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Wu Z, Wang S, Wu Z, Tao J, Li L, Zheng C, Xu Z, Du Z, Zhao C, Liang P, Xu A, Wang Z. Altered immune cell in human severe acute pancreatitis revealed by single-cell RNA sequencing. Front Immunol 2024; 15:1354926. [PMID: 39372399 PMCID: PMC11449708 DOI: 10.3389/fimmu.2024.1354926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 09/03/2024] [Indexed: 10/08/2024] Open
Abstract
Background Severe acute pancreatitis (SAP) is characterized by inflammation, with inflammatory immune cells playing a pivotal role in disease progression. This study aims to understand variations in specific immune cell subtypes in SAP, uncover their mechanisms of action, and identify potential biological markers for predicting Acute Pancreatitis (AP) severity. Methods We collected peripheral blood from 7 untreated SAP patients and employed single-cell RNA sequencing for the first time to construct a transcriptome atlas of peripheral blood mononuclear cells (PBMCs) in SAP. Integrating SAP transcriptomic data with 6 healthy controls from the GEO database facilitated the analysis of immune cell roles in SAP. We obtained comprehensive transcriptomic datasets from AP samples in the GEO database and identified potential biomarkers associated with AP severity using the "Scissor" tool in single-cell transcriptomic data. Results This study presents the inaugural construction of a peripheral blood single-cell atlas for SAP patients, identifying 20 cell subtypes. Notably, there was a significant decrease in effector T cell subsets and a noteworthy increase in monocytes compared to healthy controls. Moreover, we identified a novel monocyte subpopulation expressing high levels of PPBP and PF4 which was significantly elevated in SAP. The proportion of monocyte subpopulations with high CCL3 expression was also markedly increased compared to healthy controls, as verified by flow cytometry. Additionally, cell communication analysis revealed insights into immune and inflammation-related signaling pathways in SAP patient monocytes. Finally, our findings suggest that the subpopulation with high CCL3 expression, along with upregulated pro-inflammatory genes such as S100A12, IL1B, and CCL3, holds promise as biomarkers for predicting AP severity. Conclusion This study reveals monocytes' crucial role in SAP initiation and progression, characterized by distinct pro-inflammatory features intricately linked to AP severity. A monocyte subpopulation with elevated PPBP and CCL3 levels emerges as a potential biomarker and therapeutic target.
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Affiliation(s)
- Zheyi Wu
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of General Surgery, Huangshan City People’s Hospital, Huangshan, China
| | - Shijie Wang
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Zhiheng Wu
- Department of General Surgery, Huangshan City People’s Hospital, Huangshan, China
| | - Junjie Tao
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Lei Li
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Chuanming Zheng
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Zhipeng Xu
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Zhaohui Du
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Chengpu Zhao
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Pengzhen Liang
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Aman Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhenjie Wang
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Institute of Acute and Critical Care, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
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Establishment of Early Multi-Indicator Prediction Models of Moderately Severe Acute Pancreatitis and Severe Acute Pancreatitis. Gastroenterol Res Pract 2022; 2022:5142473. [PMID: 35419053 PMCID: PMC9001090 DOI: 10.1155/2022/5142473] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/03/2022] [Accepted: 03/14/2022] [Indexed: 12/23/2022] Open
Abstract
Background It is critical to accurately identify patients with severe acute pancreatitis (SAP) and moderately SAP (MSAP) in a timely manner. The study was done to establish two early multi-indicator prediction models of MSAP and SAP. Methods Clinical data of 469 patients with acute pancreatitis (AP) between 2015 and 2020, at the First Affiliated Hospital of Fujian Medical University, and between 2012 and 2020, at the Affiliated Union Hospital of Fujian Medical University, were retrospectively analyzed. The unweighted predictive score (unwScore) and weighted predictive score (wScore) for MSAP and SAP were derived using logistic regression analysis and were compared with four existing systems using receiver operating characteristic curves. Results Seven prognostic indicators were selected for incorporation into models, including white blood cell count, lactate dehydrogenase, C-reactive protein, triglyceride, D-dimer, serum potassium, and serum calcium. The cut-offs of the unwScore and wScore for predicting severity were set as 3 points and 0.513 points, respectively. The unwScore (AUC = 0.854) and wScore (AUC = 0.837) were superior to the acute physiology and chronic health evaluation II score (AUC = 0.526), the bedside index for severity in AP score (AUC = 0.766), and the Ranson score (AUC = 0.693) in predicting MSAP and SAP, which were equivalent to the modified computed tomography severity index score (AUC = 0.823). Conclusions The unwScore and wScore have good predictive value for MSAP and SAP, which could provide a valuable clinical reference for management and treatment.
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Deng H, Yu X, Gao K, Liu Y, Tong Z, Liu Y, Li W. Dynamic Nomogram for Predicting Thrombocytopenia in Adults with Acute Pancreatitis. J Inflamm Res 2021; 14:6657-6667. [PMID: 34916817 PMCID: PMC8667610 DOI: 10.2147/jir.s339981] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022] Open
Abstract
Objective Thrombocytopenia increases the risk of hemorrhage in patients with acute pancreatitis (AP), leading to poor clinical outcomes. Currently, there is no reliable tool for the early assessment of thrombocytopenia in these patients. We aimed to develop a nomogram based on available clinical parameters and validate its efficacy in predicting thrombocytopenia. Methods This was a retrospective study. All the data were extracted from an electronic database from May 2018 to May 2019. Patients with a diagnosis of AP and staying in the intensive care unit for more than 3 days were retrospectively analyzed. A clinical signature was built based on reproducible features, using the least absolute shrinkage and selection operator method (LASSO), and logistic regression established the model (P < 0.05). Nomogram performance was determined by its discrimination, calibration, and clinical usefulness. Results A total of 594 eligible patients were enrolled, of whom 399 were allocated to the training sets and the 195 in the test sets. The clinical features, including blood urea nitrogen (BUN), fibrinogen (FIB), and antithrombase III, were significantly associated with the incidence of thrombocytopenia after acute pancreatitis (p < 0.05) in training sets. The individualized nomogram showed good discrimination in the training sample (area under the receiver operating characteristic curve [AUC], 0.881) and in the validation sample (AUC, 0.883) with good calibration. Conclusion The proposed nomogram has good performance for predicting thrombocytopenia in patients with acute pancreatitis and may facilitate clinical decision-making.
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Affiliation(s)
- Hongbin Deng
- Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xianqiang Yu
- School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Kun Gao
- Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Yang Liu
- Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China
| | - Zhihui Tong
- Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Yuxiu Liu
- Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Weiqin Li
- Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, People's Republic of China.,School of Medicine, Southeast University, Nanjing, People's Republic of China.,Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China
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Zhang D, Wang T, Dong X, Sun L, Wu Q, Liu J, Sun X. Systemic Immune-Inflammation Index for Predicting the Prognosis of Critically Ill Patients with Acute Pancreatitis. Int J Gen Med 2021; 14:4491-4498. [PMID: 34413676 PMCID: PMC8370754 DOI: 10.2147/ijgm.s314393] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/28/2021] [Indexed: 12/25/2022] Open
Abstract
Background Systemic immune-inflammation index (SII) has been identified as a prognostic biomarker in various diseases. However, its significance in acute pancreatitis (AP) has not been reported. Therefore, the main aim of this study was to determine the association of SII with clinical outcomes of AP patients, after adjusting for several confounders. Methods This retrospective cohort study was conducted using data retrieved from the Medical Information Mart for Intensive Care III database (MIMIC-III). The study only included patients diagnosed with AP. SII was calculated as the platelet counts x neutrophil counts/lymphocyte counts. Cox regression models were employed to assess the impact of SII on the 30- and 90-day mortality of AP patients. Subgroup analysis was carried out to explore the stability of the relationship between SII and AP mortality. Results A total of 513 patients were found to be eligible based on the inclusion and exclusion criteria. For 30-day all-cause mortality, in the model adjusted for multiple confounders, the HR (95% CI) for mid-SII group (SII: 75.6−104.2) and high-SII groups (SII: >104.2) were 1.29 (0.65, 2.56) and 2.57 (1.35, 4.88), respectively, compared to the low-SII group (SII: <75.5). A similar trend was observed for 90-day mortality. Subgroup analyses presented a stable relationship between SII and 30-day all-cause mortality of AP patients. Conclusion SII is a potentially useful prognostic biomarker for AP. However, prospective studies are needed to confirm this finding.
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Affiliation(s)
- Daguan Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Tingting Wang
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Xiuli Dong
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Liang Sun
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Qiaolin Wu
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Jianpeng Liu
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Xuecheng Sun
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
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Kim TY, Kim SJ, Kim YS, Lee JW, Park EJ, Lee SJ, Lee KJ, Cha YS. Delta neutrophil index as an early predictive marker of severe acute pancreatitis in the emergency department. United European Gastroenterol J 2019; 7:488-495. [PMID: 31065366 DOI: 10.1177/2050640619838359] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 02/18/2019] [Indexed: 12/20/2022] Open
Abstract
Background Predicting severe acute pancreatitis (AP) in the early clinical stage is important for low morbidity and mortality. Delta neutrophil index (DNI) is used to detect infection and inflammation, but no previous studies have evaluated the usefulness of DNI as an early predictor of progression to severe AP (SAP). Methods The medical records of patients who were diagnosed with AP at the emergency department (ED) of Wonju Severance Christian Hospital from January 2012 to August 2016 were retrospectively reviewed. The initial DNI obtained in the ED was compared with other inflammatory markers to predict SAP. Multivariate logistic regression was used for statistical analysis. Results Of the 209 cases included in the analysis, 13 were classified as SAP. Compared to the DNI of the mild to moderately SAP group, that in the SAP group was considerably higher. The DNI showed a positive correlation with the Atlanta classification and bedside index of severity in AP. Using multivariate logistic regression analysis, DNI was an independent predictor of early SAP detection (odds ratio 1.122, 95% CI 1.045-1.205, p = 0.001). Among the biomarkers, DNI had the highest predictive value for SAP. Conclusions The DNI measured in the ED at presentation is a potentially useful adjunctive marker to predict SAP.
