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Xia T, Han F, Wang Y, Xie X, Yuan C, Lu G, Xiao W, Tu B, Ren H, Gong W, Wang Y. Inhibition of CD53 Reduces the Formation of ROS-Induced Neutrophil Extracellular Traps and Protects Against Inflammatory Injury in Acute Pancreatitis. J Inflamm Res 2025; 18:3725-3739. [PMID: 40098997 PMCID: PMC11913036 DOI: 10.2147/jir.s507886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 03/04/2025] [Indexed: 03/19/2025] Open
Abstract
Background The tetraspanin CD53 transmembrane protein is vital in immune cells like B cells and T cells, playing a crucial role in various inflammatory conditions. However, its involvement in neutrophils regarding inflammation remains uncertain. This study aims to examine the impact of CD53 on neutrophil extracellular traps (NETs) formation. Methods Phorbol 12-myristate 13-acetate (PMA) was utilized to establish an in vitro classical NETs model to investigate the influence of CD53 on NETs formation and its regulatory mechanisms. Subsequently, the link between CD53 and acute pancreatitis (AP), a model of aseptic inflammatory responses connected to NETs, was verified. Peripheral blood neutrophils from clinical AP patients were collected to explore the role of CD53 in AP, while an AP mouse model induced by caerulein was employed to confirm the impact of CD53 inhibition on AP mice pancreatic tissue. Results Our study has shown that CD53 is significantly elevated in in vitro NETs models and neutrophils from AP patients. The expression of CD53 is closely related to the clinical prognosis of AP patients. At the same time, CD53 neutralizing antibody (Anti-CD53) can significantly inhibit the formation of NETs in vitro, inflammatory injury in AP mice and the formation of NETs in damaged tissues. Mechanistically, CD53 can modulate the PI3K/AKT pathway and promote the formation of NETs. Finally, targeted regulation of CD53 can effectively reduce inflammatory injury and NETs formation in damaged tissues of AP mice. Conclusion The results of this study mark the first confirmation that CD53 plays a crucial role in NETs formation. Targeting CD53 inhibition could potentially serve as a novel therapeutic approach for the treatment of AP.
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Affiliation(s)
- Tianqi Xia
- Pancreatic Center, Department of Gastroenterology, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
- Yangzhou Key Laboratory of Pancreatic Disease, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
| | - Fei Han
- Pancreatic Center, Department of Gastroenterology, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
- Yangzhou Key Laboratory of Pancreatic Disease, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
| | - Yaning Wang
- Pancreatic Center, Department of Gastroenterology, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
- Yangzhou Key Laboratory of Pancreatic Disease, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
| | - Xinyue Xie
- Pancreatic Center, Department of Gastroenterology, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
- Yangzhou Key Laboratory of Pancreatic Disease, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
| | - Chenchen Yuan
- Pancreatic Center, Department of Gastroenterology, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
- Yangzhou Key Laboratory of Pancreatic Disease, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
| | - Guotao Lu
- Pancreatic Center, Department of Gastroenterology, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
- Yangzhou Key Laboratory of Pancreatic Disease, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
| | - Weiming Xiao
- Pancreatic Center, Department of Gastroenterology, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
- Yangzhou Key Laboratory of Pancreatic Disease, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
| | - Bo Tu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Hongbo Ren
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, People's Republic of China
| | - Weijuan Gong
- Pancreatic Center, Department of Gastroenterology, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
- Yangzhou Key Laboratory of Pancreatic Disease, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People's Republic of China
| | - Yaodong Wang
- Department of Gastroenterology, Kunshan Hospital of Traditional Chinese Medicine, Suzhou Key Laboratory of Integrated Traditional Chinese and Western Medicine of Digestive Diseases, Kunshan Affiliated Hospital of Yangzhou University, Kunshan, 215300, People's Republic of China
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Wang H, Ma L, Su W, Liu Y, Xie N, Liu J. NLRP3 inflammasome in health and disease (Review). Int J Mol Med 2025; 55:48. [PMID: 39930811 PMCID: PMC11781521 DOI: 10.3892/ijmm.2025.5489] [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: 09/19/2024] [Accepted: 12/16/2024] [Indexed: 02/13/2025] Open
Abstract
Activation of inflammasomes is the activation of inflammation‑related caspase mediated by the assembly signal of multi‑protein complex and the maturity of inflammatory factors, such as IL‑1β and IL‑18. Among them, the Nod‑like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most thoroughly studied type of inflammatory corpuscle at present, which is involved in the occurrence and development of numerous human diseases. Therefore, targeting the NLRP3 inflammasome has become the focus of drug development for related diseases. In this paper, the research progress of the NLRP3 inflammasome in recent years is summarized, including the activation and regulation of NLRP3 and its association with diseases. A deep understanding of the regulatory mechanism of NLRP3 will be helpful to the discovery of new drug targets and the development of therapeutic drugs.
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Affiliation(s)
- Haoran Wang
- Department of Orthopaedics, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, P.R. China
| | - Li Ma
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Weiran Su
- Department of Internal Medicine, Jiading District Central Hospital, Shanghai 201800, P.R. China
| | - Yangruoyu Liu
- Department of Orthopaedics, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, P.R. China
| | - Ning Xie
- Department of Orthopaedics, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, P.R. China
| | - Jun Liu
- Department of Orthopaedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
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Wu CY, Wang KQ, Qin YY, Wang HW, Wu MM, Zhu XD, Lu XY, Zhu MM, Lu CS, Hu QQ. Micheliolide ameliorates severe acute pancreatitis in mice through potentiating Nrf2-mediated anti-inflammation and anti-oxidation effects. Int Immunopharmacol 2024; 143:113490. [PMID: 39467351 DOI: 10.1016/j.intimp.2024.113490] [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: 09/22/2024] [Revised: 10/19/2024] [Accepted: 10/21/2024] [Indexed: 10/30/2024]
Abstract
Severe acute pancreatitis (SAP) is an acute inflammatory injury disease with significant mortality rate and currently without effective strategy being available. Inflammation and oxidative stress play central roles in the etiology of SAP. Micheliolide (MCL), an active monomeric component isolated from Michelia champaca, has been proved its multiple therapeutic properties including anti-inflammatory, antioxidant and anti-cancer. Nevertheless, the therapeutic effect and underlying mechanism of MCL in SAP still remain unclear. Here, we found that caerulein with lipopolysaccharide (LPS)-induced SAP murine models exhibited severe pancreatic injury, including necrosis, edema, and vacuolation of acinar cells in the pancreas, elevated serum levels of amylase and lipase, and reduced number of the exocrine cells. As expected, MCL treatment alleviated these side effects. Mechanistically, MCL triggered nuclear factor erythroid 2-related factor 2 (Nrf2) activation, thereby activating Nrf2-regulated antioxidative pathways and inhibiting nuclear factor kappa B p65 (NF-κB p65)-mediated inflammatory response, resulting in protection against pancreatic injury in SAP mice. In addition, Nrf2 gene deficiency abolished the beneficial effects of MCL on SAP-induced pancreatic inflammation and oxidative stress and blocked the ability of MCL to alleviate the pancreatic injury in SAP mice. Collectively, these findings indicated that the suppression of SAP-induced pancreatic injury by MCL was at least in part due to Nrf2-mediated anti-oxidation effect and inhibition of inflammation.
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Affiliation(s)
- Chen-Yu Wu
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Ke-Qi Wang
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Yu-Ying Qin
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Hong-Wei Wang
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Min-Min Wu
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Xian-Dong Zhu
- Department of Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Xin-Yu Lu
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; The First Clinical Medical College of Wenzhou Medical University, Wenzhou 325000, China
| | - Mian-Mian Zhu
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Chao-Sheng Lu
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
| | - Qing-Qing Hu
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
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Yang L, He C, Wang W. Association between neutrophil to high-density lipoprotein cholesterol ratio and disease severity in patients with acute biliary pancreatitis. Ann Med 2024; 56:2315225. [PMID: 38335727 PMCID: PMC10860409 DOI: 10.1080/07853890.2024.2315225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 02/02/2024] [Indexed: 02/12/2024] Open
Abstract
BACKGROUND The neutrophil to high-density lipoprotein cholesterol ratio (NHR) is independently associated with the severity of various diseases. However, its association with acute biliary pancreatitis (ABP) remains unknown. METHODS This study included 1335 eligible patients diagnosed with ABP from April 2016 to December 2022. Patients were divided into low- and high-NHR level groups using an optimal cut-off value determined utilizing Youden's index. Multivariate logistic regression analysis was used to investigate the correlation between NHR and ABP severity. Multivariate analysis-based limited restricted cubic spline (RCS) method was used to evaluate the nonlinear relationship between NHR and the risk of developing moderate or severe ABP. RESULTS In this study, multivariate logistic regression analysis indicated an independent association between NHR and ABP severity (p < .001). The RCS analysis showed a linear correlation between NHR and the risk of developing moderate or severe ABP (P for non-linearity > 0.05), and increased NHR was found to be independently associated with a more severe form of the disease. CONCLUSIONS Our study suggests that NHR is a simple and practical independent indicator of disease severity, serving as a potential novel predictor for patients with ABP.
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Affiliation(s)
- Lin Yang
- Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Chiyi He
- Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Wei Wang
- Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
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Papantoniou K, Aggeletopoulou I, Michailides C, Pastras P, Triantos C. Understanding the Role of NLRP3 Inflammasome in Acute Pancreatitis. BIOLOGY 2024; 13:945. [PMID: 39596901 PMCID: PMC11592098 DOI: 10.3390/biology13110945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 10/31/2024] [Accepted: 11/14/2024] [Indexed: 11/29/2024]
Abstract
Acute pancreatitis (AP) remains a serious clinical condition, with current treatment options being largely supportive. The discovery of inflammasomes, particularly the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, has significantly advanced our knowledge regarding many inflammatory diseases' pathogenesis, including AP. The NLRP3 inflammasome is central in mediating the inflammatory process in AP through its diverse activation mechanisms and its involvement in multiple signal transduction pathways. This has made NLRP3 an appealing target for novel therapeutic strategies aimed at modulating inflammation in AP. Despite the growing interest in NLRP3 as a therapeutic target, there remains a notable gap in clinical research, with few clinical trials exploring the efficacy of NLRP3 inhibitors in AP. Results of several preclinical studies and animal models are promising and suggest that the use of NLRP3 inhibitors could result in reduced inflammation and improved patient outcomes in AP. Further research is urgently needed to assess their potential benefits, safety, and applicability in human patients and address the underlying inflammatory processes driving AP.
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Affiliation(s)
- Konstantinos Papantoniou
- Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (K.P.); (C.M.)
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (P.P.)
| | - Christos Michailides
- Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (K.P.); (C.M.)
| | - Ploutarchos Pastras
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (P.P.)
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (P.P.)
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6
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Kim RJ, Bishir M, Chang SL. Network meta-analysis on the mechanisms underlying alcohol augmentation of acute pancreatitis and diabetes type II. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2024; 48:1837-1852. [PMID: 39251378 DOI: 10.1111/acer.15428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/05/2024] [Accepted: 08/06/2024] [Indexed: 09/11/2024]
Abstract
BACKGROUND Pancreatitis is a severe inflammatory pathology that occurs from pancreatic duct and exocrine acinar injury, leading to improper secretion of digestive enzymes, auto-digestion of the pancreas, and subsequent inflammation. Clinical reports show that 60%-90% of pancreatitis patients have a history of chronic alcohol use. More recent studies reveal that exocrine pancreas disorders like acute pancreatitis can precede diabetes type II onset, though mechanisms are not yet fully known. This study identified molecules and key signaling pathways underlying alcohol-induced acute pancreatitis and their effects on diabetes type II onset. METHODS Data on human peripheral blood samples with or without acute pancreatitis were retrieved from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (accession number GSE194331). Acute pancreatitis-mediated differentially expressed genes (DEGs) were generated from GSE194331 using CLC Genomics Workbench 12. Molecules associated with ethanol (EtOH), acute pancreatitis, and diabetes type II were collected from QIAGEN Knowledge Base (QKB). The relationship between the molecules and signaling pathways associated with EtOH, acute pancreatitis, or diabetes type II was examined using various Ingenuity Pathway Analysis (IPA) tools. RESULTS Our investigation showed that acute pancreatitis-mediated DEGs were closely associated with EtOH by revealing that EtOH-induced acute pancreatitis appears to lead to the onset of diabetes type II. We found that diabetes type II onset was mediated by pro-inflammatory and metabolic mechanisms underlying EtOH-induced acute pancreatitis, involving increased expression of cytokines including macrophage migration inhibitory factor (MIF), and decreased expression of hormones such as insulin. CONCLUSIONS Exposure to alcohol may promote diabetes type II by affecting the activity of key inflammatory and metabolic mediators involved in acute pancreatitis. These findings call for further investigation into the role of pro-inflammatory and metabolic mediators like resistin, IL-6, and insulin in EtOH-induced diabetes type II associated with acute pancreatitis pathologies.
