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Wei ZX, Jiang SH, Qi XY, Cheng YM, Liu Q, Hou XY, He J. scRNA-seq of the intestine reveals the key role of mast cells in early gut dysfunction associated with acute pancreatitis. World J Gastroenterol 2025; 31:103094. [PMID: 40182603 PMCID: PMC11962851 DOI: 10.3748/wjg.v31.i12.103094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 01/09/2025] [Accepted: 02/21/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Intestinal barrier dysfunction is a prevalent and varied manifestation of acute pancreatitis (AP). Molecular mechanisms underlying the early intestinal barrier in AP remain poorly understood. AIM To explore the biological processes and mechanisms of intestinal injury associated with AP, and to find potential targets for early prevention or treatment of intestinal barrier injury. METHODS This study utilized single-cell RNA sequencing of the small intestine, alongside in vitro and in vivo experiments, to examine intestinal barrier function homeostasis during the early stages of AP and explore involved biological processes and potential mechanisms. RESULTS Seventeen major cell types and 33232 cells were identified across all samples, including normal, AP1 (4x caerulein injections, animals sacrificed 2 h after the last injection), and AP2 (8x caerulein injections, animals sacrificed 4 h after the last injection). An average of 980 genes per cell was found in the normal intestine, compared to 927 in the AP1 intestine and 1382 in the AP2 intestine. B cells, dendritic cells, mast cells (MCs), and monocytes in AP1 and AP2 showed reduced numbers compared to the normal intestine. Enterocytes, brush cells, enteroendocrine cells, and goblet cells maintained numbers similar to the normal intestine, while cytotoxic T cells and natural killer (NK) cells increased. Enterocytes in early AP exhibited elevated programmed cell death and intestinal barrier dysfunction but retained absorption capabilities. Cytotoxic T cells and NK cells showed enhanced pathogen-fighting abilities. Activated MCs, secreted chemokine (C-C motif) ligand 5 (CCL5), promoted neutrophil and macrophage infiltration and contributed to barrier dysfunction. CONCLUSION These findings enrich our understanding of biological processes and mechanisms in AP-associated intestinal injury, suggesting that CCL5 from MCs is a potential target for addressing dysfunction.
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Affiliation(s)
- Zu-Xing Wei
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Shi-He Jiang
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Xiao-Yan Qi
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Yi-Miao Cheng
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Qiong Liu
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Xu-Yang Hou
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Jun He
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
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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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Liu Q, Zhu X, Guo S. From pancreas to lungs: The role of immune cells in severe acute pancreatitis and acute lung injury. Immun Inflamm Dis 2024; 12:e1351. [PMID: 39023414 PMCID: PMC11256889 DOI: 10.1002/iid3.1351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/25/2024] [Accepted: 07/08/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND Severe acute pancreatitis (SAP) is a potentially lethal inflammatory pancreatitis condition that is usually linked to multiple organ failure. When it comes to SAP, the lung is the main organ that is frequently involved. Many SAP patients experience respiratory failure following an acute lung injury (ALI). Clinicians provide insufficient care for compounded ALI since the underlying pathophysiology is unknown. The mortality rate of SAP patients is severely impacted by it. OBJECTIVE The study aims to provide insight into immune cells, specifically their roles and modifications during SAP and ALI, through a comprehensive literature review. The emphasis is on immune cells as a therapeutic approach for treating SAP and ALI. FINDINGS Immune cells play an important role in the complicated pathophysiology ofSAP and ALI by maintaining the right balance of pro- and anti-inflammatory responses. Immunomodulatory drugs now in the market have low thepeutic efficacy because they selectively target one immune cell while ignoring immune cell interactions. Accurate management of dysregulated immune responses is necessary. A critical initial step is precisely characterizing the activity of the immune cells during SAP and ALI. CONCLUSION Given the increasing incidence of SAP, immunotherapy is emerging as a potential treatment option for these patients. Interactions among immune cells improve our understanding of the intricacy of concurrent ALI in SAP patients. Acquiring expertise in these domains will stimulate the development of innovative immunomodulation therapies that will improve the outlook for patients with SAP and ALI.
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Affiliation(s)
- Qi Liu
- Emergency Medicine Clinical Research Center, Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
- Beijing Key Laboratory of Cardiopulmonary Cerebral ResuscitationBeijingChina
| | - Xiaomei Zhu
- Emergency Medicine Clinical Research Center, Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
- Beijing Key Laboratory of Cardiopulmonary Cerebral ResuscitationBeijingChina
| | - Shubin Guo
- Emergency Medicine Clinical Research Center, Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
- Beijing Key Laboratory of Cardiopulmonary Cerebral ResuscitationBeijingChina
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Huang Q, Liu JW, Dong HB, Wei ZJ, Liu JZ, Ren YT, Jiang X, Jiang B. Mesenteric adipose tissue B lymphocytes promote intestinal injury in severe acute pancreatitis by mediating enteric pyroptosis. Hepatobiliary Pancreat Dis Int 2024; 23:300-309. [PMID: 38057185 DOI: 10.1016/j.hbpd.2023.11.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 11/17/2023] [Indexed: 12/08/2023]
Abstract
BACKGROUND Visceral adipose tissue (VAT) has been linked to the severe acute pancreatitis (SAP) prognosis, although the underlying mechanism remains unclear. It has been reported that pyroptosis worsens SAP. The present study aimed to verify whether mesenteric adipose tissue (MAT, a component of VAT) can cause secondary intestinal injury through the pyroptotic pathway. METHODS Thirty-six male Sprague Dawley (SD) rats were divided into six different groups. Twelve rats were randomly divided into the SAP and control groups. We monitored the changes of MAT and B lymphocytes infiltration in MAT of SAP rats. Twelve SAP rats were injected with MAT B lymphocytes or phosphate buffer solution (PBS). The remaining twelve SAP rats were first injected with MAT B lymphocytes, and then with MCC950 (NLRP3 inhibitor) or PBS. We collected blood and tissue samples from pancreas, gut and MAT for analysis. RESULTS Compared to the control rats, the SAP group showed inflammation in MAT, including higher expression of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6), lower expression of IL-10, and histological changes. Flow cytometry analysis revealed B lymphocytes infiltration in MAT but not T lymphocytes and macrophages. The SAP rats also exhibited intestinal injury, characterized by lower expression of zonula occludens-1 (ZO-1) and occludin, higher levels of lipopolysaccharide and diamine oxidase, and pathological changes. The expression of NLRP3 and n-GSDMD, which are responsible for pyroptosis, was increased in the intestine of SAP rats. The injection of MAT B lymphocytes into SAP rats exacerbated the inflammation in MAT. The upregulation of pyroptosis reduced tight junction in the intestine, which contributed to the SAP progression, including higher inflammatory indicators and worse histological changes. The administration of MCC950 to SAP + MAT B rats downregulated pyroptosis, which subsequently improved the intestinal barrier and ameliorated inflammatory response of SAP. CONCLUSIONS In SAP, MAT B lymphocytes aggravated local inflammation, and promoted the injury to the intestine through the enteric pyroptotic pathway.