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Affiliation(s)
- Tae Y Kim
- Department of Emergency Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Sun J Kim
- Department of Emergency Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Yoon S Kim
- Department of Emergency Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Jong W Lee
- Department of Laboratory Medicine, Konyang University Hospital, Daejeon, Republic of Korea
| | - Eung J Park
- Center of Biomedical Data Science, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Seok J Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Kyong J Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Yong S Cha
- Department of Emergency Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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Fonteh P, Smith M, Brand M. Adaptive Immune Cell Dysregulation and Role in Acute Pancreatitis Disease Progression and Treatment. Arch Immunol Ther Exp (Warsz) 2018; 66:199-209. [PMID: 29189884 DOI: 10.1007/s00005-017-0495-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 08/31/2017] [Indexed: 12/18/2022]
Abstract
Acute pancreatitis (AP) is an inflammation of the pancreas caused by various stimuli including excessive alcohol consumption, gallstone disease and certain viral infections. Managing specifically the severe form of AP is limited due to lack of an understanding of the complex immune events that occur during AP involving immune cells and inflammatory molecules such as cytokines. The relative abundance of various immune cells resulting from the immune dysregulation drives disease progression. In this review, we examine the literature on the adaptive immune cells in AP, the prognostic value of these cells in stratifying patients into appropriate care and treatment strategies based on cell frequency in different AP severities are discussed.
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Affiliation(s)
- Pascaline Fonteh
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa.
| | - Martin Smith
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa
| | - Martin Brand
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa
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Barlass U, Dutta R, Cheema H, George J, Sareen A, Dixit A, Yuan Z, Giri B, Meng J, Banerjee S, Banerjee S, Dudeja V, Dawra RK, Roy S, Saluja AK. Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis. Gut 2018. [PMID: 28642332 DOI: 10.1136/gutjnl-2017-313717] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Opioids such as morphine are widely used for the management of pain associated with acute pancreatitis. Interestingly, opioids are also known to affect the immune system and modulate inflammatory pathways in non-pancreatic diseases. However, the impact of morphine on the progression of acute pancreatitis has never been evaluated. In the current study, we evaluated the impact of morphine on the progression and severity of acute pancreatitis. METHODS Effect of morphine treatment on acute pancreatitis in caerulein, L-arginine and ethanol-palmitoleic acid models was evaluated after induction of the disease. Inflammatory response, gut permeability and bacterial translocation were compared. Experiments were repeated in mu (µ) opioid receptor knockout mice (MORKO) and in wild-type mice in the presence of opioid receptor antagonist naltrexone to evaluate the role of µ-opioid receptors in morphine's effect on acute pancreatitis. Effect of morphine treatment on pathways activated during pancreatic regeneration like sonic Hedgehog and activation of embryonic transcription factors like pdx-1 and ptf-1 were measured by immunofluorescence and quantitative PCR. RESULTS Histological data show that treatment with morphine after induction of acute pancreatitis exacerbates the disease with increased pancreatic neutrophilic infiltration and necrosis in all three models of acute pancreatitis. Morphine also exacerbated acute pancreatitis-induced gut permeabilisation and bacteraemia. These effects were antagonised in the MORKO mice or in the presence of naltrexone suggesting that morphine's effect on severity of acute pancreatitis are mediated through the µ-opioid receptors. Morphine treatment delayed macrophage infiltration, sonic Hedgehog pathway activation and expression of pdx-1 and ptf-1. CONCLUSION Morphine treatment worsens the severity of acute pancreatitis and delays resolution and regeneration. Considering our results, the safety of morphine for analgesia during acute pancreatitis should be re-evaluated in future human studies.
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Affiliation(s)
- Usman Barlass
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - Raini Dutta
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - Hassam Cheema
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - John George
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - Archana Sareen
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - Ajay Dixit
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - Zuobiao Yuan
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - Bhuwan Giri
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - Jingjing Meng
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - Santanu Banerjee
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - Sulagna Banerjee
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - Vikas Dudeja
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - Rajinder K Dawra
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - Sabita Roy
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
| | - Ashok K Saluja
- Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
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Gukovskaya AS, Gukovsky I, Algül H, Habtezion A. Autophagy, Inflammation, and Immune Dysfunction in the Pathogenesis of Pancreatitis. Gastroenterology 2017; 153:1212-1226. [PMID: 28918190 PMCID: PMC6338477 DOI: 10.1053/j.gastro.2017.08.071] [Citation(s) in RCA: 243] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 08/09/2017] [Accepted: 08/17/2017] [Indexed: 12/13/2022]
Abstract
Pancreatitis is a common disorder with significant morbidity and mortality, yet little is known about its pathogenesis, and there is no specific or effective treatment. Its development involves dysregulated autophagy and unresolved inflammation, demonstrated by studies in genetic and experimental mouse models. Disease severity depends on whether the inflammatory response resolves or amplifies, leading to multi-organ failure. Dysregulated autophagy might promote the inflammatory response in the pancreas. We discuss the roles of autophagy and inflammation in pancreatitis, mechanisms of deregulation, and connections among disordered pathways. We identify gaps in our knowledge and delineate perspective directions for research. Elucidation of pathogenic mechanisms could lead to new targets for treating or reducing the severity of pancreatitis.
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Affiliation(s)
- Anna S Gukovskaya
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, California; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California.
| | - Ilya Gukovsky
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, California; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - Hana Algül
- II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
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Gao E, Jiang Y, Li Z, Xue D, Zhang W. Association between high mobility group box‑1 protein expression and cell death in acute pancreatitis. Mol Med Rep 2017; 15:4021-4026. [PMID: 28440506 PMCID: PMC5436195 DOI: 10.3892/mmr.2017.6496] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 02/20/2017] [Indexed: 01/03/2023] Open
Abstract
The present study used caerulein stimulation of AR42J rat pancreatic cells as an in vitro acute pancreatitis (AP) model to investigate proteins differentially expressed in apoptosis and necrosis. AR42J cells were stimulated with 10‑8mol/l caerulein and incubated for 24 h. Apoptosis and necrosis were detected using flow cytometry. The sorted Annexin V‑positive cells (apoptotic) and the Annexin V/propidium iodide double‑positive cells (necrotic) were analysed using proteomics. Results showed that numerous proteins were differentially expressed in these 2 groups. Functional enrichment analysis was performed on the differentially expressed genes using the Database for Annotation, Visualization and Integrated Discovery. High mobility group box‑1 protein (HMGB1) was specifically expressed in the necrosis group. Models of varying degrees of AP were established using caerulein at concentrations of 10‑9, 10‑8, 10‑7, 10‑6 and 10‑5 mol/l. The percentage of apoptotic and necrotic cells in each group was determined using flow cytometry. Protein expression levels of HMGB1 were detected by western blot analysis. The present study showed that as the concentration of caerulein increased, the percentage of necrotic cells and the protein expression levels of HMGB1 increased. HMGB1 is involved in many biological processes, including the chromosomal protein glycyl lysine isopeptide cross‑link. HMGB1 may be involved in the early stage of pancreatitis, potentially by inducing the development of cell death by necrosis. These results provide an experimental basis for clinical intervention in AP.
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Affiliation(s)
- Enjun Gao
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yanfeng Jiang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Zhituo Li
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Dongbo Xue
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Weihui Zhang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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Abstract
Alcohol and gallstones are the most common etiologic factors in acute pancreatitis (AP). Recurrent AP can lead to chronic pancreatitis (CP). Although the underlying pathophysiology of the disease is complex, immune cells are critical in the pathogenesis of pancreatitis and determining disease severity. In this review, we discuss the role of innate and adaptive immune cells in both AP and CP, potential immune-based therapeutic targets, and animal models used to understand our knowledge of the disease. The relative difficulty of obtaining human pancreatic tissue during pancreatitis makes animal models necessary. Animal models of pancreatitis have been generated to understand disease pathogenesis, test therapeutic interventions, and investigate immune responses. Although current animal models do not recapitulate all aspects of human disease, until better models can be developed available models are useful in addressing key research questions. Differences between experimental and clinical pancreatitis need consideration, and when therapies are tested, models with established disease ought to be included.
