Acute pancreatitis was considered severe in 16 (15%) patients, moderately severe in 25 (24%) patients, and mild in 63 (61%) patients.There were statistically significant trends for an increase in severity (P = 0.04, P = 0.003) and mortality (P < 0.031, P = 0.01) with raising NGAL-as and NGAL-first day concentrations, respectively. The areas under the curve for severity predicted by NGAL-as and NGAL-first day were 0.75 and 0.93, respectively. The areas under the curve for mortality prediction by NGAL-as and NGAL-first day were 0.980 and 0.92, respectively. CONCLUSIONS The urinary level of NGAL is a promising new diagnostic and prognostic factor for severe AP in an early stage of the disease.
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Wang Y, Liu W, Liu X, Sheng M, Pei Y, Lei R, Zhang S, Tao R. Role of liver in modulating the release of inflammatory cytokines involved in lung and multiple organ dysfunction in severe acute pancreatitis. Cell Biochem Biophys 2015; 71:765-776. [PMID: 25260395 DOI: 10.1007/s12013-014-0261-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The objective of this study was to understand the role of liver in modulating remote organ dysfunction during severe acute pancreatitis (SAP). We used sodium taurocholate and endotoxin to induce SAP in the rats and confirmed the development of this condition by measuring serum and ascite levels of the biomarkers of liver and lung damage. Our results showed that expression of tumor necrosis factor (TNF)-α was up-regulated sequentially, first in the gut, then in the liver, and finally in lung. Moreover, the SAP-induced increase in the expressions of TNF-α and IL-6 occurring in gut, liver, and lung was directly related to the increase in time. However, in liver and lung, the transcriptional activity of NF-κB and expression of TNF-α at 4 and 8 h were not increased. The distribution sequence of the pro-inflammatory cytokines to various organs was determined by their detection in the blood from portal vein and inferior vena cava. Although liver received TNF-α during 0.5-8 h of the SAP induction, the release of this cytokine into vena cava was not increased in this period of time. In conclusion, our results suggest that the aggravation of SAP leading to development of MODS exhibited the gut-liver-lung cytokine axis. Furthermore, this study indicates that liver performs both protective and stimulatory activities in the modulation of pro-inflammatory cytokine generation and their distribution to remote organs, such as lungs.
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Affiliation(s)
- Yilin Wang
- Center for Organ Transplantation and Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 7W Surgical Building, 197 2nd Ruijin Road, Shanghai, 200025, China
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44
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Patel K, Trivedi RN, Durgampudi C, Noel P, Cline RA, DeLany JP, Navina S, Singh VP. Lipolysis of visceral adipocyte triglyceride by pancreatic lipases converts mild acute pancreatitis to severe pancreatitis independent of necrosis and inflammation. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:808-19. [PMID: 25579844 DOI: 10.1016/j.ajpath.2014.11.019] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 11/13/2014] [Accepted: 11/20/2014] [Indexed: 02/06/2023]
Abstract
Visceral fat necrosis has been associated with severe acute pancreatitis (SAP) for over 100 years; however, its pathogenesis and role in SAP outcomes are poorly understood. Based on recent work suggesting that pancreatic fat lipolysis plays an important role in SAP, we evaluated the role of pancreatic lipases in SAP-associated visceral fat necrosis, the inflammatory response, local injury, and outcomes of acute pancreatitis (AP). For this, cerulein pancreatitis was induced in lean and obese mice, alone or with the lipase inhibitor orlistat and parameters of AP induction (serum amylase and lipase), fat necrosis, pancreatic necrosis, and multisystem organ failure, and inflammatory response were assessed. Pancreatic lipases were measured in fat necrosis and were overexpressed in 3T3-L1 cells. We noted obesity to convert mild cerulein AP to SAP with greater cytokines, unsaturated fatty acids (UFAs), and multisystem organ failure, and 100% mortality without affecting AP induction or pancreatic necrosis. Increased pancreatic lipase amounts and activity were noted in the extensive visceral fat necrosis of dying obese mice. Lipase inhibition reduced fat necrosis, UFAs, organ failure, and mortality but not the parameters of AP induction. Pancreatic lipase expression increased lipolysis in 3T3-L1 cells. We conclude that UFAs generated via lipolysis of visceral fat by pancreatic lipases convert mild AP to SAP independent of pancreatic necrosis and the inflammatory response.