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Affiliation(s)
- Ryan J Kim
- Institute of NeuroImmune Pharmacology (INIP), Seton Hall University, South Orange, New Jersey, USA
- Department of Biological Sciences, Seton Hall University, South Orange, New Jersey, USA
| | - Muhammed Bishir
- Institute of NeuroImmune Pharmacology (INIP), Seton Hall University, South Orange, New Jersey, USA
- Department of Biological Sciences, Seton Hall University, South Orange, New Jersey, USA
| | - Sulie L Chang
- Institute of NeuroImmune Pharmacology (INIP), Seton Hall University, South Orange, New Jersey, USA
- Department of Biological Sciences, Seton Hall University, South Orange, New Jersey, USA
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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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Oliver L, Liu C, Sadowski B. A Case of Recurrent Liver Injury-Associated Acute Pancreatitis (LIAAP). Cureus 2024; 16:e65272. [PMID: 39184768 PMCID: PMC11343480 DOI: 10.7759/cureus.65272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 08/27/2024] Open
Abstract
Many etiologies of acute liver injury (ALI) include drug-induced liver injury (DILI), viral illness, and autoimmune disease. Acute pancreatitis is an uncommon though significant etiology of ALI caused by inflammation, fluid shifts, and ischemia secondary to microthrombi formation that can progress to liver failure if left untreated. We present a case of hypertriglyceridemia-induced pancreatitis resulting in liver injury-associated acute pancreatitis (LIAAP) and a concurrent consumptive coagulopathy consistent with an ischemic hepatopathy. Through treatment of her pancreatitis with intravenous insulin and plasmapheresis and subsequent transition to an oral regimen for her hypertriglyceridemia upon hospital discharge, the patient demonstrated full resolution of her ALI and coagulopathy. Through this case, we hope to highlight the importance of recognizing LIAAP and its underlying pathogenesis.
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Affiliation(s)
- Logan Oliver
- Internal Medicine, Naval Medical Center San Diego, San Diego, USA
| | - Chuchu Liu
- Gastroenterology, Naval Medical Center San Diego, San Diego, USA
| | - Brett Sadowski
- Gastroenterology, Naval Medical Center San Diego, San Diego, USA
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Xu MS, Xu JL, Gao X, Mo SJ, Xing JY, Liu JH, Tian YZ, Fu XF. Clinical study of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in hypertriglyceridemia-induced acute pancreatitis and acute biliary pancreatitis with persistent organ failure. World J Gastrointest Surg 2024; 16:1647-1659. [PMID: 38983313 PMCID: PMC11230014 DOI: 10.4240/wjgs.v16.i6.1647] [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: 02/03/2024] [Revised: 03/10/2024] [Accepted: 05/14/2024] [Indexed: 06/27/2024] Open
Abstract
BACKGROUND The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are novel inflammatory indicators that can be used to predict the severity and prognosis of various diseases. We categorize acute pancreatitis by etiology into acute biliary pancreatitis (ABP) and hypertriglyceridemia-induced acute pancreatitis (HTGP). AIM To investigate the clinical significance of NLR and PLR in assessing persistent organ failure (POF) in HTGP and ABP. METHODS A total of 1450 patients diagnosed with acute pancreatitis (AP) for the first time at Shanxi Bethune Hospital between January 2012 and January 2023 were enrolled. The patients were categorized into two groups according to the etiology of AP: ABP in 530 patients and HTGP in 241 patients. We collected and compared the clinical data of the patients, including NLR, PLR, and AP prognostic scoring systems, within 48 h of hospital admission. RESULTS The NLR (9.1 vs 6.9, P < 0.001) and PLR (203.1 vs 160.5, P < 0.001) were significantly higher in the ABP group than in the HTGP group. In the HTGP group, both NLR and PLR were significantly increased in patients with severe AP and those with a SOFA score ≥ 3. Likewise, in the ABP group, NLR and PLR were significantly elevated in patients with severe AP, modified computed tomography severity index score ≥ 4, Japanese Severity Score ≥ 3, and modified Marshall score ≥ 2. Moreover, NLR and PLR showed predictive value for the development of POF in both the ABP and HTGP groups. CONCLUSION NLR and PLR vary between ABP and HTGP, are strongly associated with AP prognostic scoring systems, and have predictive potential for the occurrence of POF in both ABP and HTGP.
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Affiliation(s)
- Mu-Sen Xu
- The Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, Shanxi Province, China
| | - Jia-Le Xu
- The Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, Shanxi Province, China
| | - Xin Gao
- Department of Environmental Health, School of Public Health, Shanxi Medical University, Taiyuan 030032, Shanxi Province, China
| | - Shao-Jian Mo
- The Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, Shanxi Province, China
| | - Jia-Yu Xing
- The Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, Shanxi Province, China
| | - Jia-Hang Liu
- The Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, Shanxi Province, China
| | - Yan-Zhang Tian
- The Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, Shanxi Province, China
| | - Xi-Feng Fu
- The Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, Shanxi Province, China
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11
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Yu NJ, Li XH, Liu C, Chen C, Xu WH, Chen C, Chen Y, Liu TT, Chen TW, Zhang XM. Radiomics models of contrast-enhanced computed tomography for predicting the activity and prognosis of acute pancreatitis. Insights Imaging 2024; 15:158. [PMID: 38902394 PMCID: PMC11190132 DOI: 10.1186/s13244-024-01738-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 06/02/2024] [Indexed: 06/22/2024] Open
Abstract
BACKGROUND The modified pancreatitis activity scoring system (mPASS) was proposed to assess the activity of acute pancreatitis (AP) while it doesn't include indicators that directly reflect pathophysiology processes and imaging characteristics. OBJECTIVES To determine the threshold of admission mPASS and investigate radiomics and laboratory parameters to construct a model to predict the activity of AP. METHODS AP inpatients at institution 1 were randomly divided into training and validation groups based on a 5:5 ratio. AP inpatients at Institution 2 were served as test group. The cutoff value of admission mPASS scores in predicting severe AP was selected to divide patients into high and low level of disease activity group. LASSO was used in screening features. Multivariable logistic regression was used to develop radiomics model. Meaningful laboratory parameters were used to construct combined model. RESULTS There were 234 (48 years ± 10, 155 men) and 101 (48 years ± 11, 69 men) patients in two institutions. The threshold of admission mPASS score was 112.5 in severe AP prediction. The AUC of the radiomics model was 0.79, 0.72, and 0.76 and that of the combined model incorporating rad-score and white blood cell were 0.84, 0.77, and 0.80 in three groups for activity prediction. The AUC of the combined model in predicting disease without remission was 0.74. CONCLUSIONS The threshold of admission mPASS was 112.5 in predicting severe AP. The model based on CECT radiomics has the ability to predict AP activity. Its ability to predict disease without remission is comparable to mPASS. CRITICAL RELEVANCE STATEMENT This work is the first attempt to assess the activity of acute pancreatitis using contrast-enhanced CT radiomics and laboratory parameters. The model provides a new method to predict the activity and prognosis of AP, which could contribute to further management. KEY POINTS Radiomics features and laboratory parameters are associated with the activity of acute pancreatitis. The combined model provides a new method to predict the activity and prognosis of AP. The ability of the combined model is comparable to the modified Pancreatitis Activity Scoring System.
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Affiliation(s)
- Ning Jun Yu
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, No.1 South Maoyuan Road, Nanchong, 637001, Sichuan, China
| | - Xing Hui Li
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, No.1 South Maoyuan Road, Nanchong, 637001, Sichuan, China
| | - Chao Liu
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, No.1 South Maoyuan Road, Nanchong, 637001, Sichuan, China
| | - Chao Chen
- Department of Radiology, The Second Clinical Medical College of North Sichuan Medical College Nanchong Central Hospital, Nanchong, Sichuan, China
| | - Wen Han Xu
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, No.1 South Maoyuan Road, Nanchong, 637001, Sichuan, China
| | - Chao Chen
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, No.1 South Maoyuan Road, Nanchong, 637001, Sichuan, China
| | - Yong Chen
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ting Ting Liu
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, No.1 South Maoyuan Road, Nanchong, 637001, Sichuan, China
| | - Tian Wu Chen
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, No.1 South Maoyuan Road, Nanchong, 637001, Sichuan, China
| | - Xiao Ming Zhang
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, No.1 South Maoyuan Road, Nanchong, 637001, Sichuan, China.
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12
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Yang DJ, Chen KL, Lv ZY, Zhou B, Zhou ZG, Li Y. PD-L1 blockade in mitigating severe acute pancreatitis induced pancreatic damage through modulation of immune cell apoptosis. Int Immunopharmacol 2024; 133:112081. [PMID: 38652963 DOI: 10.1016/j.intimp.2024.112081] [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: 01/04/2024] [Revised: 04/07/2024] [Accepted: 04/10/2024] [Indexed: 04/25/2024]
Abstract
Acute pancreatitis (AP) is a prevalent gastrointestinal disorder. The immune response plays a crucial role in AP progression. However, the impact of immune regulatory checkpoint PD-L1 on severe acute pancreatitis (SAP) remains uncertain. Hence, this study aimed to examine the influence of PD-L1 on SAP. We assessed PD-L1 expression in neutrophils and monocytes obtained from SAP patients. We induced SAP in C57BL/6J mice, PD-L1 gene-deficient mice, and PD-L1 humanized mice using intraperitoneal injections of cerulein plus lipopolysaccharide. Prior to the initial cerulein injection, a PD-L1 inhibitor was administered. Pancreatic tissues were collected for morphological and immunohistochemical evaluation, and serum levels of amylase, lipase, and cytokines were measured. Flow cytometry analysis was performed using peripheral blood cells. The expression of PD-L1 in neutrophils and monocytes was significantly higher in SAP patients compared to healthy individuals. Likewise, the expression of PD-L1 in inflammatory cells in the peripheral blood of SAP-induced C57BL/6J mice was notably higher than in the control group. In mice with PD-L1 deficiency, SAP model exhibited lower pancreatic pathology scores, amylase, lipase, and cytokine levels compared to wild-type mice. PD-L1 deletion resulted in reduced neutrophil apoptosis, leading to an earlier peak in neutrophil apoptosis. Furthermore, it decreased early monocyte apoptosis and diminished the peak of T lymphocyte apoptosis. Within the SAP model, administration of a PD-L1 inhibitor reduced pancreatic pathology scores, amylase, lipase, and cytokine levels in both C57BL/6J mice and PD-L1 humanized mice. These findings suggest that inhibiting PD-L1 expression can alleviate the severity of SAP.
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Affiliation(s)
- Du-Jiang Yang
- Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 1 Ke-yuan-si-lu, Chengdu 610093, Sichuan Province, China; Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu 610041, Sichuan Province, China
| | - Ke-Ling Chen
- Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 1 Ke-yuan-si-lu, Chengdu 610093, Sichuan Province, China
| | - Zhao-Ying Lv
- Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 1 Ke-yuan-si-lu, Chengdu 610093, Sichuan Province, China
| | - Bin Zhou
- Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 1 Ke-yuan-si-lu, Chengdu 610093, Sichuan Province, China
| | - Zong-Guang Zhou
- Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 1 Ke-yuan-si-lu, Chengdu 610093, Sichuan Province, China
| | - Yuan Li
- Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 1 Ke-yuan-si-lu, Chengdu 610093, Sichuan Province, China.