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Yang F, Xie J, Wang W, Xie Y, Sun H, Jin Y, Xu D, Chen B, Andersson R, Zhou M. Regional arterial infusion with lipoxin A4 attenuates experimental severe acute pancreatitis. PLoS One 2014; 9:e108525. [PMID: 25265022 PMCID: PMC4180750 DOI: 10.1371/journal.pone.0108525] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 08/27/2014] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE Investigate the therapeutic effect of regional arterial infusion (RAI) with Aspirin-Triggered Lipoxin A4 (ATL) in experimental severe acute pancreatitis (SAP) in rats. MATERIALS AND METHODS SAP was induced by injection of 5% sodium taurocholate into the pancreatic duct. Rats with SAP were treated with ATL (the ATL group) or physiological saline (the SAP group) infused via the left gastric artery 30 min after injection of sodium taurocholate. The sham group was subjected to the same surgical procedure, though without induction of SAP. Serum levels of amylase, phospholipase A2 (PLA2), interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) were measured at 12 and 24 h after induction of SAP. Ascitic fluid, the pancreatic index (wet weight ratio) and myeloperoxidase (MPO) levels in the pancreas were determined and histopathological findings were evaluated. The expression of intercellular adhesion molecule-1 (ICAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1), NF-κB p65, and heme oxygenase-1 (HO-1) in the pancreas were estimated by immunofluorescence and western blot, respectively. RESULTS ATL rats had lower serum levels of TNF-α, IL-1β, and IL-6 (P<0.01), PLA2 (P<0.05), and amylase levels (P<0.05) studied as compared with the SAP group. The pancreatic index in the ATL group decreased only at 24 h as compared with the SAP group (P<0.05). The histopathological findings and MPO levels in the pancreas significantly decreased in the ATL group as compared to the SAP group (P<0.05 and P<0.01, respectively). Immunofluorescence and western blot showed that ATL attenuated the expression of NF-κB p65, ICAM-1 and PECAM-1 in the pancreas, and increased the expression of HO-1 in SAP animals. CONCLUSIONS We demonstrated that RAI with ATL attenuated the severity of experimental SAP, maybe achieved by improving the expression of HO-1, and down-regulating the NF-κB signaling pathway, with decreased expression of ICAM-1 and PECAM-1 and reduced generation of pro-inflammatory cytokines.
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Affiliation(s)
- Fajing Yang
- Department of Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Jianming Xie
- Department of Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Weiming Wang
- Department of Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Yangyun Xie
- Department of Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Hongwei Sun
- Department of Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Yuepeng Jin
- Department of Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Dan Xu
- School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Bicheng Chen
- Zhejiang Provincial Top Key Discipline in surgery, Wenzhou Key Laboratory of Surgery, Department of Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejaing Province, China
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Lund University and Lund University Hospital, Lund, Sweden
| | - Mengtao Zhou
- Department of Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
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Inman KS, Francis AA, Murray NR. Complex role for the immune system in initiation and progression of pancreatic cancer. World J Gastroenterol 2014; 20:11160-11181. [PMID: 25170202 PMCID: PMC4145756 DOI: 10.3748/wjg.v20.i32.11160] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/27/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
The immune system plays a complex role in the development and progression of pancreatic cancer. Inflammation can promote the formation of premalignant lesions and accelerate pancreatic cancer development. Conversely, pancreatic cancer is characterized by an immunosuppressive environment, which is thought to promote tumor progression and invasion. Here we review the current literature describing the role of the immune response in the progressive development of pancreatic cancer, with a focus on the mechanisms that drive recruitment and activation of immune cells at the tumor site, and our current understanding of the function of the immune cell types at the tumor. Recent clinical and preclinical data are reviewed, detailing the involvement of the immune response in pancreatitis and pancreatic cancer, including the role of specific cytokines and implications for disease outcome. Acute pancreatitis is characterized by a predominantly innate immune response, while chronic pancreatitis elicits an immune response that involves both innate and adaptive immune cells, and often results in profound systemic immune-suppression. Pancreatic adenocarcinoma is characterized by marked immune dysfunction driven by immunosuppressive cell types, tumor-promoting immune cells, and defective or absent inflammatory cells. Recent studies reveal that immune cells interact with cancer stem cells and tumor stromal cells, and these interactions have an impact on development and progression of pancreatic ductal adenocarcinoma (PDAC). Finally, current PDAC therapies are reviewed and the potential for harnessing the actions of the immune response to assist in targeting pancreatic cancer using immunotherapy is discussed.
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Increased expression of the intercellular adhesion molecule-1 (ICAM-1) on peripheral blood neutrophils in acute pancreatitis. Adv Med Sci 2014; 59:102-7. [PMID: 24797984 DOI: 10.1016/j.advms.2014.01.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 09/13/2013] [Indexed: 02/06/2023]
Abstract
PURPOSE Considering the important role of neutrophils' activation in the pathogenesis of acute pancreatitis (AP), the aim of our study was to evaluate the expression of leukocytes' adhesion molecules in patients with AP. PATIENTS/METHODS Thirty-five patients (16 women and 19 men; age 32-77 years, median 56 years) with AP were prospectively included into our study. The absolute number of leukocytes was estimated by haematologic analyser. Surface neutrophils antigens (CD) were assayed by the direct fluorescence method for whole blood, using a flow cytometer. RESULTS At the day 1, significant increase of ICAM-1 expression was found in patients with severe AP (S-AP) (7280 mm(-3) vs 2850 mm(-3) in healthy control; p<0.05). In the days 2, 3 and 5 it sharply decreased and peaked again to 4860 mm(-3) at the day 10. In patients with mild AP (M-AP), not significant elevation of ICAM-1 quickly returned to normal level. In both forms of AP, neutrophil CD62L (L-selectin) expression reached the highest level at the day 1 (8800 mm(-3) and 9020 mm(-3), respectively in M-AP and S-AP, in comparison to 3400 mm(-3) in control; p<0.05). Expression of CD69 (neutrophils' marker of early activation) significantly increased in both M-AP and S-AP. CONCLUSIONS We have found an early and significant increase of peripheral blood neutrophil CD54/ICAM-1 expression, specific for S-AP but not for M-AP. It may provide a good marker predicting severe course of pancreatitis.
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Seifert GJ, Poxleitner PJ, Richter SC, Hopt UT, Wittel UA. Dissecting the effect of moxifloxacin in mice with infected necrosis in taurocholate induced necrotizing pancreatitis. Pancreatology 2014; 14:179-85. [PMID: 24854613 DOI: 10.1016/j.pan.2014.02.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 02/05/2014] [Accepted: 02/13/2014] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To investigate the limited benefit of antibiotics in ameliorating the outcome of acute necrotizing pancreatitis, we analyzed antibiotic therapy in primarily infected necrotizing pancreatitis in mice with respect to the local pancreatic pathology as well as systemic, pancreatitis induced adverse events. METHODS Sterile pancreatic necrosis (SN) was induced by retrograde injection of 4% taurocholate in the common bile duct of Balb/c mice. Primarily infected pancreatic necrosis (IN) was induced by co-injecting 10(8) CFU/ml Escherichia coli. 10 mg/kg of moxifloxacin was administered prior to pancreatitis induction (AN). After 24 h, animals were sacrificed to examine serum as well as organs for signs of SIRS. RESULTS Moxifloxacin significantly reduced bacterial count in pancreatic lysates of animals with infected pancreatic necrosis (IN 4.1·10(7) ± 2.4·10(7) vs. AN 4.9·10(4) ± 2.6·10(4) CFU/g; p < 0.001). However, it did not alter pancreatic histology or pulmonary damage (Histology score: IN 23.8 ± 2.7 vs. AN 22.6 ± 1.7). Moxifloxacin reduced systemic immunoactivation (Serum IL-6: IN 330.5 ± 336.6 vs. 38.7 ± 25.5 pg/ml; p < 0.001), hypoglycemia (serum glucose: IN 105.8 ± 12.7 vs. AN 155.7 ± 39.5 mg/dl; p < 0.001), and serum aspartate aminotransferase (IN 606 ± 89.7 vs. AN 255 ± 52.1; p < 0.05). These parameters were significantly increased in animals with necrotizing pancreatitis. CONCLUSION In the experimental setting, initial antibiotic therapy with moxifloxacin in acute infected necrotizing pancreatitis in mice does not have a beneficial impact on pancreatic pathology or pulmonary damage. However, other systemic complications induced by infected necrosis in acute pancreatitis are reduced by the administration of moxifloxacin.
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Affiliation(s)
- Gabriel J Seifert
- Department of General and Visceral Surgery, Universitätsklinik Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany
| | - Philipp J Poxleitner
- Department of General and Visceral Surgery, Universitätsklinik Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany
| | - Sabine C Richter
- Department of General and Visceral Surgery, Universitätsklinik Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany
| | - Ulrich T Hopt
- Department of General and Visceral Surgery, Universitätsklinik Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany
| | - Uwe A Wittel
- Department of General and Visceral Surgery, Universitätsklinik Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.
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Lesina M, Wörmann SM, Neuhöfer P, Song L, Algül H. Interleukin-6 in inflammatory and malignant diseases of the pancreas. Semin Immunol 2014; 26:80-7. [DOI: 10.1016/j.smim.2014.01.002] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 01/06/2014] [Indexed: 02/07/2023]
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16
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Gómez-Lázaro M, Rinn C, Aroso M, Amado F, Schrader M. Proteomic analysis of zymogen granules. Expert Rev Proteomics 2014; 7:735-47. [DOI: 10.1586/epr.10.31] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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17
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Zheng L, Xue J, Jaffee EM, Habtezion A. Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma. Gastroenterology 2013; 144:1230-40. [PMID: 23622132 PMCID: PMC3641650 DOI: 10.1053/j.gastro.2012.12.042] [Citation(s) in RCA: 249] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 12/12/2012] [Accepted: 12/21/2013] [Indexed: 12/22/2022]
Abstract
Immune cells are important in the pathogenesis of acute pancreatitis and determine disease severity. Results from cytokine-based clinical trials for acute pancreatitis have been disappointing, so strategies that target and alter the behavior of infiltrating immune cells require consideration. Recurrent acute pancreatitis can progress to chronic pancreatitis, which is a well-described risk factor for pancreatic ductal adenocarcinoma (PDA). However, most patients with chronic pancreatitis do not develop PDA, and most patients with PDA do not have a history of pancreatitis. Interestingly, chronic pancreatitis and PDA tissues have similarities in their desmoplasia and inflammatory infiltrates, indicating overlapping inflammatory responses. Further studies are needed to determine the differences and similarities of these responses, improve our understanding of PDA pathogenesis, and develop specific immune-based therapies. Immune cells in PDA produce immunosuppressive signals that allow tumors to evade the immune response. Unlike single therapeutic agent studies that block immunosuppressive mechanisms, studies of combination therapies that include therapeutic vaccines have provided promising results.