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Affiliation(s)
- Qing Huang
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Jia-Wen Liu
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Hai-Bin Dong
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Zheng-Jie Wei
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Jin-Zhe Liu
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yu-Tang Ren
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Xuan Jiang
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China.
| | - Bo Jiang
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
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Liu W, Wang X, Zhao S, Yang S, Zheng X, Gong F, Pei L, Xu D, Li R, Yang Z, Mao E, Chen E, Chen Y. Unraveling the immunological landscape in acute pancreatitis progression to sepsis: insights from a Mendelian randomization study on immune cell traits. Front Immunol 2024; 15:1374787. [PMID: 38601150 PMCID: PMC11004341 DOI: 10.3389/fimmu.2024.1374787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 03/15/2024] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND Acute pancreatitis (AP) is a severe digestive system disorder with a significant risk of progressing to sepsis, a major cause of mortality. Unraveling the immunological pathways in AP is essential for developing effective treatments, particularly understanding the role of specific immune cell traits in this progression. METHODS Employing a bidirectional two-sample Mendelian Randomization (MR) approach, this study first examined the causal relationship between AP and 731 immune cell traits to identify those significantly associated with AP. Subsequently, we explored the causal associations between 731 immune cell traits and sepsis. The analysis utilized extensive genome-wide association studies (GWAS) summary datasets, with a focus on identifying common immune cell traits with statistically significant causal associations between AP and sepsis. RESULTS Our investigation identified 44 immune cell traits unidirectionally associated with AP and 36 traits unidirectionally associated with sepsis. Among these, CD127 on CD28+ CD45RA- CD8+ T cells emerged as a common mediator, accounting for 5.296% of the increased risk of sepsis in AP patients. This finding highlights the significant role of specific memory CD8+ T cells in the pathophysiology of AP and its progression to sepsis. CONCLUSION This study elucidates the critical role of specific immune cell traits, particularly CD127hi memory CD8+ T cells, in the progression of AP to sepsis. Our findings provide a foundation for future research into targeted immune-modulatory therapies, potentially improving patient outcomes in AP-related sepsis and offering new insights into the complex immunological dynamics of this condition.
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Affiliation(s)
- Wenbin Liu
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaofeng Wang
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shanzhi Zhao
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Song Yang
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiangtao Zheng
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fangchen Gong
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Pei
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dan Xu
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ranran Li
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhitao Yang
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Enqiang Mao
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Erzhen Chen
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Chen
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Idiz UO, Aru B, Kaya C, Peker KD, Tatar C, Guler M, Tunay A, Demirel GY, Gurol AO. Could we use PD-1 and PD-L1 expression on lymphocytes and monocytes as predictive markers for prognosis of acute biliary pancreatitis? Immunol Lett 2024; 265:37-43. [PMID: 38199503 DOI: 10.1016/j.imlet.2024.106836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 01/03/2024] [Accepted: 01/07/2024] [Indexed: 01/12/2024]
Abstract
PURPOSE This study aimed to assess the significance of immunophenotyping and serum cytokines in predicting the clinical progression of acute biliary pancreatitis (ABP). MATERIALS AND METHODS Cytokine levels, T-helper, cytotoxic T, natural killer (NK) cells, monocytes, HLA-DR, and PD-1, as well as PDL-1 immune checkpoints, were measured in ABP patients at the time of diagnosis and compared with results from healthy volunteers. The study also compared leukocyte counts, hematocrit, immunophenotyping results, cytokine statuses, and PD-1, PDL-1 expression between healthy volunteers and ABP subgroups categorized by pancreatitis severity. RESULTS The study included 65 ABP patients and 20 healthy volunteers. Significant differences were observed between groups in hematocrit, leukocyte counts, total monocytes, lymphocytes, CD3+ total T cells, CD4+ Th cells, PD-1 expression on CD4+ and CD8+T lymphocytes, HLA-DR expression on CD14+ monocytes, NK cells, PD-L1 expression on CD14+ monocytes, classical and intermediate monocytes, as well as levels of IL-6, IL-8, IL-10, IL-18, and IL-33 cytokines. Moderate correlations were found with lymphocyte counts, PD-1+CD4+ cells, PD-L1+CD14+ cells, and strong correlations with HLA-DR+CD14+ cells. Hematocrit, CD3+ total T cells, NK cells, CD4+PD-1 + T cells, and CD8+PD-1 + T cells showed independent associations with the severity of ABP. Lymphocyte counts, CD14+HLA-DR+ cells, CD14+PD-L1+ cells, CD4+PD-1 + T cells, classical, and intermediate monocytes exhibited the highest Area Under the Curve rates in determining organ failure. CONCLUSIONS Hematocrit, lymphocyte counts, CD14+HLA-DR+ cells, CD14+PD-L1+ cells, and intermediate monocytes emerged as parameters most closely associated with the severity and these parameters could be useful in predicting the severity of ABP.
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Affiliation(s)
- Ufuk Oguz Idiz
- Department of General Surgery, Istanbul Training and Research Hospital, Istanbul, Turkey; Institute of Health Sciences, Istanbul University, Istanbul, Turkey; Department of Immunology, Istanbul University, DETAE, Istanbul, Turkey.
| | - Basak Aru
- Department of Immunology, Faculty of Medicine, Yeditepe University, Istanbul, Turkey
| | - Cemal Kaya
- Department of General Surgery, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Kivanc Derya Peker
- Department of General Surgery, Hisar Hospital Intercontinental, Istanbul, Turkey
| | - Cihad Tatar
- Department of General Surgery, Acibadem University, Istanbul, Turkey
| | - Mert Guler
- Department of General Surgery, Istanbul Training and Research Hospital, Istanbul, Turkey
| | - Abdurrahman Tunay
- Department of Anesthesia and Reanimation, Istanbul Training and Research Hospital, Istanbul, Turkey
| | | | - Ali Osman Gurol
- Department of Immunology, Istanbul University, DETAE, Istanbul, Turkey
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Stojanovic B, Jovanovic IP, Stojanovic MD, Jovanovic M, Vekic B, Milosevic B, Cvetkovic A, Spasic M, Stojanovic BS. The Emerging Roles of the Adaptive Immune Response in Acute Pancreatitis. Cells 2023; 12:1495. [PMID: 37296616 PMCID: PMC10253175 DOI: 10.3390/cells12111495] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/13/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Acute pancreatitis (AP) is an abrupt, variable inflammatory condition of the pancreas, potentially escalating to severe systemic inflammation, rampant pancreatic necrosis, and multi-organ failure. Its complex pathogenesis involves an intricate immune response, with different T cell subsets (Th1, Th2, Th9, Th17, Th22, TFH, Treg, and CD8+ T cells) and B cells playing pivotal roles. Early T cell activation initiates the AP development, triggering cytokines associated with the Th1 response, which stimulate macrophages and neutrophils. Other T cell phenotypes contribute to AP's pathogenesis, and the balance between pro-inflammatory and anti-inflammatory cytokines influences its progression. Regulatory T and B cells are crucial for moderating the inflammatory response and promoting immune tolerance. B cells further contribute through antibody production, antigen presentation, and cytokine secretion. Understanding these immune cells' roles in AP could aid in developing new immunotherapies to enhance patient outcomes. However, further research is required to define these cells' precise roles in AP and their potential as therapeutic targets.