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13
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Hagar HH, Alhazmi SM, Arafah M, Bayoumy NM. Inhibition of sepsis-induced pancreatic injury by leukotriene receptor antagonism via modulation of oxidative injury, and downregulation of inflammatory markers in experimental rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:3425-3435. [PMID: 37962585 DOI: 10.1007/s00210-023-02812-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 10/22/2023] [Indexed: 11/15/2023]
Abstract
The purpose of this study is to investigate the effect of montelukast on lipopolysaccharide (LPS)-induced pancreatitis. Adult male Wistar rats were divided into 5 groups: normal control, control montelukast, LPS group, and two LPS + montelukast-treated groups. Acute pancreatitis (AP) was induced by a single dose of LPS (6 mg/kg, i.p.), while montelukast was given in two different doses (10 and 20 mg/kg/day) for 3 consecutive days prior to the injection of LPS. AP was demonstrated by significant increases in serum levels of lactate dehydrogenase (LDH) and pancreatic enzymes lipase and amylase. Proinflammatory response activation was evident by elevated serum levels of nitric oxide (NO) and increased pancreatic concentrations of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), and intercellular adhesion molecule-1 (ICAM-1). The activity of myeloperoxidase (MPO), a neutrophil infiltration marker, has also been increased. Oxidative stress was confirmed by significant increases in the concentrations of lipid peroxides measured as thiobarbituric acid reactive substances (TBARS) and decreases in the concentrations of reduced glutathione (GSH) in the pancreatic tissues of animals treated with LPS. Histological examination confirmed the biochemical alterations. Montelukast treatment reversed all these biochemical indices and histopathological changes that LPS induced. Montelukast reduced the increase in serum levels of lipase, amylase, LDH, total nitrite/nitrate, TNF-α, IL-1β, and ICAM-1. MPO activities and TBARS concentrations were also suppressed while GSH content was increased in pancreatic tissues. These results show that montelukast may be a beneficial pharmacological agent in protection against LPS-induced oxidative pancreatic injury by inhibiting neutrophil infiltration, counteracting oxidative stress, and suppressing inflammatory mediators.
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Affiliation(s)
- Hanan H Hagar
- Department of Physiology, College of Medicine & King Khalid University Hospital, King Saud University, P.O. BOX 2925, Riyadh, 11461, Saudi Arabia.
| | - Shaima M Alhazmi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Maha Arafah
- Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Nervana Mustafa Bayoumy
- Department of Physiology, College of Medicine & King Khalid University Hospital, King Saud University, P.O. BOX 2925, Riyadh, 11461, Saudi Arabia
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14
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Sahin A. Neutrophil-Creatinine Index: A New Prognostic Factor for Severity of Acute Pancreatitis. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:607. [PMID: 38674253 PMCID: PMC11051984 DOI: 10.3390/medicina60040607] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 03/28/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024]
Abstract
Background and Objectives: Determining the severity of acute pancreatitis (AP) is the main goal in the early stage of AP. The aim of this study was to compare laboratory parameters and indices, including the neutrophil to lymphocyte ratio (NLR) and the neutrophil-creatinine index (NCI), at admission in order to predict the severity of AP. Materials and Methods: Data from 421 patients who were admitted with a diagnosis of AP were collected retrospectively. Disease severity was assessed using the Bedside Index of Severity in Acute Pancreatitis (BISAP) and the revised Atlanta classification (RAC). BISAP was graded as mild and severe, and RAC was graded as mild (MAP), moderately severe (MSAP), and severe (SAP). The laboratory parameters and indices, including the NLR and NCI, were compared. Results: Of the patients, 70 (16.6%) had severe AP according to BISAP; the AP subgroups according to the RAC were as follows: MAP (n = 213), MSAP (n = 158), and SAP (n = 50). The NCI had the highest area under the receiver operator characteristic (AUROC) curve value (0.862), demonstrating severe disease according to BISAP, with a sensitivity of 78.6% and a specificity of 79.8%. Age (OR:1.046), white blood cell count (WBC) (OR:1.141), hematocrit (OR:1.081), blood urea nitrogen (BUN) (OR:1.040), and NCI (OR:1.076) were independently associated with severe disease, according to the multivariate analysis results, and were determined as components of the newly developed nomogram. The AUROC of the nomogram (0.891) was superior to the AUROCs of all the components of the nomogram except the NCI. Moreover, the NCI was the only parameter to distinguish MSAP from MAP (OR:1.119, 95% CI: 1.015-1.235, p = 0.023) and SAP from MSAP (OR:1.095, 95% CI: 1.031-1.162, p = 0.003). Conclusions: The present study enabled the identification of the neutrophil-creatinine index as a new prognostic tool for the assessment of AP severity at hospital admission.
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Affiliation(s)
- Abdurrahman Sahin
- Gastroenterology Department, Faculty of Medicine, Tokat Gaziosmanpasa University, 60030 Tokat, Turkey
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15
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Ishqi HM, Ali M, Dawra R. Recent advances in the role of neutrophils and neutrophil extracellular traps in acute pancreatitis. Clin Exp Med 2023; 23:4107-4122. [PMID: 37725239 DOI: 10.1007/s10238-023-01180-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 08/28/2023] [Indexed: 09/21/2023]
Abstract
Pancreatitis is an inflammatory disease, which is triggered by adverse events in acinar cells of the pancreas. After the initial injury, infiltration of neutrophils in pancreas is observed. In the initial stages of pancreatitis, the inflammation is sterile. It has been shown that the presence of neutrophils at the injury site can modulate the disease. Their depletion in experimental animal models of the acute pancreatitis has been shown to be protective. But information on mechanism of contribution to inflammation by neutrophils at the injury site is not clear. Once at injury site, activated neutrophils release azurophilic granules containing proteolytic enzymes and generate hypochlorous acid which is a strong microbicidal agent. Additionally, emerging evidence shows that neutrophil extracellular traps (NETs) are formed which consist of decondensed DNA decorated with histones, proteases and granular and cytosolic proteins. NETs are considered mechanical traps for microbes, but there is preliminary evidence to indicate that NETs, which constitute a special mechanism of the neutrophil defence system, play an adverse role in pancreatitis by contributing to the pancreatic inflammation and distant organ injury. This review presents the overall current information about neutrophils and their role including NETs in acute pancreatitis (AP). It also highlights current gaps in knowledge which should be explored to fully elucidate the role of neutrophils in AP and for therapeutic gains.
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Affiliation(s)
- Hassan Mubarak Ishqi
- Department of Surgery and Sylvester Comprehensive Cancer Centre, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Misha Ali
- Department of Radiation Oncology and Sylvester Comprehensive Cancer Centre, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Rajinder Dawra
- Department of Surgery and Sylvester Comprehensive Cancer Centre, Miller School of Medicine, University of Miami, Miami, FL, USA.
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16
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Xu Q, Shi M, Ding L, Xia Y, Luo L, Lu X, Zhang X, Deng DYB. High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca 2+/PAD4 pathway to exacerbate acute pancreatitis. Front Immunol 2023; 14:1265344. [PMID: 37841279 PMCID: PMC10568494 DOI: 10.3389/fimmu.2023.1265344] [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: 07/22/2023] [Accepted: 09/11/2023] [Indexed: 10/17/2023] Open
Abstract
Background Excessive neutrophil extracellular traps (NETs) is involved in the progression of acute pancreatitis (AP) but the mechanisms controlling NETs formation in AP are not fully understood. Therefore, our study sought to investigate the mechanism of the highly expressed P-selectin stimulating the formation of NETs in AP. Methods NETs formation was detected by flow cytometry, immunofluorescence staining, and cf-DNA and MPO-DNA complexes were measured as biomarkers of NETs formation. Neutrophils treated with P-selectin and pharmacological inhibitors were examined by western blot, immunofluorescence staining and flow cytometry. Mouse model of AP was established by caerulein and the effect of inhibiting P-selectin by PSI-697 on the level of NETs and PAD4 in pancreatic tissue was observed. The severity of AP was evaluated by histopathological score and the detection of serum amylase and lipase. Results Patients with AP had elevated levels of NETs and P-selectin compared with healthy volunteers. Stimulation of P-selectin up-regulated the expression of PSGL-1, increased the phosphorylation of Syk, mediated intracellular calcium signal and led to the activation and expression of PAD4, which modulated NETs formation in neutrophils. Pretreament with PSI-697 blunted NETs formation and PAD4 expression in the pancreatic tissue, and ameliorated the severity of AP in mice. Conclusion Taken together, these results suggest that P-selectin induces NETs through PSGL-1 and its downstream Syk/Ca2+/PAD4 signaling pathway, and that targeting this pathway might be a promising strategy for the treatment of AP.
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Affiliation(s)
- Qi Xu
- Department of Scientific Research Center, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Ming Shi
- Department of Scientific Research Center, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Lu Ding
- Department of Scientific Research Center, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Yu Xia
- Department of Scientific Research Center, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Liang Luo
- Department of Critical Care Medicine, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Xiaofang Lu
- Department of Pathology, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Xiaoying Zhang
- Department of Health Management Center, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - David Y. B. Deng
- Department of Scientific Research Center, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
- Department of Critical Care Medicine, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
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17
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Chen K, Zhang Z, Fang Z, Zhang J, Liu Q, Dong W, Liu Y, Wang Y, Wang J. Aged-Signal-Eliciting Nanoparticles Stimulated Macrophage-Mediated Programmed Removal of Inflammatory Neutrophils. ACS NANO 2023; 17:13903-13916. [PMID: 37458397 DOI: 10.1021/acsnano.3c03815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
Excessive infiltration of activated neutrophils is regarded as a predominant cause of tissue injury in neutrophilic inflammation. Although programmed cell death like apoptosis maintains the homeostasis of activated neutrophils, this process is disrupted by an abnormal inflammatory response. Unlike endogenous calreticulin exposed during apoptosis, exogenous calreticulin acts as an "aged" signal and initiates premature macrophage-mediated programmed cell removal (PrCR), which is independent of apoptosis. Here, we report a nano-mediated strategy to stimulate the precise clearance of activated neutrophils initiated with artificial aged signal and alleviated inflammation. Polymeric nanoparticles PC@PLGA were fabricated by cloaking poly(lactic-co-glycolic acid) (PLGA) with a hybrid membrane derived from platelet-derived extracellular vesicles (PEVs, denoted by P) and the calreticulin-expressed membrane obtained from doxorubicin-treated cells (denoted by C). P-selectin in PEVs favors PC@PLGA to anchor activated neutrophils, while calreticulin mimics exogenous "aged" signal secreted by macrophages to trigger PrCR. We showed that PC@PLGA specifically targeted activated neutrophils and misled macrophages to recognize them as "aged" neutrophils and then initiated premature PrCR and prevented proinflammatory response and tissue damage in a mouse model of acute lung injury and severe acute pancreatitis. The collective findings indicate the efficiency of specific elimination of activated neutrophils with exogenous aged signal in improving inflammation therapy.