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Affiliation(s)
- Krutika Patel
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania; Mayo Clinic, Scottsdale, Arizona
| | - Ram N Trivedi
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania; Mayo Clinic, Scottsdale, Arizona
| | - Chandra Durgampudi
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Pawan Noel
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania; Mayo Clinic, Scottsdale, Arizona
| | - Rachel A Cline
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania
| | - James P DeLany
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Sarah Navina
- Department of Pathology, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Vijay P Singh
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania; Mayo Clinic, Scottsdale, Arizona.
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45
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Durgampudi C, Noel P, Patel K, Cline R, Trivedi RN, DeLany JP, Yadav D, Papachristou GI, Lee K, Acharya C, Jaligama D, Navina S, Murad F, Singh VP. Acute lipotoxicity regulates severity of biliary acute pancreatitis without affecting its initiation. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:1773-84. [PMID: 24854864 DOI: 10.1016/j.ajpath.2014.02.015] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 02/07/2014] [Accepted: 02/27/2014] [Indexed: 02/07/2023]
Abstract
Obese patients have worse outcomes during acute pancreatitis (AP). Previous animal models of AP have found worse outcomes in obese rodents who may have a baseline proinflammatory state. Our aim was to study the role of acute lipolytic generation of fatty acids on local severity and systemic complications of AP. Human postpancreatitis necrotic collections were analyzed for unsaturated fatty acids (UFAs) and saturated fatty acids. A model of biliary AP was designed to replicate the human variables by intraductal injection of the triglyceride glyceryl trilinoleate alone or with the chemically distinct lipase inhibitors orlistat or cetilistat. Parameters of AP etiology and outcomes of local and systemic severity were measured. Patients with postpancreatitis necrotic collections were obese, and 13 of 15 had biliary AP. Postpancreatitis necrotic collections were enriched in UFAs. Intraductal glyceryl trilinoleate with or without the lipase inhibitors resulted in oil red O-positive areas, resembling intrapancreatic fat. Both lipase inhibitors reduced the glyceryl trilinoleate-induced increase in serum lipase, UFAs, pancreatic necrosis, serum inflammatory markers, systemic injury, and mortality but not serum alanine aminotransferase, bilirubin, or amylase. We conclude that UFAs are enriched in human necrotic collections and acute UFA generation via lipolysis worsens pancreatic necrosis, systemic inflammation, and injury associated with severe AP. Inhibition of lipolysis reduces UFA generation and improves these outcomes of AP without interfering with its induction.
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Affiliation(s)
- Chandra Durgampudi
- Department of Medicine, University of Pittsburgh Medical Center Pasavant, Pittsburgh, Pennsylvania
| | - Pawan Noel
- Department of Medicine, Mayo Clinic, Scottsdale, Arizona
| | - Krutika Patel
- Department of Medicine, Mayo Clinic, Scottsdale, Arizona
| | - Rachel Cline
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ram N Trivedi
- Department of Medicine, Mayo Clinic, Scottsdale, Arizona
| | - James P DeLany
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Dhiraj Yadav
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Kenneth Lee
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Chathur Acharya
- Department of Medicine, University of Pittsburgh Medical Center Pasavant, Pittsburgh, Pennsylvania
| | - Deepthi Jaligama
- Department of Medicine, University of Pittsburgh Medical Center Pasavant, Pittsburgh, Pennsylvania
| | - Sarah Navina
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Faris Murad
- Department of Medicine, Washington University, St. Louis, Missouri
| | - Vijay P Singh
- Department of Medicine, Mayo Clinic, Scottsdale, Arizona.