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Affiliation(s)
- Bojan Stojanovic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (B.S.)
| | - Ivan P. Jovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | | | - Marina Jovanovic
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Berislav Vekic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (B.S.)
| | - Bojan Milosevic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (B.S.)
| | - Aleksandar Cvetkovic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (B.S.)
| | - Marko Spasic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (B.S.)
| | - Bojana S. Stojanovic
- Department of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
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Venkatesh K, Glenn H, Delaney A, Andersen CR, Sasson SC. Fire in the belly: A scoping review of the immunopathological mechanisms of acute pancreatitis. Front Immunol 2023; 13:1077414. [PMID: 36713404 PMCID: PMC9874226 DOI: 10.3389/fimmu.2022.1077414] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 12/21/2022] [Indexed: 01/13/2023] Open
Abstract
Introduction Acute pancreatitis (AP) is characterised by an inflammatory response that in its most severe form can cause a systemic dysregulated immune response and progression to acute multi-organ dysfunction. The pathobiology of the disease is unclear and as a result no targeted, disease-modifying therapies exist. We performed a scoping review of data pertaining to the human immunology of AP to summarise the current field and to identify future research opportunities. Methods A scoping review of all clinical studies of AP immunology was performed across multiple databases. Studies were included if they were human studies of AP with an immunological outcome or intervention. Results 205 studies met the inclusion criteria for the review. Severe AP is characterised by significant immune dysregulation compared to the milder form of the disease. Broadly, this immune dysfunction was categorised into: innate immune responses (including profound release of damage-associated molecular patterns and heightened activity of pattern recognition receptors), cytokine profile dysregulation (particularly IL-1, 6, 10 and TNF-α), lymphocyte abnormalities, paradoxical immunosuppression (including HLA-DR suppression and increased co-inhibitory molecule expression), and failure of the intestinal barrier function. Studies including interventions were also included. Several limitations in the existing literature have been identified; consolidation and consistency across studies is required if progress is to be made in our understanding of this disease. Conclusions AP, particularly the more severe spectrum of the disease, is characterised by a multifaceted immune response that drives tissue injury and contributes to the associated morbidity and mortality. Significant work is required to develop our understanding of the immunopathology of this disease if disease-modifying therapies are to be established.
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Affiliation(s)
- Karthik Venkatesh
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
| | - Hannah Glenn
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Anthony Delaney
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- Division of Critical Care, The George Institute for Global Health, Newtown, NSW, Australia
| | - Christopher R. Andersen
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
- Division of Critical Care, The George Institute for Global Health, Newtown, NSW, Australia
| | - Sarah C. Sasson
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
- Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW, Australia
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Liu S, Szatmary P, Lin JW, Wang Q, Sutton R, Chen L, Liu T, Huang W, Xia Q. Circulating monocytes in acute pancreatitis. Front Immunol 2022; 13:1062849. [PMID: 36578487 PMCID: PMC9791207 DOI: 10.3389/fimmu.2022.1062849] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
Acute pancreatitis is a common gastrointestinal disease characterized by inflammation of the exocrine pancreas and manifesting itself through acute onset of abdominal pain. It is frequently associated with organ failure, pancreatic necrosis, and death. Mounting evidence describes monocytes - phagocytic, antigen presenting, and regulatory cells of the innate immune system - as key contributors and regulators of the inflammatory response and subsequent organ failure in acute pancreatitis. This review highlights the recent advances of dynamic change of numbers, phenotypes, and functions of circulating monocytes as well as their underling regulatory mechanisms with a special focus on the role of lipid modulation during acute pancreatitis.
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Affiliation(s)
- Shiyu Liu
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
| | - Peter Szatmary
- Liverpool Pancreatitis Research Group, Liverpool University Hospitals NHS Foundation Trust and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Jing-wen Lin
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Qiqi Wang
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
| | - Robert Sutton
- Liverpool Pancreatitis Research Group, Liverpool University Hospitals NHS Foundation Trust and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Lu Chen
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Tingting Liu
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Tingting Liu, ; Wei Huang, ; Qing Xia,
| | - Wei Huang
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China,Institutes for Systems Genetics & Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Tingting Liu, ; Wei Huang, ; Qing Xia,
| | - Qing Xia
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Tingting Liu, ; Wei Huang, ; Qing Xia,
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Shi S, Ye L, Jin K, Xiao Z, Yu X, Wu W. Innate Lymphoid Cells: Emerging Players in Pancreatic Disease. Int J Mol Sci 2022; 23:3748. [PMID: 35409105 PMCID: PMC8998564 DOI: 10.3390/ijms23073748] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/19/2022] [Accepted: 03/27/2022] [Indexed: 02/07/2023] Open
Abstract
Common pancreatic diseases have caused significant economic and social burdens worldwide. The interstitial microenvironment is involved in and plays a crucial part in the occurrence and progression of pancreatic diseases. Innate lymphoid cells (ILCs), an innate population of immune cells which have only gradually entered our visual field in the last 10 years, play an important role in maintaining tissue homeostasis, regulating metabolism, and participating in regeneration and repair. Recent evidence indicates that ILCs in the pancreas, as well as in other tissues, are also key players in pancreatic disease and health. Herein, we examined the possible functions of different ILC subsets in common pancreatic diseases, including diabetes mellitus, pancreatitis and pancreatic cancer, and discussed the potential practical implications of the relevant findings for future further treatment of these pancreatic diseases.