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Affiliation(s)
- Kaige Chen
- Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
- Intelligent Nanomedicine Institute, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Zheng Zhang
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 511442, China
| | - Ziyuan Fang
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Jiachen Zhang
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Qian Liu
- Intelligent Nanomedicine Institute, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
| | - Wang Dong
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Yang Liu
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Yucai Wang
- Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
- Intelligent Nanomedicine Institute, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Jun Wang
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 511442, China
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Ling X, Nie C, Sheng LP, Han CQ, Ding Z. Disulfiram relieves severe acute pancreatitis by inhibiting GSDMD-dependent NETs formation. J Dig Dis 2023; 24:359-368. [PMID: 37503822 DOI: 10.1111/1751-2980.13211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 06/18/2023] [Accepted: 07/25/2023] [Indexed: 07/29/2023]
Abstract
OBJECTIVES Severe acute pancreatitis (SAP) is characterized by pancreatic and systemic inflammation and persistent organ failure. Neutrophil extracellular traps (NETs) are considered to play an important role in the development of SAP. We aimed to explore the effect of disulfiram (DSL), a newly developed anti-inflammatory drug, on NETs in SAP. METHODS A mouse model of SAP was induced by caerulein and lipopolysaccharide, and the mice were divided into the normal control group, the DSL group, the SAP group, and the SAP treated with 50 mg/kg (50DSLSAP) and 100 mg/kg DSL (100DSLSAP) groups, respectively. The severity of SAP was evaluated based on the morphological and biochemical changes. Gasdermin D (GSDMD) expression was evaluated in vivo and in vitro to verify the effect of DSL. Additionally, the expressions of NETs were also evaluated in vivo and in vitro in SAP with and without DSL treatment to explore the possible mechanism of DSL on SAP. RESULTS Pancreatic inflammatory injury increased in the SAP group, which was alleviated by DSL. GSDMD, a protein related to the formation of NETs, increased in SAP. Expressions of NETs were also promoted in the in vivo SAP model and by phorbol myristate acetate (PMA) in vitro. Moreover, DSL inhibited the expressions of GSDMD and NETs in vivo. The results were further confirmed in the in vitro experiment. CONCLUSIONS NETs are highly associated with inflammatory injury in SAP. DSL inhibits NETs formation by downregulating GSDMD, which in turn relieves the inflammation of SAP. Our study may provide a possible therapeutic target for SAP.
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Affiliation(s)
- Xin Ling
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Chi Nie
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Li Ping Sheng
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Chao Qun Han
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Zhen Ding
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
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Hu Q, Tao R, Hu X, Wu H, Xu J. Effects of piperlonguminine on lung injury in severe acute pancreatitis <em>via</em> the TLR4/NF-κB pathway. Eur J Histochem 2023; 67. [PMID: 36951266 PMCID: PMC10080291 DOI: 10.4081/ejh.2023.3639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 03/03/2023] [Indexed: 03/24/2023] Open
Abstract
Acute pancreatitis is an inflammatory response in the pancreas, involving activation of pancreatic enzymes. Severe acute pancreatitis (SAP) often causes systemic complications that affect distant organs, including the lungs. The aim of this study was to explore the therapeutic potential of piperlonguminine on SAP-induced lung injury in rat models. Acute pancreatitis was induced in rats by repetitive injections with 4% sodium taurocholate. Histological examination and biochemical assays were used to assess the severity of lung injury, including tissue damage, and levels of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), reactive oxygen species (ROS), and inflammatory cytokines. We found that piperlonguminine significantly ameliorated pulmonary architectural distortion, hemorrhage, interstitial edema, and alveolar thickening in rats with SAP. In addition, NOX2, NOX4, ROS, and inflammatory cytokine levels in pulmonary tissues were notably decreased in piperlonguminine-treated rats. Piperlonguminine also attenuated the expression levels of toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB). Together, our findings demonstrate for the first time that piperlonguminine can ameliorate acute pancreatitis-induced lung injury via inhibitory modulation of inflammatory responses by suppression of the TLR4/NF-κB signaling pathway.
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Affiliation(s)
- Qian Hu
- Department of Emergency Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi.
| | - Ran Tao
- Department of Emergency Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi.
| | - Xiaoyun Hu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi.
| | - Haibo Wu
- Department of Emergency Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi.
| | - Jianjun Xu
- Department of Cardio-Thoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi.
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Yildiz R, Uyanikoglu A, Cindoglu C, Eren MA, Koyuncu I. Evaluation of the Paraoxonase-1 Level in Patients with Acute Pancreatitis. CURRENT HEALTH SCIENCES JOURNAL 2023; 49:28-32. [PMID: 37780188 PMCID: PMC10541059 DOI: 10.12865/chsj.49.01.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 12/23/2022] [Indexed: 10/03/2023]
Abstract
BACKGROUND This study, aimed to evaluate the role of paraoxonase-1 (PON-1), in the pathogenesis of acute pancreatitis (AP). PON-1 plays a significant role in antioxidant, anti-inflammatory and antiatherogenic responses and may help predict the severity of AP. METHODS A total of 50 patients with AP and 45 healthy volunteers were included in the study. AP was diagnosed when serum amylase and/or lipase values increased threefold and/or more than the upper limit of normal, together with a complaint of abdominal pain. Modified Atlanta and Ranson scoring were used for AP severity. RESULTS AP causes were biliary for 35 (70%) patients and idiopathic for 8 (16%) patients, AP developed in 6 (12%) patients after endoscopic retrograde pancreatography, and AP in 1 (2%) patient was a consequence hypertriglyceridemia. No difference in PON-1 level was found between the groups (PON-1=197.06±164.6 and 192.1±111.78, respectively, p=0.86). On the other hand, patients were stratified according to the modified Atlanta (177.5±166.8 for mild to moderate vs. 268.5±64.2 for severe, p<0.018) or Ranson (163.2±133.06 for mild vs. 208.8±158.0 for severe, p<0.016). PON-1 level was significantly higher in patients with severe AP compared to patients with mild and/or moderate disease. CONCLUSION Although PON-1 level did not differ in patients with and without AP, PON-1 level increased significantly in parallel with the severity of AP. Thus, PON-1 can be a potential marker for the severity of the disease and can predict prognosis.
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Affiliation(s)
- Rukiye Yildiz
- Department of Internal Medicine, Nusaybin State Hospital, Mardin, Turkey
| | - Ahmet Uyanikoglu
- Department of Gastroenterology, Faculty of Medicine, Harran University, Turkey
| | - Cigdem Cindoglu
- Department of Internal Medicine, Nusaybin State Hospital, Mardin, Turkey
| | - Mehmet Ali Eren
- Department of Internal Medicine, Medical Faculty, Harran University, Sanliurfa, Turkey
| | - Ismail Koyuncu
- Department of Endocrinology and Metabolism, Faculty of Medicine, Harran University, Turkey
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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: 10] [Impact Index Per Article: 3.3] [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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Yu R, Hou C, Peng Y, Zhu X, Shi C, Huang D, Miao Y, Li Q. The mechanism underlying ICAM-1 and E-selectin-mediated hypertriglyceridemic pancreatitis-associated lung injury. Mol Immunol 2022; 152:55-66. [DOI: 10.1016/j.molimm.2022.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 10/03/2022] [Accepted: 10/05/2022] [Indexed: 11/07/2022]
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Hey-Hadavi J, Velisetty P, Mhatre S. Trends and recent developments in pharmacotherapy of acute pancreatitis. Postgrad Med 2022; 135:334-344. [PMID: 36305300 DOI: 10.1080/00325481.2022.2136390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Acute pancreatitis (AP), a complex inflammatory disease of the pancreas, is associated with increased morbidity and mortality. Currently, no specific therapies are approved for its treatment, and management is primarily based on supportive care. Despite enhanced understanding of AP pathogenesis, patients remain at significant risk owing to a lack of targeted drug treatments. Therefore, there is an urgent need for effective pharmacological therapeutic measures which may inhibit the early systemic inflammation, thereby preventing subsequent organ failure. This narrative review summarizes the available treatment options for AP and highlights the potential drug classes and pharmacologic therapies including those under clinical development. Although, several therapies targeting different aspects of AP pathogenesis have been investigated, some therapies with promising preclinical activity have been rendered ineffective in clinical trials. Other novel drug classes or molecules including dabigatran (anticoagulant), ulinastatin (protease inhibitor), infliximab (monoclonal antibody), spautin-A41 (autophagy inhibitor), and CM4620-Injectible Emulsion (calcium channel inhibitor) await further clinical assessment. Alternative treatment options using stem cells and nanoparticles are also being explored and may hold promise for AP therapy. However, challenges for exploring targeted treatment approaches include disease complexity, timing of therapeutic intervention, and establishing appropriate clinical endpoints. Understanding the role of specific biomarkers may help in identifying appropriate targets for drug discovery and facilitate determining relevant clinical study endpoints to monitor disease severity and progression, thereby aiding in design of more precise therapies with improved clinical outcomes.
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Sharma MK, Priyam K, Kumar P, Garg PK, Roy TS, Jacob TG. Effect of calorie-restriction and rapamycin on autophagy and the severity of caerulein-induced experimental acute pancreatitis in mice. FRONTIERS IN GASTROENTEROLOGY 2022; 1. [DOI: 10.3389/fgstr.2022.977169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
BackgroundImpaired autophagy contributes to development of acute pancreatitis (AP). We studied the effect of inducing autophagy by calorie-restriction and rapamycin, separately, in the caerulein-induced model of severe AP.MethodsAdult, male, Swiss albino mice were given eight, hourly, intraperitoneal injections of caerulein (Ce) (50µg/Kg/dose). The interventions were calorie restriction (CR) and rapamycin (2mg/Kg). Mice were sacrificed at the 9th hour. Pancreas was harvested for histopathology and immunoblotting. Amylase activity and the levels of cytokines were measured in plasma.ResultsThe histopathological score and amylase activity were significantly lower in calorie-restricted caerulein-induced AP (CRCeAP) in comparison to animals that had unrestricted access to chow. In the CRCeAP group, levels of IL-6 and GM-CSF in plasma were lower and the expression of LC3II and Beclin-1 were higher. On transmission electron-microscopy, the area occupied by autophagic vacuoles was higher in CRCeAP. The expression of caspase-8 and caspase-9 was also higher in CRCeAP. In rapamycin with caerulein-induced AP (Rapa+CeAP), the histopathological score and amylase activity were significantly lower than caerulein-induced AP (CeAP). In Rapa+CeAP, the expression of LC3II and Beclin-1 were higher, whereas; SQSTM1 was decreased. The number of autophagic vacuoles in Rapa+CeAP group was fewer. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were lower in Rapa+CeAP. Caspase-3 increased and high mobility group box 1 (HMGB1) decreased in Rapa+CeAP.ConclusionCalorie-restriction and rapamycin can individually decrease the severity of injury in the caerulein-induced model of severe AP.
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Zhou X, Jin S, Pan J, Lin Q, Yang S, Ambe PC, Basharat Z, Zimmer V, Wang W, Hong W. Damage associated molecular patterns and neutrophil extracellular traps in acute pancreatitis. Front Cell Infect Microbiol 2022; 12:927193. [PMID: 36034701 PMCID: PMC9411527 DOI: 10.3389/fcimb.2022.927193] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 07/21/2022] [Indexed: 11/15/2022] Open
Abstract
Previous researches have emphasized a trypsin-centered theory of acute pancreatitis (AP) for more than a century. With additional studies into the pathogenesis of AP, new mechanisms have been explored. Among them, the role of immune response bears great importance. Pro-inflammatory substances, especially damage-associated molecular patterns (DAMPs), play an essential role in activating, signaling, and steering inflammation. Meanwhile, activated neutrophils attach great importance to the immune defense by forming neutrophil extracellular traps (NETs), which cause ductal obstruction, premature trypsinogen activation, and modulate inflammation. In this review, we discuss the latest advances in understanding the pathological role of DAMPs and NETs in AP and shed light on the flexible crosstalk between these vital inflammatory mediators. We, then highlight the potentially promising treatment for AP targeting DAMPs and NETs, with a focus on novel insights into the mechanism, diagnosis, and management of AP.