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46
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Zhu SF, Guo H, Zhang RR, Zhang Y, Li J, Zhao XL, Chen TR, Wan MH, Chen GY, Tang WF. Effect of electroacupuncture on the inflammatory response in patients with acute pancreatitis: an exploratory study. Acupunct Med 2014; 33:115-20. [PMID: 25520280 DOI: 10.1136/acupmed-2014-010646] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES To examine the effects of electroacupuncture (EA) on inflammatory responses in patients with acute pancreatitis (AP). METHODS Eighty patients with mild or severe AP were randomly allocated to a control group or an EA group. All patients were managed conservatively. In addition, the EA group received acupuncture for 30 min per day for 7 days at bilateral points ST36, LI4, TE6, ST37 and LR3. Interleukin (IL)-6, IL-10 and C-reactive protein (CRP) levels were measured on admission and on day 7. The time to re-feeding and length of stay in hospital were also recorded. RESULTS A total of 58 patients provided complete data. The characteristics of the patients in the EA and control groups were similar. After 7 days the serum concentrations of IL-10 were higher in the EA group than in the control group (mild AP: 6.2±1.2 vs 5.2±0.9 pg/mL, p<0.05; severe AP: 14.9±7.8 vs 7.9±6.3 pg/mL, p<0.05). For patients with severe AP, the CRP level in the EA group was lower than in the control group (p<0.05). CONCLUSIONS EA may reduce the severity of AP by inducing anti-inflammatory effects and reducing the time to re-feeding; however, it did not reduce the length of hospital stay. TRIAL REGISTRATION NUMBER ChiCTR-TRC-13003572.
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Affiliation(s)
- Shi-Feng Zhu
- Department of Integrative Medicine, Sichuan Center for Pancreatitis, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Hui Guo
- Department of Integrative Medicine, Sichuan Center for Pancreatitis, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Rong-Rong Zhang
- Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, China
| | - Yumei Zhang
- Department of Integrative Medicine, Sichuan Center for Pancreatitis, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Juan Li
- Department of Integrative Medicine, Sichuan Center for Pancreatitis, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xian-Lin Zhao
- Department of Integrative Medicine, Sichuan Center for Pancreatitis, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tian-Rong Chen
- Mianyang Attached Hospital of Chengdu University of TCM, Mianyang, Sichuan Province, China
| | - Mei-Hua Wan
- Department of Integrative Medicine, Sichuan Center for Pancreatitis, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Guang-Yuan Chen
- Department of Integrative Medicine, Sichuan Center for Pancreatitis, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Wen-Fu Tang
- Department of Integrative Medicine, Sichuan Center for Pancreatitis, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
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Park J, Chang JH, Park SH, Lee HJ, Lim YS, Kim TH, Kim CW, Han SW. Interleukin-6 is associated with obesity, central fat distribution, and disease severity in patients with acute pancreatitis. Pancreatology 2014; 15:59-63. [PMID: 25434497 DOI: 10.1016/j.pan.2014.11.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 11/06/2014] [Accepted: 11/08/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVE Acute pancreatitis (AP) is a systemic inflammatory disease, and cytokines are suggested to be related to the course of AP. Obesity and central fat distribution are considered to have been associated with severe AP. This study investigated the profile of inflammatory cytokines in AP to determine how they are related to obesity, central fat distribution, and AP severity. METHODS Fifty-nine patients with AP were prospectively enrolled in the study. Body mass index and waist circumference were obtained at admission. Serum levels of inflammatory cytokines, IL-Iβ, IL-1ra, IL-6, TNF-α, sTNFR-I, and sTNFR-II, were measured on day 1 and 2 of AP. RESULTS Of the patients included in the study, 19 (32%) were overweight, 23 (39%) had central fat distribution, and 23 (39%) had moderate AP. IL-1ra and IL-6 were significantly higher in overweight patients compared with non-overweight patients. IL-1ra, IL-6, TNF-α, and sTNFR-I were significantly higher in patients with central fat distribution compared with patients with non-central fat distribution. IL-6, sTNFR-I, and sTNFR-II were significantly higher in patients with moderate pancreatitis compared to those with mild pancreatitis. Among the six cytokines, IL-6 was commonly elevated in patients with central fat distribution, overweight, and moderate AP. The areas under the receiver operating characteristic curves of IL-6 for predicting the association with overweight, central fat distribution, and AP severity were 0.678, 0.716, and 0.801, respectively (P < 0.05). CONCLUSIONS IL-6 is a good marker for AP severity and is associated with obesity and central fat distribution in AP patients.