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Affiliation(s)
- Saimeng Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (S.S.); (L.Y.); (K.J.); (Z.X.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Longyun Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (S.S.); (L.Y.); (K.J.); (Z.X.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Kaizhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (S.S.); (L.Y.); (K.J.); (Z.X.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Zhiwen Xiao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (S.S.); (L.Y.); (K.J.); (Z.X.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (S.S.); (L.Y.); (K.J.); (Z.X.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Weiding Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (S.S.); (L.Y.); (K.J.); (Z.X.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
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11
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Manohar M, Jones EK, Rubin SJS, Subrahmanyam PB, Swaminathan G, Mikhail D, Bai L, Singh G, Wei Y, Sharma V, Siebert JC, Maecker HT, Husain SZ, Park WG, Pandol SJ, Habtezion A. Novel Circulating and Tissue Monocytes as Well as Macrophages in Pancreatitis and Recovery. Gastroenterology 2021; 161:2014-2029.e14. [PMID: 34450180 PMCID: PMC8796698 DOI: 10.1053/j.gastro.2021.08.033] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 07/28/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Acute pancreatitis (AP) is an inflammatory disease with mild to severe course that is associated with local and systemic complications and significant mortality. Uncovering inflammatory pathways that lead to progression and recovery will inform ways to monitor and/or develop effective therapies. METHODS We performed single-cell mass Cytometry by Time Of Flight (CyTOF) analysis to identify pancreatic and systemic inflammatory signals during mild AP (referred to as AP), severe AP (SAP), and recovery using 2 independent experimental models and blood from patients with AP and recurrent AP. Flow cytometric validation of monocytes subsets identified using CyTOF analysis was performed independently. RESULTS Ly6C+ inflammatory monocytes were the most altered cells in the pancreas during experimental AP, recovery, and SAP. Deep profiling uncovered heterogeneity among pancreatic and blood monocytes and identified 7 novel subsets during AP and recovery, and 6 monocyte subsets during SAP. Notably, a dynamic shift in pancreatic CD206+ macrophage population was observed during AP and recovery. Deeper profiling of the CD206+ macrophage identified 7 novel subsets during AP, recovery, and SAP. Differential expression analysis of these novel monocyte and CD206+ macrophage subsets revealed significantly altered surface (CD44, CD54, CD115, CD140a, CD196, podoplanin) and functional markers (interferon-γ, interleukin 4, interleukin 22, latency associated peptide-transforming growth factor-β, tumor necrosis factor-α, T-bet, RoRγt) that were associated with recovery and SAP. Moreover, a targeted functional analysis further revealed distinct expression of pro- and anti-inflammatory cytokines by pancreatic CD206+ macrophage subsets as the disease either progressed or resolved. Similarly, we identified heterogeneity among circulating classical inflammatory monocytes (CD14+CD16-) and novel subsets in patients with AP and recurrent AP. CONCLUSIONS We identified several novel monocyte/macrophage subsets with unique phenotype and functional characteristics that are associated with AP, recovery, and SAP. Our findings highlight differential innate immune responses during AP progression and recovery that can be leveraged for future disease monitoring and targeting.
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Affiliation(s)
- Murli Manohar
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California; Division of Pediatric Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
| | - Elaina K Jones
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California; Division of Pediatric Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Stanford, California
| | - Samuel J S Rubin
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Priyanka B Subrahmanyam
- Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, California
| | - Gayathri Swaminathan
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - David Mikhail
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Lawrence Bai
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Gulshan Singh
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Yi Wei
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Vishal Sharma
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | | | - Holden T Maecker
- Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, California
| | - Sohail Z Husain
- Division of Pediatric Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Stanford, California
| | - Walter G Park
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Stephen J Pandol
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California; Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, California.
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12
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Bharmal SH, Kimita W, Ko J, Petrov MS. Cytokine signature for predicting new-onset prediabetes after acute pancreatitis: A prospective longitudinal cohort study. Cytokine 2021; 150:155768. [PMID: 34823207 DOI: 10.1016/j.cyto.2021.155768] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/26/2021] [Accepted: 11/03/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND/PURPOSE Acute inflammation of the pancreas often leads to metabolic sequelae, the most common of which is new-onset prediabetes (and, ultimately, diabetes). However, there is a lack of studies on predictors of this sequela. The aim was to investigate whether cytokines/chemokines measured at baseline are predictive of new-onset prediabetes after acute pancreatitis (NOPAP). METHODS This was a prospective longitudinal cohort study (as part of the LACERTA project) that included 68 individuals with non-necrotising acute pancreatitis who had no diabetes mellitus. Of them, 17 individuals had prediabetes at baseline and during follow-up, 37 individuals had normoglycaemia at baseline and during follow-up, and 14 individuals had normoglycaemia at baseline and developed NOPAP during follow-up. A commercially available human cytokine/chemokine multiplex kit was used to measure a total of 28 analytes at baseline. Multinomial regression analyses were conducted to investigate the associations between the cytokines/chemokines and the three study groups. RESULTS Interleukin-1β and interferon γ significantly predicted progression to NOPAP with an odds ratio (95% confidence interval) of 1.097 (1.002, 1.201) and 1.094 (1.003, 1.192), respectively (after accounting for age, sex, body mass index, and aetiology of acute pancreatitis). None of the studied cytokines/chemokines showed statistically significant associations with the antecedent prediabetes group (after accounting for the above covariates). CONCLUSION Elevated levels of interleukin-1β and interferon γ in acute pancreatitis individuals with normoglycaemia at baseline may predict progression to NOPAP during follow-up.
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Affiliation(s)
| | - Wandia Kimita
- School of Medicine, University of Auckland, New Zealand
| | - Juyeon Ko
- School of Medicine, University of Auckland, New Zealand
| | - Maxim S Petrov
- School of Medicine, University of Auckland, New Zealand.