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Affiliation(s)
- Xiaoying Zhou
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Shengchun Jin
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Jingyi Pan
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qingyi Lin
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Shaopeng Yang
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Peter C. Ambe
- Department of General Surgery, Visceral Surgery and Coloproctology, Vinzenz-Pallotti-Hospital Bensberg, Bensberg, Germany
| | - Zarrin Basharat
- Jamil-ur-Rahman Center for Genome Research, Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Vincent Zimmer
- Department of Medicine, Marienhausklinik St. Josef Kohlhof, Neunkirchen, Germany
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Wei Wang
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, China
- *Correspondence: Wandong Hong, ; Wei Wang,
| | - Wandong Hong
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Wandong Hong, ; Wei Wang,
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Fan C, Song Y, Wang X, Mao C, Xiong Y. Identification of Early Derangements of Coagulation, Hematological and Biochemical Profiles in Patients with Acute Pancreatitis. Clin Biochem 2022; 109-110:37-43. [PMID: 35964680 DOI: 10.1016/j.clinbiochem.2022.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/25/2022] [Accepted: 08/08/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Acute pancreatitis (AP) is a severe disease involving various pathological processes. We aimed to use rapid -thromboelastography (r-TEG) combined with conventional coagulation assays (CCAs) and other laboratory tests, to identify early derangements in coagulation, hematological, and biochemical profiles in patients with AP. METHODS We enrolled 177 patients diagnosed with AP and 121 controls. Blood samples were analyzed using r-TEG, CCAs, and hematological and biochemical tests within 2 h of patient admission. All testing parameters were compared between the patients and the controls. Pearson's correlation coefficient was used to determine the correlation between the parameters among the patients. Logistic regression analysis was performed to evaluate the effects of the variables (demographic, coagulation, hematological and biochemical) on AP. RESULTS Using r-TEG and CCAs, we observed differences in coagulation parameters between the patients with AP and the controls. The r-TEG results showed a pro-coagulant state and increased platelet activation in AP patients. Pearson's correlation analysis showed that inflammatory indicators were strongly correlated with coagulation/platelets in the pathological process of AP. Logistic regression analysis revealed that age, K, neutrophil (NEUT), triglyceride (TG) and blood amylase (AMY) were significantly associated with the development of AP. CONCLUSION Coagulation profile and platelet play essential roles in the pathogenesis of AP. Pro-coagulant state and increased platelet activation in patients with AP were demonstrated using r-TEG. The r-TEG parameter K, age, NEUT, TG, and AMY may be used as potential indicators of AP.
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Affiliation(s)
- Cheng Fan
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yi Song
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xuan Wang
- Department of Biomedical Informatics, Harvard University, Boston, MA, USA
| | - Chaoqin Mao
- Department of Rehabilitation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Yueshan Xiong
- Department of Mathematics, School of Mathematics and Statistics, Huazhong University of Science and Technology, Wuhan 430074, China.
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Abstract
BACKGROUND Acute pancreatitis (AP) is the most common pancreatic disease. Predicting the severity of AP is critical for making preventive decisions. However, the performance of existing scoring systems in predicting AP severity was not satisfactory. The purpose of this study was to develop predictive models for the severity of AP using machine learning (ML) algorithms and explore the important predictors that affected the prediction results. METHODS The data of 441 patients in the Department of Gastroenterology in our hospital were analyzed retrospectively. The demographic data, blood routine and blood biochemical indexes, and the CTSI score were collected to develop five different ML predictive models to predict the severity of AP. The performance of the models was evaluated by the area under the receiver operating characteristic curve (AUC). The important predictors were determined by ranking the feature importance of the predictive factors. RESULTS Compared to other ML models, the extreme gradient boosting model (XGBoost) showed better performance in predicting severe AP, with an AUC of 0.906, an accuracy of 0.902, a sensitivity of 0.700, a specificity of 0.961, and a F1socre of 0.764. Further analysis showed that the CTSI score, ALB, LDH, and NEUT were the important predictors of the severity of AP. CONCLUSION The results showed that the XGBoost algorithm can accurately predict the severity of AP, which can provide an assistance for the clinicians to identify severe AP at an early stage.
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Tang J, Chen T, Ni W, Chen X. Dynamic nomogram for persistent organ failure in acute biliary pancreatitis: Development and validation in a retrospective study. Dig Liver Dis 2022; 54:805-811. [PMID: 34305014 DOI: 10.1016/j.dld.2021.06.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/21/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Persistent organ failure (POF) increases the risk of death in patients with acute biliary pancreatitis (ABP). Currently, there is no early risk assessment tool for POF in patients with ABP. AIMS To establish and validate a dynamic nomogram for predicting the risk of POF in ABP. METHODS This was a retrospective study of 792 patients with ABP, with 595 cases in the development group and 197 cases in the validation group. Least absolute shrinkage and selection operator regression screened the predictors of POF, and logistic regression established the model (P < 0.05). A dynamic nomogram showed the model. We evaluated the model's discrimination, calibration, and clinical effectiveness; used the bootstrap method for internal validation; and conducted external validation in the validation group. RESULTS Neutrophils, haematocrit, serum calcium, and blood urea nitrogen were predictors of POF in ABP. In the development group and validation group, the areas under the receiver operating characteristic curves (AUROCs) were 0.875 and 0.854, respectively, and the Hosmer-Lemeshow test (P > 0.05) and calibration curve showed good consistency between the actual and prediction probability. Decision curve analysis showed that the dynamic nomogram has excellent clinical value. CONCLUSION This dynamic nomogram helps with the early identification and screening of high-risk patients with POF in ABP.
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Affiliation(s)
- Jia Tang
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Tao Chen
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wei Ni
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xia Chen
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou, China.
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Fawzy HA, Mohammed AA, Fawzy HM, Fikry EM. Reorienting of pramipexole as a promising therapy for acute pancreatitis in a rat model by suppressing TLR-4\NF-κB p65\NLRP3 inflammasome signaling. Can J Physiol Pharmacol 2022; 100:542-552. [PMID: 35413206 DOI: 10.1139/cjpp-2021-0664] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Acute pancreatitis (AP), a disorder of global importance, has a growing incidence and prevalence, particularly in the western world. Its complications include pseudo-cysts and chronic pancreatitis. Pramipexole (PMX), a D2/3 receptor selecting agonist used in Parkinsonism, has reported anti-inflammatory effects lately. PURPOSE Exploring the potential curative role of PMX in an l-arginine-induced acute pancreatitis rat model besides a possible mechanistic pathway. METHODS Rats were divided randomly into three groups: control, l-arginine, and "l-arginine + PMX". 7 days after AP induction, rats decapitated and estimated for serum amylase, lipase, glucose, pancreatic inflammatory mediators "toll-like receptor-4, nuclear factor- kappa B p65 ,serum tumor necrosis factor-α, NLRP3 inflammasome, caspase-1, interleukin-1 beta, oxidative biomarkers "malondialdehyde, myeloperoxidase, nitrite/nitrate, reduced glutathione, and the apoptotic marker "caspase-3", with pancreatic histopathological changes. RESULTS L-arginine mediated AP proved by elevated serum lipase and amylase, pancreatic inflammatory, oxidative and apoptotic markers with infiltration of inflammatory cells using hematoxylin and eosin stain. PMX improved all these adverse signs of AP greatly. CONCLUSION PMX might be considered as an innovative therapy for AP due to its remarkable antioxidant, anti-apoptotic, and anti-inflammatory effects, which are attributed to the suppression of the NLRP3 inflammasome and its downstream inflammatory cytokines.
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Affiliation(s)
| | - Asmaa A Mohammed
- Al-Azhar University, 68820, Department of Pharmacology and Toxicology, Cairo, Egypt;
| | - Hala M Fawzy
- NODCAR, 204596, Department of Pharmacology, Giza, Egypt;
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Xiong Y, Ji L, Zhao Y, Liu A, Wu D, Qian J. Sodium Butyrate Attenuates Taurocholate-Induced Acute Pancreatitis by Maintaining Colonic Barrier and Regulating Gut Microorganisms in Mice. Front Physiol 2022; 13:813735. [PMID: 35370779 PMCID: PMC8969109 DOI: 10.3389/fphys.2022.813735] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 02/09/2022] [Indexed: 12/12/2022] Open
Abstract
BackgroundAcute pancreatitis (AP) damages the intestinal barrier, which aggravates AP. Butyrate exhibits anti-inflammatory effects in AP, but it is unknown if such a protective effect is associated with the regulation of gut microorganisms. We aim to investigate the effects of sodium butyrate (SB) on pancreatic inflammation, colonic barrier, and gut microorganisms.MethodsC57BL/6 mice were divided into groups of sham operation (Sham), AP, 200 mg/kg SB intervention (SB-200), and 500 mg/kg SB intervention group (SB-500). Samples were harvested 24 h after the model was established. The gut microbiota was analyzed using 16S rRNA gene sequencing.ResultsPancreatic infiltration of neutrophils, macrophages, and M2-type macrophages was significantly reduced in the SB-500 intervention group. Supplementation of SB-500 improved colon mucosal histology and the expression of ZO-1 and occluding. The relative abundance of Alloprevotella and Muribaculaceae was increased and that of Akkermansia was decreased in the SB-500 group compared with the AP group. Ruminococcaceae was the most significantly increased species and Prevotellaceae was the most significantly decreased species in the SB-500 group compared with the AP group.ConclusionHigh dose of SB inhibits pancreatic inflammation probably by maintaining the intestinal barrier and regulating gut microbiota in mice with AP.
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Lu Z, Chen X, Ge H, Li M, Feng B, Wang D, Guo F. Neutrophil-Lymphocyte Ratio in Patients with Hypertriglyceridemic Pancreatitis Predicts Persistent Organ Failure. Gastroenterol Res Pract 2022; 2022:8333794. [PMID: 35340692 PMCID: PMC8942680 DOI: 10.1155/2022/8333794] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/18/2022] [Accepted: 03/02/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The neutrophil-lymphocyte ratio (NLR) has been proposed as a surrogate marker of inflammation with prognostic value in various diseases. Our objective was to investigate the predictive value of the NLR as an indicator of persistent organ failure (POF) in patients with hypertriglyceridemic pancreatitis (HTGP). METHODS We retrospectively reviewed the data from patients with HTGP between 2016 and 2019. The NLR was obtained at admission. The diagnostic performance of the NLR for POF was evaluated by the area under the receiver operator characteristics curve (AUROC). Multivariate logistic regression determined whether elevated NLR was independently associated with POF. RESULTS Of the 446 patients enrolled, 89 (20.0%) developed POF. Patients with POF showed a significantly higher NLR than those without POF (P < 0.001). A positive trend for the association across increasing NLR quartiles and the incidence of POF was observed (P trend < 0.001). The AUROC of NLR to predict POF was 0.673 (95% confidence interval, 0.627-0.716). With a cut-off of NLR > 6.56, the sensitivity and specificity were 73.0% and 55.7%, respectively. Multivariate analysis suggested that high NLR (>6.56) was independently associated with POF (odds ratio, 2.580; 95% confidence interval, 1.439-4.626; P = 0.001). Patients with a high NLR (>6.56) had a worse overall clinical course in HTGP. CONCLUSION Elevated NLR was significantly associated with an increased risk of developing POF and could be an early independent predictor of POF in patients with HTGP.
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Affiliation(s)
- Zhihua Lu
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xiangping Chen
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Huiqing Ge
- Department of Respiratory Care, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Man Li
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Binbin Feng
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Donghai Wang
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Feng Guo
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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Akdur G, Bardakcı O, Das M, Akdur O, Beyazit Y. Diagnostic utility of hematological indices in predicting adverse outcomes and severity of acute pancreatitis based on BISAP and modified Glasgow score. ULUS TRAVMA ACIL CER 2022; 28:268-275. [PMID: 35485556 PMCID: PMC10493544 DOI: 10.14744/tjtes.2020.26348] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 12/10/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte-ratio (PLR), and red blood cell distribution width (RDW) are simple indicators of inflammatory status previously established as a severity indicator in distinct disease states. This study aimed to determine the impact of these simple hematologic indices with conventional inflammation markers such as C-reactive pro-tein (CRP) and white blood cells in acute pancreatitis (AP) patients and their relationship with AP risk stratification scores including Bedside Index for Severity of Acute Pancreatitis (BISAP) and modified Glaskow Prognostic score (mGPS) scores. METHODS This retrospective study was performed in the emergency department of Canakkale Onsekiz Mart University. A total of 171 patients (male/female: 68 [39.8%]/103 [60.3%]) with AP and 59 age and gender matched healthy subjects (male/female: 23 [39%]/36[61%]) as controls were enrolled in the present study. The patients were grouped according to severity and adverse outcomes according to BISAP and mGPS and a comparative analysis was performed to compare the NLR, PLR, and RDW between groups. RESULTS The mean NLR values of AP patients and control group were 9.62±6.34 and 2.04±1.08, respectively (p<0.001), while the mean PLR values of AP patients and control group were 221.83±122.43 and 83.30±38.89, respectively (p<0.001). Except from RDW, all the other hematologic indices were found to be elevated (p<0.05 for WBC; NLR, PLR, and CRP) on both mild and severe disease at disease onset. NLR and PLR showed significant predictive ability for estimating serious complications associated with AP. CONCLUSION The present study showed that NLR and PLR is increased in AP. Moreover, peripheral blood NLR and PLR values can predict disease severity and adverse outcomes associated with AP and can be used as an adjunctive marker for estimating disease severity.