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Affiliation(s)
- Lei Zheng
- Stanford University School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, California and The Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jing Xue
- Stanford University School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, California and The Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Elizabeth M. Jaffee
- Stanford University School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, California and The Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Aida Habtezion
- Stanford University School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, California and The Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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18
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Zhang H, Neuhöfer P, Song L, Rabe B, Lesina M, Kurkowski MU, Treiber M, Wartmann T, Regnér S, Thorlacius H, Saur D, Weirich G, Yoshimura A, Halangk W, Mizgerd JP, Schmid RM, Rose-John S, Algül H. IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality. J Clin Invest 2013; 123:1019-1031. [PMID: 23426178 PMCID: PMC3582130 DOI: 10.1172/jci64931] [Citation(s) in RCA: 211] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Accepted: 12/17/2012] [Indexed: 02/06/2023] Open
Abstract
Acute lung injury (ALI) is an inflammatory disease with a high mortality rate. Although typically seen in individuals with sepsis, ALI is also a major complication in severe acute pancreatitis (SAP). The pathophysiology of SAP-associated ALI is poorly understood, but elevated serum levels of IL-6 is a reliable marker for disease severity. Here, we used a mouse model of acute pancreatitis-associated (AP-associated) ALI to determine the role of IL-6 in ALI lethality. Il6-deficient mice had a lower death rate compared with wild-type mice with AP, while mice injected with IL-6 were more likely to develop lethal ALI. We found that inflammation-associated NF-κB induced myeloid cell secretion of IL-6, and the effects of secreted IL-6 were mediated by complexation with soluble IL-6 receptor, a process known as trans-signaling. IL-6 trans-signaling stimulated phosphorylation of STAT3 and production of the neutrophil attractant CXCL1 in pancreatic acinar cells. Examination of human samples revealed expression of IL-6 in combination with soluble IL-6 receptor was a reliable predictor of ALI in SAP. These results demonstrate that IL-6 trans-signaling is an essential mediator of ALI in SAP across species and suggest that therapeutic inhibition of IL-6 may prevent SAP-associated ALI.
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Affiliation(s)
- Hong Zhang
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Patrick Neuhöfer
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Liang Song
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Björn Rabe
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Marina Lesina
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Magdalena U. Kurkowski
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Matthias Treiber
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Thomas Wartmann
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Sara Regnér
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Henrik Thorlacius
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Dieter Saur
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Gregor Weirich
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Akihiko Yoshimura
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Walter Halangk
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Joseph P. Mizgerd
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Roland M. Schmid
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Stefan Rose-John
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Hana Algül
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany.
Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden.
Pathologisches Institut, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Department of Microbiology and Immunology, Keio University School of Tokyo, and Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo, Japan.
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
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Serum proinflammatory cytokine levels and white blood cell differential count in patients with different degrees of severity of acute alcoholic pancreatitis. POLISH JOURNAL OF SURGERY 2012; 84:230-7. [PMID: 22763297 DOI: 10.2478/v10035-012-0038-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
UNLABELLED Several studies suggest that cytokines and neutrophils play an important role in the pathogenesis of acute pancreatitis (AP). The AIM OF THE STUDY was to assess the systemic release of proinflammatory cytokines and WBC (white blood cells) count with differential in patients with acute alcoholic pancreatitis (AAP) and to characterize the differences between patients with mild and severe forms of the disease. MATERIAL AND METHODS Thirty-five patients with the mild form of acute alcoholic pancreatitis (MAAP) were compared to 11 patients with severe acute alcoholic pancreatitis (SAAP). Serum levels of IL-6, IL-8, IL-12p40 and WBC differential count were measured every second day during the first week after admission. RESULTS During the course of the study, the average level of IL-6 was significantly (p<0.05) higher in patients with SAAP than in patients with the mild form of the disease (MAAP). Serum levels of IL-8 and IL-12p40 on admission were higher in patients with SAAP than in patients with MAAP but the difference was not statistically significant. Of all the types of WBCs, neutrophils were significantly (p<0.05) elevated the entire time in SAAP patients when compared to patients with MAAP on 5th and 7th day from admission to hospital. CONCLUSIONS Patients with SAAP had significantly higher proinflammatory cytokine IL-6 levels and neutrophil counts than patients with MAAP. The results suggest that proliferation and overstimulation of this subset of leukocytes might contribute to the development of the systemic inflammatory response in patients with SAAP.
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S-Adenosyl-L-Methionine Protects against Haemorrhagic Pancreatitis in Partially Immunosuppressed Pancreaticoduodenal Transplant Recipients. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/bf03258366] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Muzammil S, Cooper HC. Acute pancreatitis and fibromyalgia: Cytokine link. NORTH AMERICAN JOURNAL OF MEDICAL SCIENCES 2012; 3:206-8. [PMID: 22540093 PMCID: PMC3336914 DOI: 10.4297/najms.2011.3205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Context: Fibromyalgia is a widespread musculoskeletal pain disorder found in 2% of the general population and with a preponderance of 85% in females, and has both genetic and environmental contribution. Acute pancreatitis is a severe condition and in most cases gallstones disease represents approximately half of the cases of acute pancreatitis, and 20-25% are related to alcohol abuse. Small numbers of cases are caused by a variety of other reasons but a few cases have no obvious cause, referred to as ‘idiopathic’. Here we present a case where fibromyalgia might be linked to acute pancreatitis. We believe this has not been reported in this context in literature. Case Report: Fibromyalgia is a widespread musculoskeletal pain disorder found in 2% of the general population and with a preponderance of 85% in females, and has both genetic and environmental contribution. Patient had a cholecystectomy eight years previously. Patient feels tired almost all the time due to her fibromyalgia and requires family support for daily routine. Patient's blood results showed alanine transaminase 527 IU/L, alkaline phosphatase 604 IU/L, bilirubin 34 μmol/L, amylase 2257 IU/L, C-reactive protein 19 mg/L, Gamma-Glutamyl transpeptidase 851 IU/L, renal function and electrolytes were within normal limits. The patient was admitted to the high dependency unit with a diagnosis of acute pancreatitis. Conclusion: There is a known increase in levels of cytokines in patients with fibromyalgia. Part of the pathophysiology of acute pancreatitis is related to raised cytokines and immune deregulations. We hypothesize that elevated levels of cytokines in fibromyalgia has led to acute pancreatitis in our patient. Further epidemiological research on the incidence of pancreatitis in cytokine mediated conditions such as fibromyalgia is required.
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Affiliation(s)
- Sadat Muzammil
- Mid Cheshire Hospitals NHS Foundation Trust, Crewe, Cheshire CW1 4QJ, England, UK
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Ma Q, Zhang M, Wang Z, Ma Z, Sha H. The beneficial effect of resveratrol on severe acute pancreatitis. Ann N Y Acad Sci 2011; 1215:96-102. [PMID: 21261646 DOI: 10.1111/j.1749-6632.2010.05847.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Acute pancreatitis is a common kind of acute abdominal disease. The management of severe acute pancreatitis (SAP) is a challenge because of its high morbidity, which is due to systemic inflammatory response syndrome and multiorgan dysfunction syndrome. Therefore, it is important to explore therapies to control the disease's progression. A series of in vivo and in vitro experiments has demonstrated that resveratrol-an extract from Chinese herbs, grapes, and many plants-exhibits a wide range of biological and pharmacological activities, including anti-inflammatory, antioxidation, and chemopreventive effects, as well as the inhibition of platelet aggregation, which could benefit the treatment of SAP. Here, we examine the possible mechanism of resveratrol in treating the progression of SAP. Resveratrol could inhibit the production and progression of SAP through down-regulating pro-inflammatory cytokines, improving microcirculation, modulating cell apoptosis, and blocking calcium overload. We propose that resveratrol has a potentially therapeutic effect on the progression of SAP.
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Affiliation(s)
- Qingyong Ma
- Department of Hepatobiliary and Pancreas Surgery, First Affiliated Hospital of Xi'an Jiaotong University, China.
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Zhou M, Chen B, Sun H, Deng Z, Andersson R, Zhang Q. The protective effects of Lipoxin A4 during the early phase of severe acute pancreatitis in rats. Scand J Gastroenterol 2011; 46:211-219. [PMID: 20950211 DOI: 10.3109/00365521.2010.525715] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Our aim was to investigate the protective effects of a Lipoxin A(4) analogue (LXA4) in the early phase of acute pancreatitis in rats. MATERIALS AND METHODS Severe acute pancreatitis (SAP) was induced by injection of 5% sodium taurocholate into the pancreatic duct. Rats with SAP were treated with LXA4 (0.1 mg/kg), 10 min after the 5% sodium taurocholate injection, after which LXA4 was administrated every 8 hours, three times (LXA4 group). The sham group was only given the vehicle after operation. Plasma amylase activity, serum levels of interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) were measured at 4, 12, and 24 h after induction of SAP. The pancreatic index and histopathologic observations were evaluated and the expression of intercellular adhesion molecule-1 (ICAM-1) and NF-κB p65 in the pancreas, and the expression of ICAM-1 in the lungs were detected by immunohistochemistry. RESULTS LXA4 treated rats had lower serum levels of TNF-α, IL-1, and IL-6 at all time points measured (p < 0.05), but significantly differed in plasma amylase activity only at 24 h as compared with the SAP group. The pancreatic index and the scores of pancreatitic histopathologic evaluations were lower in the LXA4 group as compared to the SAP group. Immunohistochemistry showed that LXA4 attenuated the expression of ICAM-1 and NF-κB p65 in the pancreas, as well as the expression of ICAM-1 in the lungs in animals with pancreatitis (p < 0.05). CONCLUSIONS We demonstrate that LXA4 has protective effects in experimental SAP, which may be achieved by inhibiting the NF-κB signalling pathway, thereby reducing the production of proinflammatory cytokines.