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13
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Nalisa M, Nweke EE, Smith MD, Omoshoro-Jones J, Devar JWS, Metzger R, Augustine TN, Fru PN. Chemokine receptor 8 expression may be linked to disease severity and elevated interleukin 6 secretion in acute pancreatitis. World J Gastrointest Pathophysiol 2021; 12:115-133. [PMID: 34877026 PMCID: PMC8611186 DOI: 10.4291/wjgp.v12.i6.115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 07/08/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute pancreatitis (AP) is an inflammatory disease, which presents with epigastric pain and is clinically diagnosed by amylase and lipase three times the upper limit of normal. The 2012 Atlanta classification stratifies the severity of AP as one of three risk categories namely, mild AP (MAP), moderately severe AP (MSAP), and severe AP (SAP). Challenges in stratifying AP upon diagnosis suggest that a better understanding of the underlying complex pathophysiology may be beneficial. AIM To identify the role of the chemokine receptor 8 (CCR8), expressed by T-helper type-2 Lymphocytes and peritoneal macrophages, and its possible association to Interleukin (IL)-6 and AP stratification. METHODS This study was a prospective case-control study. A total of 40 patients were recruited from the Chris Hani Baragwanath Academic Hospital and the Charlotte Maxeke Johannesburg Academic Hospital. Bioassays were performed on 29 patients (14 MAP, 11 MSAP, and 4 SAP) and 6 healthy controls as part of a preliminary study. A total of 12 mL of blood samples were collected at Day (D) 1, 3, 5, and 7 post epigastric pain. Using multiplex immunoassay panels, real-time polymerase chain reaction (qRT-PCR) arrays, and multicolour flow cytometry analysis, immune response-related proteins, genes, and cells were profiled respectively. GraphPad Prism™ software and fold change (FC) analysis was used to determine differences between the groups. P<0.05 was considered significant. RESULTS The concentration of IL-6 was significantly different at D3 post epigastric pain in both the MAP group and MSAP group with P = 0.001 and P = 0.013 respectively, in a multiplex assay. When a FC of 2 was applied to identify differentially expressed genes using RT2 Profiler, CCR8 was shown to increase steadily with disease severity from MAP (1.33), MSAP (38.28) to SAP (1172.45) median FC. Further verification studies using RT-PCR showed fold change increases of CCR8 in MSAP and SAP ranging from 1000 to 1000000 times when represented as Log10, compared to healthy control respectively at D3. The findings also showed differing lymphocyte and monocyte cell frequency between the groups. With monocyte population frequency as high as 70% in MSAP at D3. CONCLUSION The higher levels of CCR8 and IL-6 in the severe patients and immune cell differences compared to MAP and controls provide an avenue for exploring AP stratification to improve management.
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Affiliation(s)
- Mwangala Nalisa
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
| | - Ekene Emmanuel Nweke
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
| | - Martin D Smith
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
- Department of Surgery, Chris Hani Baragwanath Academic Hospital, Johannesburg 1864, Gauteng, South Africa
| | - Jones Omoshoro-Jones
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
- Department of Surgery, Chris Hani Baragwanath Academic Hospital, Johannesburg 1864, Gauteng, South Africa
| | - John WS Devar
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
- Department of Surgery, Chris Hani Baragwanath Academic Hospital, Johannesburg 1864, Gauteng, South Africa
| | - Rebecca Metzger
- Institut für Immunologie, Ludwig-Maximilians-Universität München, München 80539, Germany
| | - Tanya N Augustine
- School of Anatomical Sciences, Faculty of Health Science, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
| | - Pascaline N Fru
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
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14
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Chen Y, Tang S, Wang Y. Prognostic Value of Glucose-to-Lymphocyte Ratio in Critically Ill Patients with Acute Pancreatitis. Int J Gen Med 2021; 14:5449-5460. [PMID: 34526812 PMCID: PMC8436258 DOI: 10.2147/ijgm.s327123] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/16/2021] [Indexed: 12/21/2022] Open
Abstract
Background Glucose metabolism and systemic inflammation have been associated with prognosis in acute pancreatitis (AP) patients. However, the possible value as a prognostic marker of the glucose-to-lymphocyte ratio (GLR) has not been evaluated in critically ill patients with AP. Methods This study included 1,133 critically ill patients with AP from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database, who were randomly divided into the training cohort (n=806) and the validation cohort (n=327) at a ratio of 7:3. X-tile software was used to determine the optimal cut-off values for GLR. Area under the curve (AUC) analysis was performed to compare the performance between GLR and other blood-based inflammatory biomarkers. Univariate and multivariate Cox regression analyses were applied to select prognostic factors associated with in-hospital mortality. A nomogram model was developed based on the identified prognostic factors and the validation cohort was used to further validate the nomogram. Results The optimal cut-off value for GLR was 0.9. The ROC analyses showed that the discrimination abilities of GLR were better than other blood-based inflammatory biomarkers. Multivariate Cox regression analysis demonstrated that age, platelet, albumin, bilirubin, Sequential Organ Failure Assessment (SOFA) score, and GLR are independent predictors of poor overall survival in the training cohort and were incorporated into the nomogram for in-hospital mortality as independent factors. The nomogram exhibited better discrimination with C-indexes in the training cohort and the validation cohort of 0.886 (95% CI=0.849–0.922) and 0.841 (95% CI=0.767–0.915), respectively. The calibration plot revealed an adequate fit of the nomogram for predicting the risk of in-hospital mortality in both sets. Conclusion As an easily available biomarker, GLR can independently predict the in-hospital mortality of critically ill patients with AP. The nomogram combining GLR with other significant features exerted favorable predictive performance for in-hospital mortality.
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Affiliation(s)
- Yongjun Chen
- Department of Gastroenterology, Qianjiang Central Hospital of Chongqing Municipality, Chongqing, 409000, People's Republic of China
| | - Shangjun Tang
- Department of Gastroenterology, Qianjiang Central Hospital of Chongqing Municipality, Chongqing, 409000, People's Republic of China
| | - Yumei Wang
- Department of Gastroenterology, Qianjiang Central Hospital of Chongqing Municipality, Chongqing, 409000, People's Republic of China
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15
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Peng C, Li Z, Yu X. The Role of Pancreatic Infiltrating Innate Immune Cells in Acute Pancreatitis. Int J Med Sci 2021; 18:534-545. [PMID: 33390823 PMCID: PMC7757151 DOI: 10.7150/ijms.51618] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 11/13/2020] [Indexed: 12/13/2022] Open
Abstract
Acute pancreatitis (AP) is a leading cause of gastrointestinal-related hospital admissions with significant morbidity and mortality. Although the underlying pathophysiology of AP is rather complex, which greatly limits the treatment options, more and more studies have revealed that infiltrating immune cells play a critical role in the pathogenesis of AP and determine disease severity. Thus, immunomodulatory therapy targeting immune cells and related inflammatory mediators is expected to be a novel treatment modality for AP which may improve the prognosis of patients. Cells of the innate immune system, including macrophages, neutrophils, dendritic cells, and mast cells, represent the majority of infiltrating cells during AP. In this review, an overview of different populations of innate immune cells and their role during AP will be discussed, with a special focus on neutrophils and macrophages.