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Affiliation(s)
- Gökhan Akdur
- Department of Emergency Medicine, Çanakkale Onsekiz Mart University Faculty of Medicine, Çanakkale-Turkey
| | - Okan Bardakcı
- Department of Emergency Medicine, Çanakkale Onsekiz Mart University Faculty of Medicine, Çanakkale-Turkey
| | - Murat Das
- Department of Emergency Medicine, Çanakkale Onsekiz Mart University Faculty of Medicine, Çanakkale-Turkey
| | - Okhan Akdur
- Department of Emergency Medicine, Çanakkale Onsekiz Mart University Faculty of Medicine, Çanakkale-Turkey
| | - Yavuz Beyazit
- Department of Internal Medicine, Çanakkale Onsekiz Mart University Faculty of Medicine, Çanakkale-Turkey
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Sun S, Han Y, Zhang C, Liu H, Wang B, Cao S, Yuan Q, Wei S, Chen Y. Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis. Front Cell Dev Biol 2022; 10:827714. [PMID: 35281076 PMCID: PMC8904929 DOI: 10.3389/fcell.2022.827714] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/07/2022] [Indexed: 12/14/2022] Open
Abstract
Background: Inflammatory disorder and acinar cell death contribute to the initiation and progression of severe acute pancreatitis (SAP). Adenosine kinase (ADK) has potential effects on both inflammation and cell death. However, the role of ADK in SAP remains to be explored. Methods: To establish an experimental SAP model, male C57BL/6 mice were intraperitoneally injected with cerulein (50 μg/kg, seven doses at hourly intervals) and LPS (10 mg/kg, at the last cerulein injection). For ADK inhibition, ABT702 (1.5 mg/kg) was intraperitoneally injected 1 h before cerulein treatment. The pancreas and serum were collected and analyzed to determine the severity of pancreatic injury and explore the potential pathophysiological mechanisms. Pancreatic acinar cells (AR42J) were used to explore the in vitro effects of ADK inhibition on cerulein–induced inflammation and necroptotic cell death. Results: ADK inhibition notably attenuated the severity of SAP, as indicated by the decreased serum amylase (7,416.76 ± 1,457.76 vs. 4,581.89 ± 1,175.04 U/L) and lipase (46.51 ± 11.50 vs. 32.94 ± 11.46 U/L) levels and fewer pancreatic histopathological alterations (histological scores: 6.433 ± 0.60 vs. 3.77 ± 0.70). MOMA-2 and CD11b staining confirmed that ADK inhibition prevented the infiltration of neutrophils and macrophages. The phosphorylation of nuclear factor-κB (NF-κB) was also reduced by ADK inhibition. ADK inhibition markedly limited the necrotic area of the pancreas and prevented the activation of the necroptotic signaling pathway. Endoplasmic reticulum (ER) stress was activated in the pancreas using the SAP model and cerulein–treated AR42J cells whereas ADK inhibition reversed the activation of ER stress both in vivo and in vitro. Moreover, the alleviating effects of ADK inhibition on ER stress, inflammation, and cell necroptosis were eliminated by the adenosine A2A receptor antagonist. Conclusion: ADK inhibition reduced inflammation and necroptotic acinar cell death in SAP via the adenosine A2A receptor/ER stress pathway, suggesting that ADK might be a potential therapeutic target for SAP.
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Affiliation(s)
- Shukun Sun
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Yu Han
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Chuanxin Zhang
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Han Liu
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Bailu Wang
- Clinical Trial Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shengchuan Cao
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Qiuhuan Yuan
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Shujian Wei
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- *Correspondence: Shujian Wei, ; Yuguo Chen,
| | - Yuguo Chen
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- *Correspondence: Shujian Wei, ; Yuguo Chen,
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QIAN J, WANG X, WEI B, ZHOU G, ZHU S, LIU C. Therapeutic effects of salidroside vs pyrrolidine dithiocarbamate against severe acute pancreatitis in rat. J TRADIT CHIN MED 2022; 42:49-57. [PMID: 35322632 PMCID: PMC10164628 DOI: 10.19852/j.cnki.jtcm.20210707.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 04/03/2021] [Indexed: 05/10/2023]
Abstract
OBJECTIVE To evaluate the therapeutic effectiveness of salidroside (Sal) and pyrrolidine dithiocarbamate (PDTC) against severe acute pancreatitis (SAP) in a rat model. METHODS Rat models of SAP were established by retrograde infusion of sodium taurocholate solution. SAP rats were randomly divided into 6 groups: SAP 3 h group, SAP 24 h group, low-dose Sal treatment group (Sal L+S), middle-dose Sal treatment group (Sal M+S), high-dose Sal treatment group (Sal H+S) and PDTC treatment group (PDTC+S). The serum amylase, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-10 (IL-10) levels were determined by optical turbidimetry and enzyme-linked immunosorbent assay. The expression of Beclin-1, microtubule-associated protein light chain 3II (LC3 II ), lysosome associated membrane protein 2 (LAMP2), interleukin-1 receptor associated kinase 1 (IRAK1) inhibitor α of nuclear transcription factor-kB (IkBα), nuclear transcription factor-kB 65 (p65) in the pancreas tissues were detected by quantitative real-time polymerase chain reaction and Western blot, while the pIkBα and p-p65 levels were detected by Western blot. Pathological changes of the pancreas and all the other indexes were observed at 3 and 24 h after operation. RESULTS The serum IL-10 level, IkBα and LAMP2 levels in Sal M+S, Sal H+S and PDTC+S groups were higher than those in SAP 24 h group, while all the other indexes in these three groups were all lower significantly than those in SAP 24 h group. There was no significant difference in all indexes between Sal H+S and PDTC+S groups. CONCLUSION High-dose Sal has an effectively therapeutic effect on SAP in rats, which was similar to PDTC.
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Affiliation(s)
- Jing QIAN
- 1 Department of General Surgery, Yizheng Hospital of Nanjing Drum Tower Hospital Group, Yizheng 211900, China
| | - Xiaohong WANG
- 2 Department of Gastroenterology, Yizheng Hospital of Nanjing Drum Tower Hospital Group, Yizheng 211900, China
| | - Benzhong WEI
- 3 Department of Anesthesiology, Yizheng Hospital of Nanjing Drum Tower Hospital Group, Yizheng 211900, China
| | - Guoxiong ZHOU
- 4 Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Shunxing ZHU
- 5 Department of Laboratory Animal Center, Nantong University, Nantong 226001, China
| | - Chun LIU
- 5 Department of Laboratory Animal Center, Nantong University, Nantong 226001, China
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Liu X, Guan G, Cui X, Liu Y, Liu Y, Luo F. Systemic Immune-Inflammation Index (SII) Can Be an Early Indicator for Predicting the Severity of Acute Pancreatitis: A Retrospective Study. Int J Gen Med 2021; 14:9483-9489. [PMID: 34949937 PMCID: PMC8689009 DOI: 10.2147/ijgm.s343110] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Objective Systemic immune-inflammation index (SII) is a new systemic inflammatory prognostic indicator associated with outcomes in patients with different tumors. Studies have shown an association between SII and many chronic/acute inflammatory diseases. This study aimed at exploring whether SII can be used as an effective parameter for predicting the severity of acute pancreatitis (AP). Methods A total of 101 acute pancreatitis patients were enrolled in this study (mild acute pancreatitis (MAP): n = 73 and severe acute pancreatitis (SAP): n = 28). Patient demographics and SII were analyzed using the chi-square test, Student’s t-test, and Mann–Whitney U-test. A receiver operating characteristic curve was generated to test the potential of using neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and SII to predict AP’s severity. Logistic regression analysis was performed to determine major risk factors. Results Patients with SII value ≥2207.53 had a higher probability of having SAP (sensitivity = 92.9%, specificity = 87.7%, and AUC = 0.920), and SII was a significantly better predictive value than PLR and NLR. Logistic regression analysis results showed SII could differentiate MAP from SAP as a major risk factor. Conclusion This study has shown that SII is a potential indicator for predicting the severity of acute pancreatitis. The findings suggested that SII is more sensitive and specific than NLR and PLR in predicting the severity of acute pancreatitis.
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Affiliation(s)
- Xingming Liu
- Department of General Surgery, The Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, People's Republic of China
| | - Guoxin Guan
- Department of General Surgery, The Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, People's Republic of China
| | - Xinye Cui
- Department of General Surgery, The Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, People's Republic of China
| | - Yaqing Liu
- Department of General Surgery, The Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, People's Republic of China
| | - Yinghan Liu
- Department of General Surgery, The Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, People's Republic of China
| | - Fuwen Luo
- Department of General Surgery, The Second Affiliated Hospital, Dalian Medical University, Dalian, 116023, People's Republic of China
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Sun HW, Dai SJ, Kong HR, Fan JX, Yang FY, Dai JQ, Jin YP, Yu GZ, Chen BC, Shi KQ. Accurate prediction of acute pancreatitis severity based on genome-wide cell free DNA methylation profiles. Clin Epigenetics 2021; 13:223. [PMID: 34915915 PMCID: PMC8680202 DOI: 10.1186/s13148-021-01217-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 12/12/2021] [Indexed: 01/15/2023] Open
Abstract
Background Patients with severe acute pancreatitis (SAP) have a high mortality, thus early diagnosis and interventions are critical for improving survival. However, conventional tests are limited in acute pancreatitis (AP) stratification. We aimed to assess AP severity by integrating the informative clinical measurements with cell free DNA (cfDNA) methylation markers. Methods One hundred and seventy-five blood samples were collected from 61 AP patients at multiple time points, plus 24 samples from healthy individuals. Genome-wide cfDNA methylation profiles of all samples were characterized with reduced representative bisulfite sequencing. Clinical blood tests covering 93 biomarkers were performed on AP patients within 24 h. SAP predication models were built based on cfDNA methylation and conventional blood biomarkers separately and in combination. Results We identified 565 and 59 cfDNA methylation markers informative for acute pancreatitis and its severity. These markers were used to develop prediction models for AP and SAP with area under the receiver operating characteristic of 0.92 and 0.81, respectively. Twelve blood biomarkers were systematically screened for a predictor of SAP with a sensitivity of 87.5% for SAP, and a specificity of 100% in mild acute pancreatitis, significantly higher than existing blood tests. An expanded model integrating 12 conventional blood biomarkers with 59 cfDNA methylation markers further improved the SAP prediction sensitivity to 92.2%. Conclusions These findings have demonstrated that accurate prediction of SAP by the integration of conventional and novel blood molecular markers, paving the way for early and effective SAP intervention through a non-invasive rapid diagnostic test. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-021-01217-z.