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Affiliation(s)
- Jongwon Park
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jae Hyuck Chang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Sang Hi Park
- Institute of Clinical Medicine Research, Bucheon St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hee Jin Lee
- Institute of Clinical Medicine Research, Bucheon St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yeon Soo Lim
- Department of Radiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Tae Ho Kim
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chang Whan Kim
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sok Won Han
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Hypothermia slows sequential and parallel steps initiated during caerulein pancreatitis. Pancreatology 2014; 14:459-64. [PMID: 25459565 DOI: 10.1016/j.pan.2014.06.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Revised: 06/17/2014] [Accepted: 06/23/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND OBJECTIVES Multiple deleterious signaling cascades are simultaneously activated in acute pancreatitis (AP), which may limit the success of pharmacologic approaches targeting a single step. We explored whether cooling acinar cells slows distinct steps initiated from a stimulus causing pancreatitis simultaneously, and the temperature range over which inhibition of such deleterious signaling occurs. METHODS Caerulein (100 nM) induced trypsinogen activation (TGA), CXCL1, CXCL2 mRNA levels, cell injury were studied at 37 °C, 34 °C, 31 °C, 29 °C and 25 °C in acinar cells. Trypsin, cathepsin B activities and cathepsin B mediated TGA were studied at 37 °C, 23 °C and 4 °C. RESULTS There was >80% reduction in TGA, CXCL1 and CXCL2 mRNA levels at 29 °C, and in cell injury at 34 °C, compared to those at 37 °C. Trypsin activity, cathepsin B activity and cathepsin B mediated TGA at 23 °C were respectively, 53%, 64% and 26% of that at 37 °C. Acinar cooling to 31 °C reduced LDH leakage even when cooling was initiated an hour after caerulein stimulation at 37 °C. CONCLUSIONS Hypothermia synergistically and simultaneously slows parallel and distinct signaling steps initiated by caerulein, thereby reducing TGA, upregulation of inflammatory mediators and acinar injury.
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Nieminen A, Maksimow M, Mentula P, Kyhälä L, Kylänpää L, Puolakkainen P, Kemppainen E, Repo H, Salmi M. Circulating cytokines in predicting development of severe acute pancreatitis. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2014; 18:R104. [PMID: 24886762 PMCID: PMC4095695 DOI: 10.1186/cc13885] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 05/01/2014] [Indexed: 02/06/2023]
Abstract
Introduction Severe acute pancreatitis (AP) is associated with high morbidity and mortality. Early prediction of severe AP is needed to improve patient outcomes. The aim of the present study was to find novel cytokines or combinations of cytokines that can be used for the early identification of patients with AP at risk for severe disease. Methods We performed a prospective study of 163 nonconsecutive patients with AP, of whom 25 had severe AP according to the revised Atlanta criteria. Admission serum levels of 48 cytokines and growth factors were determined using Bio-Plex Pro Human Cytokine Assay 21-plex and 27-plex magnetic bead suspension panels. Admission plasma levels of C-reactive protein (CRP), creatinine and calcium were measured for comparison. In subgroup analyses, we assessed the cytokine profiles of patients with severe AP (n = 14) who did not have organ dysfunction (OD) upon admission (modified Marshall score <2). Results Of 14 cytokines elevated in the severe AP group, interleukin 6 (IL-6) and hepatocyte growth factor (HGF) levels were independent prognostic markers of severe AP. IL-6, HGF and a combination of them predicted severe AP with sensitivities of 56.0%, 60.0% and 72.0%, respectively, and specificities of 90.6%, 92.8% and 89.9%, respectively. The corresponding positive likelihood ratio (LR+) values were 5.9, 8.3 and 7.1, respectively. The predictive values of CRP, creatinine and calcium were comparable to those of the cytokines. In subgroup analyses of patients with severe AP and without OD upon admission, we found that IL-8, HGF and granulocyte colony-stimulating factor (G-CSF) levels predicted the development of severe AP, with G-CSF being the most accurate cytokine at a sensitivity of 35.7%, a specificity of 96.1% and a LR+ of 9.1. Conclusions IL-6 and HGF levels upon admission have prognostic value for severe AP which is similar to levels of CRP, creatinine and calcium. Although IL-6 and HGF, as either single or combined markers, were not perfect in identifying patients at risk for severe AP, the possibility that combining them with novel prognostic markers other than cytokines might improve prognostic accuracy needs to be studied. The accuracy of IL-8, HGF and G-CSF levels in predicting severe AP in patients without clinical signs of OD upon admission warrants larger studies.