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Affiliation(s)
- Cheng Peng
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Zhiqiang Li
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Xiao Yu
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
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16
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Ding L, Yang Y, Li H, Wang H, Gao P. Circulating Lymphocyte Subsets Induce Secondary Infection in Acute Pancreatitis. Front Cell Infect Microbiol 2020; 10:128. [PMID: 32296650 PMCID: PMC7136471 DOI: 10.3389/fcimb.2020.00128] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 03/09/2020] [Indexed: 12/13/2022] Open
Abstract
Acute pancreatitis (AP) is considered a cascade of immune responses triggered by acinar cell necrosis. AP involves two main processes of systemic inflammatory response syndrome and subsequent compensatory anti-inflammatory response syndrome. Although great efforts have been made regarding AP therapy, the mortality rate of AP remains high. Secondary infection acts a lethal factor in AP. Lymphocytes act as major immune mediators in immune responses in the course of this disease. However, the relationship between lymphocytes and secondary infection in AP is unclear. This review summarizes the variation of lymphocytes and infection in AP. Knowledge of the characterization of circulating lymphocyte abnormalities is relevant for understanding the pathophysiology of AP.
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Affiliation(s)
- Lili Ding
- Department of Intensive Care Unit, The First Hospital of Jilin University, Changchun, China
| | - Yimin Yang
- Department of Intensive Care Unit, The First Hospital of Jilin University, Changchun, China
| | - Hongxiang Li
- Department of Intensive Care Unit, The First Hospital of Jilin University, Changchun, China
| | - Haijiao Wang
- Department of Gynecology Oncology, The First Hospital of Jilin University, Changchun, China
| | - Pujun Gao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, China
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17
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Dynamic Detection of Monocyte Subsets in Peripheral Blood of Patients with Acute Hypertriglyceridemic Pancreatitis. Gastroenterol Res Pract 2019; 2019:5705782. [PMID: 31281350 PMCID: PMC6590588 DOI: 10.1155/2019/5705782] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Accepted: 05/07/2019] [Indexed: 12/27/2022] Open
Abstract
Aim Monocytes play an important role in acute pancreatitis (AP). Hypertriglyceridemic pancreatitis (HTGP) is always more severe than normal lipid-AP, whether the mechanism of aggravation involves monocyte subsets remains unknown though. The present study was aimed to analyze changes of peripheral blood M1 and M2 monocytes in HTGP patients. Methods A total of 90 subjects were enrolled, among which 16 diagnosed with HTGP, 34 with acute biliary pancreatitis (ABP), 20 with hypertriglyceridemia (HTG), and 20 healthy controls (HC). Peripheral blood CD14+CD86+ M1 and CD14+CD206+ M2 monocytes were examined by flow cytometry on days 1, 3, and 7 after admission. Results We found a marked increase in total and M1 monocyte count in AP patients (P < 0.05). In HTGP, the percentage of M1 monocytes in white blood cells was significantly higher on days 1, 3, and 7, while M2 monocyte percentage was decreased on day 3, compared with ABP (P < 0.05). In mild HTGP, M1 monocyte count and percentage gradually decreased, while M2 monocyte percentage gradually increased from day 1 to 7. In severe HTGP, M1 monocyte count and percentage rose to the highest point while M2 were the lowest on day 3. Additionally, the level of M1 monocytes showed a positive correlation with plasma triglyceride and Ranson score of HTGP patients. Conclusions Peripheral blood M1 and M2 monocytes showed different dynamic changes in mild and severe HTGP. A more dominant role of CD14+CD86+ M1 monocytes may be involved in the pathogenesis of HTGP.
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18
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Pu WL, Bai RY, Zhou K, Peng YF, Zhang MY, Hottiger MO, Li WH, Gao XM, Sun LK. Baicalein attenuates pancreatic inflammatory injury through regulating MAPK, STAT 3 and NF-κB activation. Int Immunopharmacol 2019; 72:204-210. [PMID: 30999210 DOI: 10.1016/j.intimp.2019.04.018] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 04/04/2019] [Accepted: 04/08/2019] [Indexed: 02/06/2023]
Abstract
Acute pancreatitis (AP) is a common acute abdominal disease with local or systemic inflammatory response, caused by abnormal activation of digestive enzymes. Baicalein has been shown to exert anti-inflammatory effects and to attenuate the pathological changes of AP. The aim of the research was to investigate the effects of baicalein on caerulein induced pancreatitis, and to elucidate the putative underlying mechanism. In this study, the therapeutic potential of baicalein and its mechanism were investigated in a caerulein-induced AP in vivo and in vitro model. The results indicate that baicalein treatment alleviates the caerulein-induced pathological damage in the pancreas. Baicalein decreased the expression level of pro-inflammatory cytokines and chemokines of the pancreas in caerulein treated mice and of isolated pancreatic acinar cells. Moreover, baicalein inhibited the expression of NF-κB p65 and the phosphorylation of p38 MAPK, ERK (extracellular signal-regulated kinase) as well as STAT 3, which indicates that baicalein exerts its anti-inflammatory effects via dampening the NF-κB, MAPK and STAT 3 signaling pathways. Together, this study provides experimental evidence for the clinical application of Scutellaria baicalensis Georgi or baicalein and indicates that baicalein may be a promising candidate for treatment of AP patients in the future.
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Affiliation(s)
- Wei-Ling Pu
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Ru-Yu Bai
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Kun Zhou
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yan-Fei Peng
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Meng-Ying Zhang
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Micheal O Hottiger
- Department of Molecular Mechanisms of Disease, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
| | - Wen-Hua Li
- College of Medicine, Xizang Minzu University (Tibetan National University), Xianyang 712082, Shaanxi, China
| | - Xiu-Mei Gao
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
| | - Li-Kang Sun
- Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
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Plavsic I, Zitinic I, Tulic V, Poropat G, Marusic M, Hauser G. Early immune response in post endoscopic retrograde cholangiopancreatography pancreatitis as a model for acute pancreatitis. World J Meta-Anal 2019; 7:96-100. [DOI: 10.13105/wjma.v7.i3.96] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 03/27/2019] [Accepted: 03/28/2019] [Indexed: 02/06/2023] Open
Abstract
This opinion review summarizes comparison of clinical presentation and immunology of post-endoscopic pancreatitis and acute pancreatitis (AP) of other etiology. The rationale for this topic was found in studies that mention differences in clinical presentation between these entities, stating that severe form of AP after endoscopic retrograde cholangiopancreatography was more severe than AP of other etiology. Found difference in clinical presentation may have a background in different immunology that needs to be further investigated.