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Affiliation(s)
- Hong-Wei Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Sheng-Jie Dai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hong-Ru Kong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jie-Xiang Fan
- Translational Medicine Laboratory, Key Laboratory of Intelligent Critical Care and Life Support Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No. 1 FanHai West Road, OuHai, Wenzhou, 325000, China
| | - Fang-Yuan Yang
- Translational Medicine Laboratory, Key Laboratory of Intelligent Critical Care and Life Support Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No. 1 FanHai West Road, OuHai, Wenzhou, 325000, China
| | - Ju-Qing Dai
- Translational Medicine Laboratory, Key Laboratory of Intelligent Critical Care and Life Support Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No. 1 FanHai West Road, OuHai, Wenzhou, 325000, China
| | - Yue-Peng Jin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guan-Zhen Yu
- Translational Medicine Laboratory, Key Laboratory of Intelligent Critical Care and Life Support Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No. 1 FanHai West Road, OuHai, Wenzhou, 325000, China
| | - Bi-Cheng Chen
- Translational Medicine Laboratory, Key Laboratory of Intelligent Critical Care and Life Support Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No. 1 FanHai West Road, OuHai, Wenzhou, 325000, China
| | - Ke-Qing Shi
- Translational Medicine Laboratory, Key Laboratory of Intelligent Critical Care and Life Support Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No. 1 FanHai West Road, OuHai, Wenzhou, 325000, China. .,Key Laboratory of Intelligent Critical Care and Life Support Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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Pan B, Li Y, Liu Y, Wang W, Huang G, Ouyang Y. Circulating CitH3 Is a Reliable Diagnostic and Prognostic Biomarker of Septic Patients in Acute Pancreatitis. Front Immunol 2021; 12:766391. [PMID: 34868018 PMCID: PMC8637845 DOI: 10.3389/fimmu.2021.766391] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 10/25/2021] [Indexed: 01/02/2023] Open
Abstract
Purpose Acute pancreatitis (AP) is an inflammatory disease. AP starts with sterile inflammation and is often complicated with critical local or systemic infection or sepsis in severe cases. Septic AP activates peptidyl arginine deiminase (PAD) and citrullinates histone H3 (CitH3), leading to neutrophil extracellular trap (NET) formation. Investigating the role of NETs and underlying mechanisms in septic AP may facilitate developing diagnostic and therapeutic approaches. In this study, we sought to identify the expression of CitH3 in septic AP patients and to analyze the correlation of CitH3 concentration with NET components as well as clinical outcomes. Methods Seventy AP patients with or without sepsis (40 septic cases, 30 nonseptic cases) and 30 healthy volunteers were recruited in this study. Concentration of NET components (CitH3 and double-strain DNA) and key enzymes (PAD2/4) were measured. Clinical and laboratory characteristics of patients were recorded and analyzed. Results Levels of CitH3 were elevated significantly in septic AP patients compared with those in nonseptic AP and healthy volunteers. The area under the curve (AUC, 95% confidence interval) for diagnosing septic AP was 0.93 (0.86–1.003), and the cutoff was 43.05 pg/ml. Among septic AP cases (n = 40), the concentration of CitH3 was significantly increased in those who did not survive or were admitted to the intensive care unit, when compared with that in those who survived or did not require intensive care unit. Association analysis revealed that CitH3 concentration was positively correlated with PAD2, PAD4, dsDNA concentration, and Sequential Organ Failure Assessment scores. Conclusion CitH3 concentration increased in septic AP patients and was closely correlated with disease severity and clinical outcomes. CitH3 may potentially be a diagnostic and prognostic biomarker of septic AP.
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Affiliation(s)
- Baihong Pan
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yaozhen Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yu Liu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Wang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Gengwen Huang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yang Ouyang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
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Takauji S, Konishi H, Fujiya M, Ueno N, Tanaka H, Sato H, Isozaki S, Kashima S, Moriichi K, Mizukami Y, Okumura T. Polyphosphate, Derived from Lactobacillus brevis, Modulates the Intestinal Microbiome and Attenuates Acute Pancreatitis. Dig Dis Sci 2021; 66:3872-3884. [PMID: 33492535 DOI: 10.1007/s10620-020-06747-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 11/23/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND We previously showed that Lactobacillus brevis-derived polyphosphate (poly P) exerts a curative effect on intestinal inflammation. However, whether or not poly P improves the inflammation and injury of distant organs remains unclear. AIMS We aimed to investigate the change in the intestinal microbiome and to evaluate the protective effect of poly P on injuries in a cerulein-induced acute pancreatitis (AP) mouse. METHODS Poly P was orally administered to BALB/C mice every day for 24 days, and then mice were intraperitoneally injected with cerulein. Before cerulein injection, stool samples were collected and analyzed by 16S rRNA gene sequencing. Mice were sacrificed at 24 h after the last cerulein injection; subsequently, the serum, pancreas, and colon were collected. RESULTS The microbial profile differed markedly between poly P and control group. Notably, the levels of beneficial bacteria, including Alistipes and Candidatus_Saccharimonas, were significantly increased, while those of the virulent bacteria Desulfovibrio were decreased in the poly P group. The elevations of the serum amylase and lipase levels by cerulein treatment were suppressed by the pre-administration of poly P for 24 days, but not for 7 days. The numbers of cells MPO-positive by immunohistology were decreased and the levels of MCP-1 significantly reduced in the AP + Poly P group. An immunofluorescence analysis showed that the ZO-1 and occludin in the colon was strongly augmented in the epithelial cell membrane layer in the AP + Poly P group. CONCLUSIONS Poly P attenuates AP through both modification of the intestinal microbiome and enhancement of the intestinal barrier integrity.
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Affiliation(s)
- Shuhei Takauji
- Department of Emergency Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Hiroaki Konishi
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Mikihiro Fujiya
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan.
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan.
| | - Nobuhiro Ueno
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Hiroki Tanaka
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Hiroki Sato
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Shotaro Isozaki
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Shin Kashima
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Kentaro Moriichi
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Yusuke Mizukami
- Cancer Genetics, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Toshikatsu Okumura
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
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Amendt T, Jumaa H. Memory IgM protects endogenous insulin from autoimmune destruction. EMBO J 2021; 40:e107621. [PMID: 34369608 PMCID: PMC8408592 DOI: 10.15252/embj.2020107621] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 05/21/2021] [Accepted: 05/28/2021] [Indexed: 12/19/2022] Open
Abstract
The enormous diversity of antibody specificities is generated by random rearrangement of immunoglobulin gene segments and is important for general protection against pathogens. Since random rearrangement harbors the risk of producing self-destructive antibodies, it is assumed that autoreactive antibody specificities are removed during early B-cell development leading to a peripheral compartment devoid of autoreactivity. Here, we immunized wild-type mice with insulin as a common self-antigen and monitored diabetes symptoms as a measure for autoimmune disease. Our results show that autoreactive anti-insulin IgM and IgG antibodies associated with autoimmune diabetes can readily be generated in wild-type animals. Surprisingly, recall immunizations induced increased titers of high-affinity insulin-specific IgM, which prevented autoimmune diabetes. We refer to this phenomenon as adaptive tolerance, in which high-affinity memory IgM prevents autoimmune destruction by competing with self-destructive antibodies. Together, this study suggests that B-cell tolerance is not defined by the absolute elimination of autoreactive specificities, as harmful autoantibody responses can be generated in wild-type animals. In contrast, inducible generation of autoantigen-specific affinity-matured IgM acts as a protective mechanism preventing self-destruction.
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Affiliation(s)
- Timm Amendt
- Institute of ImmunologyUniversity Hospital UlmUlmGermany
| | - Hassan Jumaa
- Institute of ImmunologyUniversity Hospital UlmUlmGermany
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Sjöbeck M, Sternby H, Herwald H, Thorlacius H, Regnér S. Heparin-binding protein is significantly increased in acute pancreatitis. BMC Gastroenterol 2021; 21:337. [PMID: 34454419 PMCID: PMC8403433 DOI: 10.1186/s12876-021-01910-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 08/18/2021] [Indexed: 01/15/2023] Open
Abstract
Background Most patients with acute pancreatitis (AP) experience mild, self-limiting disease with little or no need for hospital care. However, 20–25% of patients develop a more severe and potentially life-threatening condition with progressive systemic inflammatory response syndrome (SIRS) and multiorgan failure, resulting in high morbidity and mortality rates. Predicting disease severity at an early stage is important, as immediate supportive care has been demonstrated to reduce the incidence of SIRS and organ failure, improving patient outcome. Several studies have demonstrated elevated levels of heparin-binding protein (HBP) in patients with sepsis and septic shock, and HBP is believed to play a part in endothelial dysfunction leading to vascular leakage. As HBP levels increase prior to other known biomarkers, HBP has emerged as a promising early predictor of severe sepsis with organ dysfunction. Methods Patients admitted to Skåne University Hospital in Malmö between 2010 and 2013 fulfilling the criteria for AP were identified in the emergency department and prospectively enrolled in this study. The primary outcome was measured levels of HBP upon hospital admission in patients with confirmed AP. Correlations among HBP concentrations, disease severity and fluid balance were considered secondary endpoints. The correlation between HBP levels and fluid balance were analysed using Pearson correlation, and the ability of HBP to predict moderately severe/severe AP was assessed using a receiver operating characteristic (ROC) curve. Results The overall median HBP level in this study was 529 (307–898) ng/ml. There were no significant group differences in HBP levels based on AP severity. Fluid balance differed significantly between patients with mild versus moderately severe and severe pancreatitis, but we found no correlation between HBP concentration and fluid balance. Conclusions HBP levels are dramatically increased in patients with AP, and these levels far exceed those previously reported in other conditions. In this study, we did not observe any significant correlation between HBP levels and disease severity or the need for intravenous fluid. Additional studies on HBP are needed to further explore the role of HBP in the pathogenesis of AP and its possible clinical implications. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-021-01910-6.
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Affiliation(s)
- Martina Sjöbeck
- Department of Surgery, Clinical Sciences, Malmö, Skåne University Hospital, Lund University, 205 02, Malmö, Sweden
| | - Hanna Sternby
- Department of Surgery, Clinical Sciences, Malmö, Skåne University Hospital, Lund University, 205 02, Malmö, Sweden
| | - Heiko Herwald
- Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Henrik Thorlacius
- Department of Surgery, Clinical Sciences, Malmö, Skåne University Hospital, Lund University, 205 02, Malmö, Sweden
| | - Sara Regnér
- Department of Surgery, Clinical Sciences, Malmö, Skåne University Hospital, Lund University, 205 02, Malmö, Sweden.
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CTRP3 ameliorates cerulein-induced severe acute pancreatitis in mice via SIRT1/NF-κB/p53 axis. Biosci Rep 2021; 40:222486. [PMID: 32219332 PMCID: PMC7560515 DOI: 10.1042/bsr20200092] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/22/2020] [Accepted: 03/26/2020] [Indexed: 12/14/2022] Open
Abstract
Severe acute pancreatitis (SAP) is a common and life-threatening clinical acute abdominal disease. C1q/tumor necrosis factor-related protein 3 (CTRP3), a novel paralog of adiponectin, has been identified as a crucial regulator in multiple types of inflammatory disorders. However, the biological role of CTRP3 in SAP remains poorly understood. The present study aimed to characterize the role of CTRP3 in SAP and illuminate the potential mechanisms involved. In the current study, SAP mouse models were induced by seven hourly intraperitoneal injection of cerulein (50 μg/kg) and an immediate intraperitoneal injection of lipopolysaccharide (10 mg/kg) after the last cerulein administration. Histological examination and serological analysis demonstrated that SAP mouse models were successfully established. Herein, we found that CTRP3 expression was significantly decreased in the pancreatic tissues of SAP mice compared with normal control mice. Furthermore, we explored the effects of CTRP3 rescue in SAP mice and discovered that CTRP3 overexpression attenuated pathological lesions, inhibited inflammatory mediator release and repressed acinar cell apoptosis. Notably, mechanistic studies revealed that CTRP3 overexpression suppressed NF-κB p65 phosphorylation and p53 acetylation to alleviate cerulein-induced SAP in mouse models through activation of silent information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent protein deacetylase. Collectively, our data indicate that CTRP3 may exert its protective effects in SAP mice via regulation of SIRT1-mediated NF-κB and p53 signaling pathways, implying a promising therapeutic strategy against SAP.