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Affiliation(s)
- Mengtao Zhou
- Department of Surgery, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou, China
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Effects of dexamethasone on intercellular adhesion molecule 1 expression and inflammatory response in necrotizing acute pancreatitis in rats. Pancreas 2010; 39:1057-63. [PMID: 20442680 DOI: 10.1097/mpa.0b013e3181da0f3e] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES Adhesion molecules are involved in the inflammatory response during acute pancreatitis (AP). We investigated the effect of dexamethasone (Dx) on intercellular adhesion molecule 1 (ICAM-1) expression during AP and its consequences on leukocyte recruitment and pancreatic damage. METHODS Acute pancreatitis was induced in rats by 3.5% sodium taurocholate for 3 hours and 6 hours. Dexamethasone (1 mg/kg) was administered either 30 minutes before or 1 hour after inducing AP. Messenger RNA ICAM-1 expression in pancreas and lung, membrane-bound ICAM-1 in acinar cells, and ICAM-1 plasma levels were analyzed. Histological examination of the pancreas and neutrophil infiltration in pancreas and lung were also measured. RESULTS Prophylactic and therapeutic administration of Dx down-regulated ICAM-1 expression in pancreas and lung from early AP. Dexamethasone given before AP reduced the pancreatic damage, but lung inflammation was not prevented. Therapeutic Dx treatment was ineffective in avoiding leukocyte recruitment into the pancreas and lung in rats with AP. High ICAM-1 concentration was found in plasma during AP, which was not reduced by Dx treatments. CONCLUSIONS Dexamethasone down-regulates ICAM-1 expression, but it does not completely prevent leukocyte recruitment during sodium taurocholate-induced AP.
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Peng Z, Pai P, Hong-Bao L, Rong L, Han-Min W, Chen H. The impacts of continuous veno-venous hemofiltration on plasma cytokines and monocyte human leukocyte antigen-DR expression in septic patients. Cytokine 2010; 50:186-91. [DOI: 10.1016/j.cyto.2010.02.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2009] [Revised: 01/11/2010] [Accepted: 02/02/2010] [Indexed: 11/24/2022]
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Targeting peripheral immune response reduces the severity of necrotizing acute pancreatitis. Crit Care Med 2009; 37:240-5. [DOI: 10.1097/ccm.0b013e31819320fc] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Sorg H, Lorch B, Jaster R, Fitzner B, Ibrahim S, Holzhueter SA, Nizze H, Vollmar B. Early rise in inflammation and microcirculatory disorder determine the development of autoimmune pancreatitis in the MRL/Mp-mouse. Am J Physiol Gastrointest Liver Physiol 2008; 295:G1274-80. [PMID: 18974312 DOI: 10.1152/ajpgi.90341.2008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Autoimmune pancreatitis (AIP) is a rare cause of chronic pancreatitis and mimics pancreatic cancer. Although there is strong interest in research, etiology and pathophysiology of AIP are still unknown. Therefore, we analyzed a total of 92 MRL/Mp-mice of either sex, which are prone to develop AIP, in four different age groups (8-12, 16-20, 24-28, and 32-40 wk). Using intravital fluorescence microscopy, histology, laboratory analysis, and Western blot, onset, severity, and pathophysiological mechanisms of AIP were evaluated. Female animals showed in vivo an age-dependent increase of intrapancreatic leukocyte accumulation, as well as a loss in functional capillary perfusion. In contrast, intrapancreatic inflammation in male mice was less pronounced and not age dependent. Furthermore, pancreatic tissue specimen of female animals exhibited major organ destruction with significantly higher values of mean pathological scores (1.5 +/- 0.3 vs. < or =0.2; P < 0.05), as well as significantly increased CD4-, CD8-, CD11b-, and CD138-positive cells compared with male animals of the same age. Interestingly, there was a significant positive correlation between intravascular leukocyte adherence and the histopathological score of the pancreas, indicating a determining role of the innate immune system for the late onset of AIP. The present study shows that the onset of AIP is characterized by an inflammatory response and microcirculatory failure, most probably constituting initiators and propagators of this autoimmune disease.
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Affiliation(s)
- Heiko Sorg
- Institute for Experimental Surgery, Division of Gastroenterology, University of Rostock, Rostock, Germany
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Study of the protective effects of dexamethasone on ileum mucosa injury in rats with severe acute pancreatitis. Pancreas 2008; 37:e74-82. [PMID: 18815542 DOI: 10.1097/mpa.0b013e3181800d11] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES To study the protecting effects of dexamethasone on ileum mucosa injury of rats with severe acute pancreatitis (SAP). METHODS The SAP rats were prepared by improved Aho's methods. The plasma endotoxin and inflammatory mediators in serum were determined. The rat mortality, pathological changes of terminal ileum, nuclear factor kappa B (NF-kappaB), apoptotic indexes, and apoptotic related protein expression were observed. RESULTS The plasma endotoxin, inflammatory mediators, and NF-kappaB protein expression as well as pathological scores of the treatment group of ileum mucosa were lower than those of the model group at different time points. P selectin in model group significantly exceeded the dexamethasone treatment group at 3 and 6 hours (P < 0.01, P < 0.05). Caspase-3 protein expression in dexamethasone treatment group significantly exceeded the model group at 3 and 6 hours (P < 0.05), and apoptotic indexes were higher than those of the model group at 6 hours (P < 0.05), but Bax protein has shown no marked difference among groups. CONCLUSIONS Dexamethasone can reduce the endotoxin level and inflammatory mediators and down-regulate NF-kappaB protein expression of ileum mucosa, and ileum mucosa epithelial cell apoptosis induction was involved as well. The tissue microarrays technique is of advantage in SAP study.
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Abstract
OBJECTIVES To evaluate the adhesion molecule time course in the early phases of acute pancreatitis and to explore the usefulness of these proteins in assessing the severity of the disease. Fifteen consecutive acute pancreatitis patients (10 patients with the mild and 5 with the severe disease) admitted to the hospital within 6 hours after the onset of pain and 15 age- and sex-matched healthy subjects. METHODS Vascular cell adhesion molecule 1, intercellular adhesion molecule 1, E-selectin, P-selectin, and L-selectin were quantified on hospital admission and for the following 2 days. RESULTS Acute pancreatitis patients had vascular cell adhesion molecule 1 and P-selectin concentrations significantly lower and L-selectin concentrations significantly higher than the healthy subjects. Only E-selectin was significantly higher in severe than in mild disease (P = 0.029); a value of E-selectin ranging from 3.83 to 3.92 ng/mL was the best cutoff value for differentiating severe from mild acute pancreatitis (sensitivity: 60.0%, specificity: 90.0%, cases correctly classified: 80%). E-selectin and P-selectin entered the multivariate logistic regression analysis, and a score was calculated showing a sensitivity of 93.3% and a specificity of 86.7% in identifying the patients with severe pancreatitis. CONCLUSIONS This score seems to be useful for the early assessment of the severity of acute pancreatitis.
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Elfar M, Gaber LW, Sabek O, Fischer CP, Gaber AO. The inflammatory cascade in acute pancreatitis: relevance to clinical disease. Surg Clin North Am 2008; 87:1325-40, vii. [PMID: 18053834 DOI: 10.1016/j.suc.2007.09.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Acute pancreatitis is an inflammatory condition that is initiated by the intra pancreatic activation of proteases. Pancreatic enzyme activation triggers a local and systemic inflammatory response that is associated with recruitment of inflammatory cells into the pancreas and a widespread up-regulation of inflammatory markers in distant tissues.
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Affiliation(s)
- Mohammed Elfar
- Weill Cornell Medical College, Department of Surgery, The Methodist Hospital, 6550 Fannin Street, Suite SM1661A, Houston, TX 77030, USA
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YUKAWA A, TANAKA S, NIIKAWA J, YAMAZAKI T, HONMA T, KITAMURA K, IKEGAMI A, YOSHIDA H, IMAWARI M. Ranitidine, a Histamine-2 Receptor Antagonist, Ameliorates Caerulein-induced Pancreatitis in Rats. THE SHOWA UNIVERSITY JOURNAL OF MEDICAL SCIENCES 2008. [DOI: 10.15369/sujms1989.20.69] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Zhao M, Xue DB, Zheng B, Zhang WH, Pan SH, Sun B. Induction of apoptosis by artemisinin relieving the severity of inflammation in caerulein-induced acute pancreatitis. World J Gastroenterol 2007. [PMID: 17948936 DOI: 10.3748/wjg.13.6558] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To observe the apoptosis and oncosis of pancreatic acinar cells and secondary inflammatory reaction in pancreatic tissue from rats with acute pancreatitis (AP), and the influences of artemisinin on them. METHODS AP was induced by 4 intraperitoneal injections of caerulein at 1 h intervals. To induce apoptosis, solution of artemisinin (50 mg/kg) was given intraperitoneally 1, 12, 24 and 36 h after the last caerulein injection. Histological examination of impairment of pancreatic tissue and detection of serum amylase were performed to evaluate the severity of acute pancreatitis. Apoptosis and oncosis were detected with acridine orange (AO) and ethylene dibromide (EB) staining. Caspase-3 and myeloperoxidase (MPO) activity were measured by colorimetric assay. Nuclear factor-kappa B (NF-kappaB) activation was detected by flow cytometry. Macrophage inflammatory protein-1alpha (MIP-1alpha) protein was measured by Western blot. Interleukin-1beta (IL-1beta) mRNA was detected by RT-PCR. RESULTS Addition of artemisinin increased the number of apoptotic cells (11.7% +/- 1.4% vs 6.3% +/- 0.7%, P < 0.05), while reduced the number of oncotic cells (13.0% +/- 2.4% vs 17.5% +/- 2.2%, P < 0.05). The activity of caspase-3 speeded up (1.52 +/- 0.21 vs 1.03 +/- 0.08, P < 0.05), the pancreas pathological impairment was relieved (3.0 +/- 0.5 vs 4.0 +/- 0.5, P < 0.05) and the level of serum amylase decreased (5642 +/- 721 U/dL vs 7821 +/- 653 U/dL, P < 0.05). The activation of NF-kB (29% +/- 4.1% vs 42% +/- 5.8%), MIP-1alpha protein (3.7 +/- 0.5 vs 5.8 +/- 0.7), MPO (0.52 +/- 0.06 U/g vs 0.68 +/- 0.09 U/g), IL-1beta mRNA (1.7 +/- 0.3 vs 2.4 +/- 0.4) in the apoptosis inducing group was obviously decreased (P < 0.05). CONCLUSION Inducing apoptosis can relieve pathological impairment and inflammatory reaction in AP rats.