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Affiliation(s)
- Ivana Plavsic
- Department of Anesthesiology and Critical care medicine, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Ivana Zitinic
- Department of Emergency Medicine, Clinical Hospital Centre, Rijeka 51000, Croatia
| | - Vera Tulic
- Department of Anesthesiology and Critical care medicine, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Poropat
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, Medical Faculty Rijeka, University of Rijeka, Rijeka 51000, Croatia
| | - Marinko Marusic
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Sv. Duh, Zagreb, Faculty of Health Studies, University of Rijeka, Rijeka 51000, Croatia
- Medical Faculty Osijek, University of J.J. Stossmayer, Osijek 31000, Croatia
| | - Goran Hauser
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, Faculty of Health Studies, University of Rijeka, Rijeka 51000, Croatia
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Zhao Z, Shen J, Zhang D, Shen J. The Prognostic Role of Peripheral Lymphocyte Subsets in Patients With Acute Pancreatitis. Am J Med Sci 2018; 357:242-246. [PMID: 30797505 DOI: 10.1016/j.amjms.2018.12.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 12/13/2018] [Accepted: 12/19/2018] [Indexed: 01/14/2023]
Abstract
BACKGROUND The prognostic role of peripheral lymphocyte subsets in early stage of acute pancreatitis (AP) is unknown. METHODS After enrollment, blood samples were collected in the first 24 hours of the onset of AP in 164 patients. The lymphocyte count and the percentage of CD3+, CD3+CD4+, CD3+CD8+, CD3-CD19+and CD3-CD (16 + 56)+ cells were assessed. RESULTS Reduction of the lymphocyte count and the percentage of CD3+CD8+ and CD3-CD (16 + 56)+ cells within 24 hours of the onset of AP as well as an increase in the percentage of CD3+ and CD3+CD4+ cells were observed. The percentage of CD3-CD (16 + 56)+ cells had the highest accuracy in prediction of AP severity. CONCLUSIONS Marked changes of the percentages of lymphocyte subset were found in peripheral blood in the early stage of AP. The percentage of CD3-CD (16 + 56)+ cells in peripheral blood could be a potent prognostic predictor.
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Affiliation(s)
- Ziqiang Zhao
- Department of General Surgery, The Fifth People's Hospital of Changshu, Changshu, Jiangsu, China
| | - Jie Shen
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Deqing Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Jiaqing Shen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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Plavsic I, Žitinić I, Mikolasevic I, Poropat G, Hauser G. Endoscopic retrograde cholangiopancreatography-induced and non-endoscopic retrograde cholangiopancreatography-induced acute pancreatitis: Two distinct clinical and immunological entities? World J Gastrointest Endosc 2018; 10:259-266. [PMID: 30364685 PMCID: PMC6198307 DOI: 10.4253/wjge.v10.i10.259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 06/10/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is common gastrointestinal disease of varied aetiology. The most common cause of AP is gallstones, followed by alcohol abuse as an independent risk factor. With the increased need for invasive techniques to treat pancreatic and bile duct pathologies such as endoscopic retrograde cholangiopancreatography (ERCP), AP has emerged as the most frequent complication. While severe AP following ERCP is rare (0.5%), if it does develop it has a greater severity index compared to non-ERCP AP. Development of a mild form of AP after ERCP is not considered a clinically relevant condition. Differences in the clinical presentation and prognosis of the mild and severe forms have been found between non-ERCP AP and post-endoscopic pancreatitis (PEP). It has been proposed that AP and PEP may also have different immunological responses to the initial injury. In this review, we summarise the literature on clinical and inflammatory processes in PEP vs non-ERCP AP.
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Affiliation(s)
- Ivana Plavsic
- Department of Anesthesiology and Critical care medicine, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Ivana Žitinić
- Department of Emergency Medicine, Clinical Hospital Centre, Rijeka 51000, Croatia
| | - Ivana Mikolasevic
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Poropat
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Hauser
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, Faculty of health Studies, University of Rijeka, Rijeka 51000, Croatia
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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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Wang W, Xiang HP, Wang HP, Zhu LX, Geng XP. CD4 + CD25 + CD127 high cells as a negative predictor of multiple organ failure in acute pancreatitis. World J Emerg Surg 2017; 12:7. [PMID: 28174597 PMCID: PMC5290669 DOI: 10.1186/s13017-017-0116-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2016] [Accepted: 01/11/2017] [Indexed: 01/07/2023] Open
Abstract
Background It has been suggested that severity of the immune response induced by immune cells is associated with morbidity and mortality from acute pancreatitis. The authors investigated and evaluated the relationship between distinct peripheral lymphocyte subsets at admission and clinical outcome prior to hospital discharge so as to find a predictor to the prognosis of acute pancreatitis in lymphocyte profile. Methods Lymphocyte subsets in admission peripheral venous blood were tested through flow cytometry on 48 patients with acute pancreatitis. Clinical data was recorded as well. The primary observational outcomes were multiple organ failure (MOF) and infection. Results There was a significant difference in natural killer cells between two subgroups sorted by the presence or absence of infection (25.5 ± 4.47 [95% CI 14.4, 36.6] vs 14.8 ± 7.62 [95% CI 12.5,1 7.1] p = 0.021). Patients who developed MOF had lower CD4 + CD25 + CD127high (4.49 ± 1.5 (MOF) [95% CI 3.83, 5.16] vs 6.57 ± 2.65 (non-MOF) [95% CI 5.5, 7.64] p = 0.002) and higher CD127low/high cell counts (1.35 ± 0.66 [95% CI 1.06, 1.65] vs 0.97 ± 0.44 [95% CI 0.79, 1.15] p = 0.02). MOF patients were significantly older (55 ± 14.58 [95% CI 48.49,61.42] vs 46 ± 15.59 [95% CI 39.39,51.99] p = 0.04), and had higher Acute Physiology and Chronic Health Evaluation IIscores (7 ± 3.66 [95% CI 5.5,7.64] vs 4 ± 2.89 [95% CI 2.45,4.78] p = 0.001) and C reactive protein (100.53 ± 94.38 [95% CI 58.69,142.48] vs 50.8 ± 59.2 [95% CI 26.88,74.71] p = 0.04). In a multivariate regression model, only CD4 + CD25 + CD127high cell was a significant predictor of non-MOF. For the detection of non-MOF, CD4 + CD25 + CD127high cell generated a receiver operating characteristic (ROC) curve with an area under the curve of 0.74. Conclusion CD4 + CD25 + CD127high cell at early phase of acute pancreatitis yields good specificity in detecting non-MOF at a suggested cutoff value 6.41%. Patients with fewer natural killer cells may be at risk in developing secondary infection.