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50
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Sigounas DE, Christodoulou DK, Karamoutsios A, Tatsioni A, Dova L, Vartholomatos G, Kolaitis N, Katsanos KH, Zervou E, Ioannidis JPA, Tsianos EV. Changes of serum adhesion molecules and cytokines in post-ERCP pancreatitis: adhesion molecules and cytokines in acute pancreatitis. Clin Biochem 2014; 47:1245-9. [PMID: 24845714 DOI: 10.1016/j.clinbiochem.2014.05.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Revised: 04/23/2014] [Accepted: 05/11/2014] [Indexed: 01/18/2023]
Abstract
OBJECTIVES To assess the early changes of soluble IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, TNF-α, TNF-β, IL-17A, IL-22, soluble (s) P-Selectin, sE-Selectin and sICAM-1 in post-ERCP pancreatitis (PEP). METHODS Single center, prospective study of 318 ERCP procedures. Serum samples were acquired from all patients prior to ERCP, 6 hours and 24 hours after the procedure. For every PEP case, another patient was chosen as a control, matched for gender, age and time period in which ERCP took place. RESULTS Totally, 28 cases and 28 controls were studied. Except for significantly higher IL-1b levels in cases at baseline, no significant differences were observed between cases and controls after Bonferroni corrections. An increase in IL-6 was noted between baseline and 6 h in cases alone (p=0.016). There was a significant fall in sP-selectin levels at 6 and 24 hours compared to baseline in all patients (corrected p=0.008 and 0.016 for cases and 0.016 and 0.048 for controls respectively). An increase of sE-selectin in cases was observed between 6 and 24 hours post-ERCP (corrected p=0.03). CONCLUSIONS Soluble forms of cytokines and adhesion molecules studied seem not to play a major role in PEP.
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Affiliation(s)
- Dimitrios E Sigounas
- 1(st) Division of Internal Medicine and Division of Gastroenterology, Medical School, University of Ioannina, Ioannina, Greece
| | - Dimitrios K Christodoulou
- 1(st) Division of Internal Medicine and Division of Gastroenterology, Medical School, University of Ioannina, Ioannina, Greece
| | | | - Athina Tatsioni
- Department of Internal Medicine, University of Ioannina School of Medicine, Ioannina, Greece; Department of Medicine, Tufts University School of Medicine and Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA
| | - Lefkothea Dova
- Hematology Laboratory, University Hospital of Ioannina, Ioannina, Greece
| | | | - Nikolaos Kolaitis
- Hematology Laboratory, University Hospital of Ioannina, Ioannina, Greece
| | - Konstantinos H Katsanos
- 1(st) Division of Internal Medicine and Division of Gastroenterology, Medical School, University of Ioannina, Ioannina, Greece
| | | | - John P A Ioannidis
- Stanford Prevention Research Center, Department of Medicine and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA
| | - Epameinondas V Tsianos
- 1(st) Division of Internal Medicine and Division of Gastroenterology, Medical School, University of Ioannina, Ioannina, Greece.
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