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Affiliation(s)
- Ming Zhao
- Department of General Surgery, First Clinical College, Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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Zhao M, Xue DB, Zheng B, Zhang WH, Pan SH, Sun B. Induction of apoptosis by artemisinin relieving the severity of inflammation in caerulein-induced acute pancreatitis. World J Gastroenterol 2007; 13:5612-7. [PMID: 17948936 PMCID: PMC4172741 DOI: 10.3748/wjg.v13.i42.5612] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the apoptosis and oncosis of pancreatic acinar cells and secondary inflammatory reaction in pancreatic tissue from rats with acute pancreatitis (AP), and the influences of artemisinin on them.
METHODS: AP was induced by 4 intraperitoneal injections of caerulein at 1 h intervals. To induce apoptosis, solution of artemisinin (50 mg/kg) was given intraperitoneally 1, 12, 24 and 36 h after the last caerulein injection. Histological examination of impairment of pancreatic tissue and detection of serum amylase were performed to evaluate the severity of acute pancreatitis. Apoptosis and oncosis were detected with acridine orange (AO) and ethylene dibromide (EB) staining. Caspase-3 and myeloperoxidase (MPO) activity were measured by colorimetric assay. Nuclear factor-kappa B (NF-κB) activation was detected by flow cytometry. Macrophage inflammatory protein-1α (MIP-1α) protein was measured by Western blot. Interleukin-1β (IL-1β) mRNA was detected by RT-PCR.
RESULTS: Addition of artemisinin increased the number of apoptotic cells (11.7% ± 1.4% vs 6.3% ± 0.7%, P < 0.05), while reduced the number of oncotic cells (13.0% ± 2.4% vs 17.5% ± 2.2%, P < 0.05). The activity of caspase-3 speeded up (1.52 ± 0.21 vs 1.03 ± 0.08, P < 0.05), the pancreas pathological impairment was relieved (3.0 ± 0.5 vs 4.0 ± 0.5, P < 0.05) and the level of serum amylase decreased (5642 ± 721 U/dL vs 7821 ± 653 U/dL, P < 0.05). The activation of NF-κB (29% ± 4.1% vs 42% ± 5.8%), MIP-1α protein (3.7 ± 0.5 vs 5.8 ± 0.7), MPO (0.52 ± 0.06 U/g vs 0.68 ± 0.09 U/g), IL-1β mRNA (1.7 ± 0.3 vs 2.4 ± 0.4) in the apoptosis inducing group was obviously decreased (P < 0.05).
CONCLUSION: Inducing apoptosis can relieve pathological impairment and inflammatory reaction in AP rats.
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Del Chiaro M, Zerbi A, Falconi M, Bertacca L, Polese M, Sartori N, Boggi U, Casari G, Longoni BM, Salvia R, Caligo MA, Di Carlo V, Pederzoli P, Presciuttini S, Mosca F. Cancer risk among the relatives of patients with pancreatic ductal adenocarcinoma. Pancreatology 2007; 7:459-69. [PMID: 17912010 DOI: 10.1159/000108963] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2007] [Accepted: 03/23/2007] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS Pancreatic cancer is a leading cause of cancer-related death; the most consistently identified risk factors are smoking and family history. Our aims were to examine familial aggregations of pancreas and other cancers, and to determine the relative risk of the family members. METHODS We prospectively collected data on the families of patients presenting with pancreatic ductal adenocarcinoma. Smoking habits and alcohol consumption of the probands were compared with the available statistics on the Italian population. Mortality from cancer was investigated in first-degree relatives, and age-dependent risks of dying from pancreatic cancer and other tumors were compared with background population levels. RESULTS Data for 570 families were collected, including 9,204 relatives. Probands were 3- to 5-fold more often heavy smokers than the general population, and 9.3% of them reported a positive family history of pancreatic cancer. In first-degree relatives, only mortality from pancreatic cancer was significantly increased (relative risk at age 85 years = 2.7). Lifetime risk of dying of pancreas cancer was 4.1% for the relatives of all probands, and was 7.2% for the relatives of probands who developed disease before 60 years of age. CONCLUSIONS The data suggest that genetic susceptibility to pancreatic cancer may be attributable, in addition to BRCA2, to moderate- to low-penetrance gene(s).
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Affiliation(s)
- Marco Del Chiaro
- Regional Referral Center for Pancreatic Diseases Treatment, University of Pisa, Pisa, Italy.
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Regulating effects of arsenic trioxide on cell death pathways and inflammatory reactions of pancreatic acinar cells in rats. Chin Med J (Engl) 2007. [DOI: 10.1097/00029330-200704020-00015] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Panek J, Karcz D, Pieton R, Zasada J, Tusinski M, Dolecki M, Winiarski M. Blood serum levels of proinflammatory cytokines in patients with different degrees of biliary pancreatitis. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2007; 20:645-8. [PMID: 17066155 PMCID: PMC2660792 DOI: 10.1155/2006/372892] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Proinflammatory cytokines play a fundamental role in the local and systemic inflammatory responses in the initial stages of acute biliary pancreatitis (ABP) and in the development of severe forms of the disease. OBJECTIVES The aim of the present study was to assess the systemic release of proinflammatory cytokines and to characterize differences between patients with mild ABP (MABP) and severe ABP (SABP). PATIENTS AND METHODS In the current study, 54 patients with MABP were compared with 14 patients with SABP. Serum levels of tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8 and IL-12p40 were measured every second day after admission for one week. RESULTS The tumour necrosis factor-alpha level was similar in all days of analysis in patients with MABP but was lower compared with SABP patients. The level of IL-1beta was higher at admission in patients with MABP. The level of IL-6 peaked on admission day in both groups, but in patients with SABP, the obtained values were higher. The level of IL-8 on admission day was slightly higher in patients with MABP and systematically decreased when measured on the following days (the third, fifth and seventh days of the study). An increased level of IL-8 during the third, fifth and seventh days of the investigation was seen in SABP patients. The level of IL-12p40 was slightly higher in patients with MABP on the day of admission. CONCLUSIONS The levels of some proinflammatory cytokines are higher in patients with SABP than in patients with MABP. The most consistent difference between the two groups was that the levels of IL-6 were significantly higher in patients with SABP throughout the study. Serum concentration of IL-6 may be helpful as a marker of severity and outcome of ABP.
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Affiliation(s)
- Józefa Panek
- Second Department of Surgery, Collegium Medicum of Jagiellonian University, Kraków, Poland.
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Pietruczuk M, Dabrowska MI, Wereszczynska-Siemiatkowska U, Dabrowski A. Alteration of peripheral blood lymphocyte subsets in acute pancreatitis. World J Gastroenterol 2006; 12:5344-5351. [PMID: 16981265 PMCID: PMC4088202 DOI: 10.3748/wjg.v12.i33.5344] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2006] [Revised: 05/28/2006] [Accepted: 06/15/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate peripheral blood lymphocyte subsets in patients with acute pancreatitis (AP). METHODS Twenty patients with mild AP (M-AP) and 15 with severe AP (S-AP) were included in our study. Peripheral blood lymphocytes were examined at d 1-3, 5, 10 and 30 by means of flow cytometry. RESULTS A significant depletion of circulating lymphocytes was found in AP. In the early AP, the magnitude of depletion was similar for T- and B- lymphocytes. In the late course of S-AP, B-lymphocytes were much more depleted than T-lymphocytes. At d 10, strong shift in the CD7+/CD19+ ratio implicating predominance of T- over B-lymphocytes in S-AP was found. Among T-lymphocytes, the significant depletion of the CD4+ population was observed in M-AP and S-AP, while CD8+ cells were in the normal range. Lymphocytes were found to strongly express activation markers: CD69, CD25, CD28, CD38 and CD122. Serum interleukin-2 (IL-2), IL-4, IL-5, IL-10, interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) levels were significantly increased in both forms of AP. The magnitude of elevation of cytokines known to be produced by Th2 was much higher than cytokines produced by Th1 cells. CONCLUSION AP in humans is characterized by significant reduction of peripheral blood T- and B-lymphocytes.
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Affiliation(s)
- Miroslawa Pietruczuk
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Sklodowska-Curie 24A, Bialystok 15-276, Poland.