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Affiliation(s)
- Wei Wang
- Department of Emergency Surgery, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601 Anhui Province People's Republic of China
| | - He-Ping Xiang
- Department of Emergency Surgery, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601 Anhui Province People's Republic of China
| | - Hui-Ping Wang
- Hematology department, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601 Anhui Province People's Republic of China
| | - Li-Xin Zhu
- Central lab of the First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui Province People's Republic of China
| | - Xiao-Ping Geng
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601 Anhui Province People's Republic of China
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Schmidt AI, Seifert GJ, Lauch R, Wolff-Vorbeck G, Chikhladze S, Hopt UT, Wittel UA. Organ-specific monocyte activation in necrotizing pancreatitis in mice. J Surg Res 2015; 197:374-81. [DOI: 10.1016/j.jss.2015.03.075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Revised: 03/04/2015] [Accepted: 03/25/2015] [Indexed: 12/11/2022]
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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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Schramm HM. Should EMT of Cancer Cells Be Understood as Epithelial-Myeloid Transition? J Cancer 2014; 5:125-32. [PMID: 24494030 PMCID: PMC3909767 DOI: 10.7150/jca.8242] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 01/02/2014] [Indexed: 12/11/2022] Open
Abstract
Cancer cells express epithelial markers, and when progressing in malignancy they may express markers of the mesenchymal cell type. Therefore an epithelial-mesenchymal transition of the cancer cells is assumed. However the mesenchymal markers can equally well be interpreted as myeloid markers since they are common in both types of cell lineages. Moreover, cancer cells express multiple specific markers of the myeloid lineages thus giving rise to the hypothesis that the transition of cancer cells may be from epithelial to myeloid cells and not to mesenchymal cells. This interpretation would better explain why cancer cells, often already in their primary cancer site, frequently show properties common to those of macrophages, platelets and pre-/osteoclasts.
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Affiliation(s)
- Henning M. Schramm
- Institute Hiscia, Society for Cancer Research, CH-4144 Arlesheim/Switzerland
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Mylona V, Koussoulas V, Tzivras D, Makrygiannis E, Georgopoulou P, Koratzanis G, Giamarellos-Bourboulis EJ, Tzivras MD. Changes in adaptive and innate immunity in patients with acute pancreatitis and systemic inflammatory response syndrome. Pancreatology 2011; 11:475-81. [PMID: 21997439 DOI: 10.1159/000329460] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Accepted: 05/18/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND Acute pancreatitis is a form of inflammation with clinical features ranging from pancreatic inflammation to fatal systemic manifestations. The aim of this study was to clarify changes in lymphocyte subsets and alterations in the functioning of natural killer (NK) cells. PATIENTS AND METHODS Forty-five patients were enrolled into the study; 35 with acute pancreatitis and systemic inflammatory response syndrome (SIRS) and 10 healthy subjects. Blood was sampled early from all patients. Blood immune cells were studied on days 1 and 4 by flow cytometry. Tumor necrosis factor-α (TNFα) and interleukin (IL)-6 were estimated from supernatants of NK cells before/after stimulation with lipopolysaccharide (LPS). RESULTS Apoptosis in patients was significantly different on days 1 and 4 compared with controls. Apoptosis of CD4(+) lymphocytes was significantly correlated with the days to resolution of SIRS (r = +0.586, p = 0.022). Significant differences were observed in TNFα and IL-6 on day 1 with/without LPS stimulation between patients and healthy individuals. Significantly increased levels of TNFα and IL-6 were found after LPS stimulation compared with unstimulated supernatants in day 1. CONCLUSION NK cells altered their secretory status when stimulated with LPS. This finding could be explained by the cellular reprogramming of NK cells in the field of acute pancreatitis and SIRS.
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Affiliation(s)
- Vassiliki Mylona
- Second Department of Internal Medicine, Sismanoglion General Hospital, Athens, Greece.
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Admission levels of soluble CD137 are increased in patients with acute pancreatitis and are associated with subsequent complications. Exp Mol Pathol 2011; 92:1-6. [PMID: 21963611 DOI: 10.1016/j.yexmp.2011.09.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2011] [Accepted: 09/13/2011] [Indexed: 12/15/2022]
Abstract
The progression of acute pancreatitis to necrotizing pancreatitis which often results in high morbidity and mortality is difficult to predict. Here we report that serum concentrations of sCD137 are increased in patients with acute pancreatitis. Admission levels and 10-day median sCD137 levels positively correlate with markers of biliary pancreatitis and the 10-day sCD137 median is significantly higher in metabolic than in alcoholic pancreatitis. Serum concentrations of sCD137 at time of admission and the 10-day median of sCD137 correlate with the Ranson and APACHE II disease scores but not with the radiological Balthazar and Schroeder scores that reflect pancreatic and peripancreatic necrosis. Further, sCD137 levels correlate with the probability of complications and lethality. The association of sCD137, a product of activated T cells, with the severity of acute pancreatitis suggests that T cells contribute to the pathogenesis of acute pancreatitis.
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Usefulness of assessing circulating levels of resistin, ghrelin, and IL-18 in alcoholic acute pancreatitis. Dig Dis Sci 2010; 55:2982-7. [PMID: 20108040 DOI: 10.1007/s10620-009-1106-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Accepted: 12/10/2009] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Acute pancreatitis (AP) is a severe inflammatory disease with high mortality and morbidity rates. We have previously demonstrated that resistin may represent an early marker of inflammation in AP. It was also revealed that ghrelin may have anti-inflammatory potential. However, the role of adipohormones in AP-resistin and ghrelin as well as the proinflammatory cytokine interleukin (IL)-18-has not yet been fully elucidated. METHODS The study group comprised 32 patients with alcoholic AP and 30 controls matched for age, sex, and body mass index (BMI). In all cases AP was classified as grade C according to Balthazar's computed tomography (CT) score and as severe (3 points) according to Ranson's criteria. Serum levels of resistin, ghrelin, and IL-18 were measured on first, third, and fifth day of hospitalization by enzyme-linked immunosorbent assay (ELISA). RESULTS On first day of hospitalization the mean serum resistin concentration in AP patients was significantly higher than in controls (P < 0.05) and further increased on third and fifth day of hospitalization (17.4 ± 4.23 ng/ml and 25.8 ± 8.14 ng/ml, respectively). On first day of hospitalization the mean serum IL-18 concentration in AP patients was significantly higher than in controls (P < 0.05), on third day its level further increased, and on fifth day it decreased to a level similar to that observed on admission. The serum ghrelin concentrations on first, third, and fifth day of hospitalization were comparable, and significantly higher than in controls (P < 0.01). Significant correlation between C-reactive protein (CRP) and resistin levels (r = 0.43; P < 0.05) and between CRP and IL-18 (r = 0.58; P <0.05) on day of admission was found. CONCLUSIONS Serum concentration of IL-18 and resistin may contribute to inflammatory response and may be useful as an early marker of inflammation in AP. We also suspect that ghrelin affects the course of AP and plays an important role in inflammatory response.
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Mylona V, Vaki I, Lymberopoulou K, Marioli A, Georgopoulou A, Lada M, Giamarellos-Bourboulis E, Koratzanis G. Alterations of the immune system in acute pancreatitis and systematic inflammatory response syndrome. Crit Care 2009. [PMCID: PMC4084033 DOI: 10.1186/cc7311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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