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Abstract
Platelet-activating factor (PAF) is a potent proinflammatory phospholipid mediator that belongs to a family of biologically active, structurally related alkyl phosphoglycerides with diverse pathological and physiological effects. This bioactive phospholipid mediates processes as diverse as wound healing, physiological inflammation, angiogenesis, apoptosis, reproduction and long-term potentiation. PAF acts by binding to a specific G protein-coupled receptor to activate multiple intracellular signaling pathways. Since most cells both synthesize and release PAF and express PAF receptors, PAF has potent biological actions in a broad range of cell types and tissues. Inappropriate activation of this signaling pathway is associated with many diseases in which inflammation is thought to be one of the underlying features. Acute pancreatitis (AP) is a common inflammatory disease. The onset of AP is pancreatic autodigestion mediated by abnormal activation of pancreatic enzyme caused by multiple agents, which subsequently induce pancreatic and systemic inflammatory reactions. A number of experimental pancreatitis and clinical trials indicate that PAF does play a critical role in the pathogenesis of AP. Administration of PAF receptor antagonist can significantly reduce local and systemic events that occur in AP. This review focuses on the aspects that are more relevant to the pathogenesis of AP.
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Affiliation(s)
- Li-Rong Liu
- Department of Gastroenterology, Pancreas Center, Affiliated Hospital of Medical College of the Chinese People's Armed Police Forces, Chenglinzhuang Road, Tianjin 300162, China
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de la Mano AM, Sevillano S, Manso MA, Pérez M, de Dios I. Cholecystokinin blockade alters the systemic immune response in rats with acute pancreatitis. Int J Exp Pathol 2004; 85:75-84. [PMID: 15154913 PMCID: PMC2517463 DOI: 10.1111/j.0959-9673.2004.00372.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Acute pancreatitis (AP) is characterized by initial pancreatic injury resulting from the activation of digestive enzymes and, later, widespread inflammation to distant organs. The aim of this study was to study whether the time-course of inflammatory events during AP induced by bile-pancreatic duct obstruction (BPDO) varies after lowering the acinar enzyme content by L364,718 (0.1 mg/kg/day) administration over 7 days before inducing AP. Flow cytometric immunophenotyping was used to analyse the following at different AP stages: distribution of major circulating leucocyte subsets, activation state of circulating neutrophils and monocytes as reflected by CD11b expression and tumour necrosis factor-alpha (TNF-alpha) production and the contribution of T-cell-derived pro-(TNF-alpha) and anti-(IL-10) inflammatory mediators. TNF-alpha plasma levels and neutrophil infiltration in pancreas and lung were also measured. At early BPDO times, L364,718 treatment partially inhibited leukocytosis and increase in peripheral blood neutrophils and monocytes as well as TNF-alpha expression by monocytes. However, from 6 h onwards after BPDO, L364,718 treatment was unable to prevent either pancreatic and lung neutrophil infiltration or the release of TNF-alpha from activated monocytes. By its action on circulating lymphocytes, L364,718 treatment enhanced the severity of the inflammatory response induced by BPDO. Peripheral blood lymphocytes were recruited from earlier BPDO times, and 12 h after BPDO, T cells displayed a significantly higher reserve of TNF-alpha able to be released under stimulation but lower functional reserve of interleukin-10 (IL-10) than observed in untreated rats. It is concluded that lowering the acinar enzyme content through L364,718 treatment prevents earlier systemic immune events in BPDO-induced AP. However, at the point of maximal injury, the inflammatory response became pronounced, largely due to the role played by activated T lymphocytes.
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Affiliation(s)
- Ana Maria de la Mano
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
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Cuzzocrea S, Rossi A, Serraino I, Di Paola R, Dugo L, Genovese T, Britti D, Sciarra G, De Sarro A, Caputi AP, Sautebin L. 5-lipoxygenase knockout mice exhibit a resistance to acute pancreatitis induced by cerulein. Immunology 2003; 110:120-30. [PMID: 12941149 PMCID: PMC1783024 DOI: 10.1046/j.1365-2567.2003.01715.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2002] [Revised: 06/17/2003] [Accepted: 06/26/2003] [Indexed: 01/05/2023] Open
Abstract
Here we compare the degree of pancreatitis caused by cerulein in mice lacking 5-lipoxygenase (5-LO) and in the corresponding wild-type mice. Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterized by oedema, neutrophil infiltration and necrosis and elevated serum levels of amylase and lipase. Infiltration of pancreatic and lung tissue with neutrophils (measured as increase in myeloperoxidase activity) was associated with enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination demonstrated a marked increase in immunoreactivity for intracellular adhesion molecule-1 (ICAM-1), P-selectin and E-selectin in the pancreas and lung of cerulein-treated mice. In contrast, the degree of (1) pancreatic inflammation and tissue injury (histological score), (2) up-regulation/expression of P-selectin, E-selectin and ICAM-1, and (3) neutrophil infiltration was markedly reduced in pancreatic and lung tissue obtained from cerulein-treated 5-LO-deficient mice. These findings support the view that 5-LO plays an important, pro-inflammatory role in the acute pancreatitis caused by cerulein in mice.
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Affiliation(s)
- Salvatore Cuzzocrea
- Department of Clinical and Experimental Medicine and Pharmacology, Policlinico Universitario, Messina, Italy.
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Cosen-Binker LI, Binker MG, Negri G, Tiscornia O. Experimental model of acute pancreatitis in Wistar rat: glucocorticoid treatment profile. Dig Dis Sci 2003. [PMID: 12924636 DOI: 10.1023/a: 1024791101859] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Severe acute pancreatitis may be triggered by an extrapancreatic insult at the peri-Vaterian duodenum such as that occurring in the short-term, 20 min closed duodenal loop model in Wistar rat, which mimics biliary acute pancreatitis or that following endoscopy. Glucocorticoids are immunological modulators whose therapeutic value is worth investigating. Wistar male rats were used under standardized conditions. Acute pancreatitis was induced by instillation of a 7% sodium tauraocholate solution with 5 drops of methylene blue to monitor absence of duodenal bilio pancreatic reflux into the peri-Vaterian duodenum for 20 min. Detection of biliopancreatic reflux with methylene blue was an exclusion criterion. Different doses and times of administration of subcutaneous hydrocortisone were evaluated. Biochemical assays were carried out in blood samples and pancreatic and lung tissue, while histpathological studies were done in the pancreas, lung liver, duodenum, spleen, kidneys, suprarenal glands, and stomach. Animals subjected to the experimental model developed severe acute pancreatitis. According to the dose and time of administration, hydrocortisone therapy was effective and beneficial at a dose of 4 mg/kg give 30 min before inducing acute pancreatitis. It was ineffective when doses were <4 mg/kg and given before sodium taurocholate harmful when the dose was >4 mg/kg and given either before or after. Thus, the proposed model is valid and useful to study the initiation mechanism of acute pancreatitis caused extrapancreatically while its amelioration by glucocorticoid is related the dose and time factor to achieve therapeutical results.
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Affiliation(s)
- Laura Iris Cosen-Binker
- Programa de Estudios Pancreáticos, Hospital de Clínicas, Universidad de Buenos Aires, Argentina
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Dugernier TL, Laterre PF, Wittebole X, Roeseler J, Latinne D, Reynaert MS, Pugin J. Compartmentalization of the inflammatory response during acute pancreatitis: correlation with local and systemic complications. Am J Respir Crit Care Med 2003; 168:148-57. [PMID: 12851244 DOI: 10.1164/rccm.2204019] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Local and systemic inflammation has been implicated in the pathogenesis of acute pancreatitis and secondary multisystem organ failure. To assess the pro- and antiinflammatory response, the site of mediator production, and their route of diffusion, we sampled simultaneously ascites, thoracic lymph, and blood at the onset of end-organ dysfunction and for the following 6 days in 60 patients with acute pancreatitis. We used immunoassays to measure pro- and antiinflammatory cytokines and cell-based bioassays to assess the net pro- and antiinflammatory activity elicited by the biological fluids. Tumor necrosis factor-alpha and interleukin-1beta were detected in less than 15% of blood and lymph samples. Secondary pro- and antiinflammatory cytokines were found to be elevated early and throughout the sampling period in all compartments. Cytokine levels decreased from ascites to lymph to blood, suggesting a splanchnic origin. Prolonged diversion of ascites and lymph did not alter cytokine gradients, suggesting mediator transfer via the splanchnic blood circulation. Although a net proinflammatory activity ascribed to interleukin-1beta was detected in ascites, a net antiinflammatory activity was measured in virtually all lymph and blood samples, suggesting that the pancreas and the splanchnic area are sites of a proinflammatory response and that an early, dominant, and sustained antiinflammatory activity takes place in circulating compartments.
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Affiliation(s)
- Thierry L Dugernier
- Department of Intensive Care and Emergency Medicine, St. Luc University Hospital, Hippocrate Avenue, 10 B-1200 Brussels, Belgium.
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Pastor CM, Rubbia-Brandt L, Hadengue A, Jordan M, Morel P, Frossard JL. Role of macrophage inflammatory peptide-2 in cerulein-induced acute pancreatitis and pancreatitis-associated lung injury. J Transl Med 2003; 83:471-8. [PMID: 12695550 DOI: 10.1097/01.lab.0000063928.91314.9f] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Acute pancreatitis is an inflammatory process of variable severity, and leukocytes are thought to play a key role in the development of pancreatitis and pancreatitis-associated lung injury. The effects of mediators released by these inflammatory cells may induce tissue damage. The aim of our study was to evaluate the role of the chemokine, macrophage inflammatory protein-2 (MIP-2), in the pathogenesis of cerulein-induced pancreatitis and pancreatitis-associated lung injury. The severity of pancreatitis was measured by serum amylase, pancreatic edema, acinar cell necrosis, and myeloperoxidase activity. Lung injury was quantitated by evaluating lung microvascular permeability and lung myeloperoxidase activity. To determine the role of MIP-2 in the pathophysiology of the disease, anti-MIP-2 antibody was administered either 1 hour before or 2 hours after the start of cerulein administration. MIP-2 concentrations increased in serum, pancreas, and lung tissues in mice treated with cerulein. Anti-MIP-2 antibody administrated either before or after cerulein partially protected against pancreas and lung injury. These results show that MIP-2 plays a key role in the pathophysiology of acute pancreatitis and that MIP-2 blockade may improve the outcome of the disease.
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Affiliation(s)
- Catherine M Pastor
- Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
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De La Torre Prados M, García AlcÁntara A, Soler García A, Fernández García I, Luque Fernández M, Merino Vega J. Pancreatitis aguda y base experimental en la respuesta fisiopatológica local y sistémica. Med Intensiva 2003. [DOI: 10.1016/s0210-5691(03)79875-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Immunomodulatory Treatment of Severe Acute Pancreatitis. Intensive Care Med 2002. [DOI: 10.1007/978-1-4757-5551-0_70] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Wu XN. Current concept of pathogenesis of severe acute pancreatitis. World J Gastroenterol 2000; 6:32-36. [PMID: 11819517 PMCID: PMC4723592 DOI: 10.3748/wjg.v6.i1.32] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/1999] [Revised: 06/22/1999] [Accepted: 07/01/1999] [Indexed: 02/06/2023] Open
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Hanck C, Rossol S, Hartmann A, Singer MV. Cytokine gene expression in peripheral blood mononuclear cells reflects a systemic immune response in alcoholic chronic pancreatitis. INTERNATIONAL JOURNAL OF PANCREATOLOGY : OFFICIAL JOURNAL OF THE INTERNATIONAL ASSOCIATION OF PANCREATOLOGY 1999; 26:137-45. [PMID: 10732290 DOI: 10.1385/ijgc:26:3:137] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Recent data provide evidence of a systemic inflammatory response in severe acute pancreatitis; in contrast, the exact immune mechanisms underlying chronic pancreatitis remain unclear. METHODS To investigate the immune response in the clinical features of chronic pancreatitis, we investigated the gene expression of tumor necrosis factor-alpha (TNF-alpha), tumor necrosis factor receptor (TNFR)-p55 and -p75 and inducible nitric oxide synthase (iNOS) in peripheral blood mononuclear cells (PBMC) of 18 patients with late-stage alcoholic chronic pancreatitis of different disease activity (Balthazar criteria). RESULTS Semiquantitative reverse transcriptase-polymerase chain reaction revealed a significantly enhanced gene expression of TNF-alpha (P < 0.05), TNFR-p55 (P < 0.05) and TNFR-p75 (P < 0.01) in unstimulated PBMC of patients with advanced chronic pancreatitis (11/18 with calcifications) compared to healthy controls (n = 8). No significant difference was found between patients with mild acute pancreatitis and patients with an inactive quiescent pancreatitis. Moreover, no expression of inducible nitric oxide synthase was detectable. CONCLUSIONS The enhanced gene expression of TNFR-p75, TNFR-p55 and TNF-alpha in unstimulated PBMC demonstrates an enhanced leucocyte activation in patients with late-stage chronic pancreatitis and suggests a pathogenetic role of the cytotoxic TNF-alpha pathway in the clinical features of alcoholic chronic pancreatitis. The pathogenetic role of nitric oxide in chronic pancreatitis remains to be fully elucidated.
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Affiliation(s)
- C Hanck
- Department of Medicine IV, University Hospital of Heidelberg at Mannheim, Germany
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Werner J, Z'graggen K, Fernández-del Castillo C, Lewandrowski KB, Compton CC, Warshaw AL. Specific therapy for local and systemic complications of acute pancreatitis with monoclonal antibodies against ICAM-1. Ann Surg 1999; 229:834-40; discussion 841-2. [PMID: 10363897 PMCID: PMC1420830 DOI: 10.1097/00000658-199906000-00010] [Citation(s) in RCA: 103] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To analyze the time points and levels of the expression of adhesion molecules in the pancreas and lung in pancreatitis of different severities, and to assess whether treatment with a monoclonal antibody against intercellular adhesion molecule-1 (ICAM-1) can reduce local and systemic complications. BACKGROUND The outcome of severe acute pancreatitis relates to its pulmonary and septic complications. Leukocyte adhesion and infiltration, both mediated by ICAM-1, are central events in the pathogenesis of necrotizing pancreatitis. METHODS Expression of ICAM-1 at different time points was assessed by immunohistochemistry and Western blot analysis in pancreas and lungs from rats with mild edematous or severe necrotizing pancreatitis. ICAM-1 expression was correlated with leukocyte infiltration and histologic changes. The possible therapeutic effect of monoclonal antibodies against ICAM-1 was assessed by measuring pancreatic and lung injury. RESULTS In edematous pancreatitis, increased ICAM-1 expression in pancreas was evident by 6 hours but did not occur in lung. In contrast, ICAM-1 was upregulated at 3 hours in the pancreas and at 12 hours in lung in necrotizing pancreatitis. Increased expression of ICAM-1 preceded leukocyte infiltration. Treatment of severe necrotizing pancreatitis with monoclonal antibodies against ICAM-1 decreased both local pancreatic injury and systemic lung injury compared with untreated controls. CONCLUSIONS Upregulation of ICAM-1 and subsequent leukocyte infiltration appear to be significant mediators of pancreatic and pulmonary injury in pancreatitis, and both the onset and extent correlate with severity. The time course should permit effective prevention of tissue damage by treatment with ICAM-1 antibodies.
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Affiliation(s)
- J Werner
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA
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Sakorafas GH, Tsiotos GG, Bower TC, Sarr MG. Ischemic necrotizing pancreatitis. Two case reports and review of the literature. INTERNATIONAL JOURNAL OF PANCREATOLOGY : OFFICIAL JOURNAL OF THE INTERNATIONAL ASSOCIATION OF PANCREATOLOGY 1998; 24:117-21. [PMID: 9816545 DOI: 10.1007/bf02788569] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Pancreatic ischemia is a very rare etiology of clinical acute pancreatitis, complicating cardiac surgery, hemorrhagic shock, and transplantation of the pancreas. In this article, we present two patients with acute ischemic necrotizing pancreatitis, complicating a generalized atheromatous disease with extensive lesions in the splanchnic circulation (patient 1) and repair of a descending thoracic aortic aneurysm (patient 2). Diagnostic approach and management of ischemic necrotizing pancreatitis are discussed.
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Affiliation(s)
- G H Sakorafas
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
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Berling R, Borgström A, Ohlsson K. Peritoneal lavage with aprotinin in patients with severe acute pancreatitis. Effects on plasma and peritoneal levels of trypsin and leukocyte proteases and their major inhibitors. INTERNATIONAL JOURNAL OF PANCREATOLOGY : OFFICIAL JOURNAL OF THE INTERNATIONAL ASSOCIATION OF PANCREATOLOGY 1998; 24:9-17. [PMID: 9746884 DOI: 10.1007/bf02787525] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
CONCLUSION Although high-dose aprotinin given intraperitoneally to patients with severe acute pancreatitis seems to inhibit activated trypsin in the peritoneal cavity, the treatment has little effect on the balance between proteases and antiproteases. Plasma levels of leukocyte proteases were high in all the patients, indicating leukocyte activation to be an important feature of the pathophysiology of severe acute pancreatitis. A surprise finding was that the patients had higher peritoneal levels of pancreatic secretory trypsin inhibitor (PSTI) after the lavage procedure. BACKGROUND Although most studies have shown protease inhibitor therapy to have little or no effect on acute pancreatitis, in an earlier study we found that very high doses of the protease inhibitor aprotinin given intraperitoneally to patients with severe acute pancreatitis seemed to reduce the need of surgical treatment for pancreatic necrosis. In the present study we have further analyzed plasma and peritoneal samples from the same patients to ascertain whether the aprotinin treatment affects the balance between proteases and endogenous antiproteases. METHODS In a prospective double-blind randomized multicenter trial, 48 patients with severe acute pancreatitis were treated with intraperitoneal lavage. One group (aprotinin group, n = 22) was also treated with high doses (20 million KIU given over 30 h) of aprotinin intraperitoneally. The remaining 26 patients made up the control group. The protease-antiprotease balance was studied by measuring immunoreactive anionic trypsin (irAT), cationic trypsin (irCT), complexes between cationic trypsin and alpha 1-protease inhibitor (irCT-alpha 1 PI), leukocyte elastase and neutrophil proteinase 4 (NP4), as well as the endogenous protease inhibitors, pancreatic secretory trypsin inhibitor (PSTI), alpha 2-macroglobulin (alpha 2M), alpha 1-protease inhibitor (alpha 1 PI), antichymotrypsin (ACHY), and secretory leukocyte protease inhibitor (SLPI). Intraperitoneal levels were studied before and after the lavage procedure, and plasma levels were followed for 21 d. RESULTS The control group had lower plasma levels of SLPI and analysis of peritoneal fluid showed the reduction of irCT-alpha 1 PI to be more pronounced in the aprotinin group. None of the other variables measured differed significantly between the two groups. All patients had very high levels of leukocyte elastase and NP4 both in peritoneal exudate and in plasma. Peritoneal levels of PSTI were higher after the lavage procedure in contrast to the other measured variables that all showed lower peritoneal levels after the lavage.
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Affiliation(s)
- R Berling
- Department of Anesthesiology, Lund University, Malmö University Hospital, Sweden
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