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El-Hamoly T, Hajnády Z, Nagy-Pénzes M, Bakondi E, Regdon Z, Demény MA, Kovács K, Hegedűs C, Abd El-Rahman SS, Szabó É, Maléth J, Hegyi P, Virág L. Poly(ADP-Ribose) Polymerase 1 Promotes Inflammation and Fibrosis in a Mouse Model of Chronic Pancreatitis. Int J Mol Sci 2021; 22:3593. [PMID: 33808340 PMCID: PMC8037143 DOI: 10.3390/ijms22073593] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/13/2021] [Accepted: 03/23/2021] [Indexed: 12/14/2022] Open
Abstract
Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by ductal obstructions, tissue fibrosis, atrophy and exocrine and endocrine pancreatic insufficiency. However, our understanding is very limited concerning the disease's progression from a single acute inflammation, via recurrent acute pancreatitis (AP) and early CP, to the late stage CP. Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor enzyme activated mostly by oxidative DNA damage. As a co-activator of inflammatory transcription factors, PARP1 is a central mediator of the inflammatory response and it has also been implicated in acute pancreatitis. Here, we set out to investigate whether PARP1 contributed to the pathogenesis of CP. We found that the clinically used PARP inhibitor olaparib (OLA) had protective effects in a murine model of CP induced by multiple cerulein injections. OLA reduced pancreas atrophy and expression of the inflammatory mediators TNFα and interleukin-6 (IL-6), both in the pancreas and in the lungs. Moreover, there was significantly less fibrosis (Masson's trichrome staining) in the pancreatic sections of OLA-treated mice compared to the cerulein-only group. mRNA expression of the fibrosis markers TGFβ, smooth muscle actin (SMA), and collagen-1 were markedly reduced by OLA. CP was also induced in PARP1 knockout (KO) mice and their wild-type (WT) counterparts. Inflammation and fibrosis markers showed lower expression in the KO compared to the WT mice. Moreover, reduced granulocyte infiltration (tissue myeloperoxidase activity) and a lower elevation of serum amylase and lipase activity could also be detected in the KO mice. Furthermore, primary acinar cells isolated from KO mice were also protected from cerulein-induced toxicity compared to WT cells. In summary, our data suggest that PARP inhibitors may be promising candidates for repurposing to treat not only acute but chronic pancreatitis as well.
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Affiliation(s)
- Tarek El-Hamoly
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.E.-H.); (Z.H.); (M.N.-P.); (E.B.); (Z.R.); (K.K.); (C.H.)
- Drug Radiation Research Department, National Centre for Radiation Research and Technology, Atomic Energy Authority, 11787 Cairo, Egypt
| | - Zoltán Hajnády
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.E.-H.); (Z.H.); (M.N.-P.); (E.B.); (Z.R.); (K.K.); (C.H.)
- Doctoral School of Molecular Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Máté Nagy-Pénzes
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.E.-H.); (Z.H.); (M.N.-P.); (E.B.); (Z.R.); (K.K.); (C.H.)
- Doctoral School of Molecular Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Edina Bakondi
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.E.-H.); (Z.H.); (M.N.-P.); (E.B.); (Z.R.); (K.K.); (C.H.)
| | - Zsolt Regdon
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.E.-H.); (Z.H.); (M.N.-P.); (E.B.); (Z.R.); (K.K.); (C.H.)
- Doctoral School of Molecular Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Máté A. Demény
- MTA-DE Cell Biology and Signaling Research Group, 4032 Debrecen, Hungary;
| | - Katalin Kovács
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.E.-H.); (Z.H.); (M.N.-P.); (E.B.); (Z.R.); (K.K.); (C.H.)
- MTA-DE Cell Biology and Signaling Research Group, 4032 Debrecen, Hungary;
| | - Csaba Hegedűs
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.E.-H.); (Z.H.); (M.N.-P.); (E.B.); (Z.R.); (K.K.); (C.H.)
| | - Sahar S. Abd El-Rahman
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, 12211 Giza, Egypt;
| | - Éva Szabó
- Department of Dermatology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - József Maléth
- First Department of Medicine, University of Szeged, 6720 Szeged, Hungary;
- HAS-USZ Momentum Epithel Cell Signalling and Secretion Research Group, 6720 Szeged, Hungary
- Department of Public Health, University of Szeged, 6720 Szeged, Hungary
| | - Péter Hegyi
- János Szentágothai Research Centre, Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Hungary;
- Momentum Gastroenterology Multidisciplinary Research Group, Hungarian Academy of Sciences, University of Szeged, 6720 Szeged, Hungary
| | - László Virág
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.E.-H.); (Z.H.); (M.N.-P.); (E.B.); (Z.R.); (K.K.); (C.H.)
- MTA-DE Cell Biology and Signaling Research Group, 4032 Debrecen, Hungary;
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Zhang X, Zhu Y. Research Progress on Regulating LncRNAs of Hepatocellular Carcinoma Stem Cells. Onco Targets Ther 2021; 14:917-927. [PMID: 33603396 PMCID: PMC7882798 DOI: 10.2147/ott.s289064] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/21/2021] [Indexed: 01/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies around the world. The self-renewal, proliferation, differentiation, and tumorigenic potential of liver cancer stem cells (LCSCs) may account for the high recurrence rate and the refractory feature of HCC. Despite extensive researches, the underlying regulatory mechanism of LCSCs has not been fully disclosed. Long nonprotein coding RNAs (lncRNAs) may exert an essential role in regulating various biological functions of LCSCs, such as maintaining the stemness of cancer stem cells (CSCs) and promoting tumor development. Therefore, it is highly critical to determine which lncRNAs can control LCSCs functions and understand how LCSCs are regulated by lncRNAs. Herein, we summarized lncRNAs and the main signaling pathways involved in the regulation of LCSCs found in recent years. Moreover, we shed light on the existence of the network system of lncRNAs and LCSCs, which may provide valuable clues on targeting LCSCs.
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Affiliation(s)
- Xiaoli Zhang
- Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China
| | - Ying Zhu
- Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China
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Shan L, Bai S, Zhao M. Early diagnosis of serum sICAM-1 and sRAGE in severe acute pancreatitis, and efficacy and prognosis prediction of glutamine combined with ulinastatin. Exp Ther Med 2021; 21:324. [PMID: 33732297 PMCID: PMC7903449 DOI: 10.3892/etm.2021.9755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 12/31/2020] [Indexed: 11/28/2022] Open
Abstract
Acute pancreatitis (AP) is a common gastrointestinal disease that can become severe, so that intensive care may be required. This study was to examine serum soluble intercellular adhesion molecule-1 (sICAM-1), and soluble receptor for advanced glycation end products (sRAGE) for efficacy and prognosis prediction of glutamine (Glu) combined with ulinastatin (UTI) on severe acute pancreatitis (SAP). Fifty-four mild acute pancreatitis (MAP) patients admitted to Yidu Central Hospital of Weifang were selected as the MAP group (MAPG), 80 with SAP were divided as the SAP group (SAPG), and 60 healthy individuals who came to Yidu Central Hospital of Weifang for physical examination during the same period were included to the normal group (NG). Serum sICAM-1 and sRAGE were measured and their predictive value of efficacy and prognosis were analyzed. In view of the treatment effectiveness and prognosis, the patients were divided into effective group (EG) and ineffective group (IG), good prognosis group (GPG) and poor prognosis group (PPG). The levels of D-lactate, diamine oxidase (DAO), endotoxin and T-lymphocyte subsets (CD3+, CD4+, CD8+ and CD4+/CD8+) were measured and the changes before and after treatment were analyzed. The AUC values of NG and MAPG, NG and SAPG, MAPG and SAPG were 0.857, 0.939 and 0.856, respectively, those of predicting efficacy were 0.920 and 0.874, respectively, and those of poor prognosis in the SAPG were 0.914 and 0.879, respectively. In the SAPG, D-lactate, DAO, endotoxin and CD8+ decreased markedly after treatment, but CD3+, CD4+, and CD4+/CD8+ were opposite. SICAM-1 and sRAGE were also independent risk factors for poor prognosis in the SAPG. Serum sICAM-1 and sRAGE have high predictive value for early diagnosis, efficacy and prognosis of Glu combined with UTI.
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Affiliation(s)
- Lini Shan
- Department of Pharmacy, Yidu Central Hospital of Weifang, Qingzhou, Shandong 262500, P.R. China
| | - Shixian Bai
- Intensive Care Unit, Yidu Central Hospital of Weifang, Qingzhou, Shandong 262500, P.R. China
| | - Min Zhao
- Department of Pharmacy, Yidu Central Hospital of Weifang, Qingzhou, Shandong 262500, P.R. China
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Autophagy in Acute Pancreatitis: Organelle Interaction and microRNA Regulation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8811935. [PMID: 33628384 PMCID: PMC7884169 DOI: 10.1155/2021/8811935] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/23/2020] [Accepted: 01/07/2021] [Indexed: 12/16/2022]
Abstract
Acute pancreatitis (AP) is a common disorder with significant hospital admission and mortality. Due to the unclarified pathological mechanism, there is still no effective and specific treatment for AP. Recently, autophagy has been found to be closely related with occurrence and development of AP, which is crucial in determining its severity and outcomes. Emerging evidence indicates that autophagy can be regulated and influenced by microRNAs and organelles, including mitochondria, endoplasmic reticulum and lysosome, through various ways in AP. Of note, the complex interplays and close relationships among autophagy, microRNA and organelles in AP are vital for figuring out pathogenesis but not clear yet. Thus, this review summarizes the role of autophagy in the pathological mechanism of AP, especially the relationship between impaired autophagy and organelles, and discusses the regulatory mechanism of microRNA on autophagy, which could offer new insights into understanding the pathogenesis of AP and developing new potential therapeutic targets against AP.
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Abstract
OBJECTIVES Acute pancreatitis (AP) is an inflammatory disease of the pancreas. We analyzed changes in inflammation markers to explore the clinical significance of using these markers to predict the severity of AP. METHODS The study included 169 patients (severe AP = 50 and nonsevere AP = 119) admitted to Yanbian University Hospital between January 2015 and July 2017. The neutrophil-to-lymphocyte ratio (NLR), prognostic nutrition index (PNI), lymphocyte-to-monocyte ratio, red blood cell distribution width coefficient of variation, mean platelet volume, platelet-to-lymphocyte ratio, and red blood cell distribution width-to-platelet ratio of the patients were detected after admission. Correlations between AP severity and various inflammatory markers were statistically analyzed. RESULTS The results indicated that the NLR on the first day after admission (area under the curve, 0.824; 95% confidence interval, 0.753-0.896) and the PNI on the third day after admission (area under the curve, 0.814; 95% confidence interval, 0.753-0.896) had more significance than other inflammation markers in predicting the severity of AP. In AP patients, the NLR showed a gradual decline, and the PNI initially decreased and then increased. CONCLUSIONS The NLR and PNI can provide new reference values for predicting the severity of AP.
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Affiliation(s)
- Guangzhe Pian
- From the Department of General Surgery, Yanbian University Hospital, Yanji, Jilin
| | - Hao Li
- From the Department of General Surgery, Yanbian University Hospital, Yanji, Jilin
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Susak YM, Dirda OO, Fedorchuk OG, Tkachenko OA, Skivka LM. Infectious Complications of Acute Pancreatitis Is Associated with Peripheral Blood Phagocyte Functional Exhaustion. Dig Dis Sci 2021; 66:121-130. [PMID: 32170475 DOI: 10.1007/s10620-020-06172-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 02/24/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Infected pancreatic necrosis is one of the most severe complications of acute pancreatitis (AP). The development of secondary infection doubles the risk of death during the late stage of necrotizing pancreatitis. Phagocytes play a major role in AP pathogenesis, as well as in local and systemic complications of the disease. AIMS We aimed to investigate the relationship between quantitative and functional indices of circulating phagocyte at the time of admission and onset of infectious complications in patients with AP afterward. METHODS A post hoc analysis of 97 patients with AP was conducted. The metabolic state of peripheral blood neutrophils and monocytes was analyzed based on their phagocytic activity and generation of reactive oxygen species (ROS), which were determined by flow cytometry on admission. The clinical end point was marked by onset of infectious complications of AP. RESULTS On admission, baseline values and reactivity reserve of monocyte and neutrophil phagocytic activity in AP patients, who developed septic complications, were substantially decreased, whereas monocyte ROS generation was dramatically increased as compared to the group without infectious processes. ROC curve was obtained both for neutrophil and monocyte phagocytosis reactivity reserve expressed as modulation coefficient values and categorized as the risk factor of infectious complications, showing an area under curve of 0.95 (P < 0.0001) and 0.84 (P < 0.0001), respectively. CONCLUSIONS Early (at the time of admission) detection of quantitative and functional indices of circulating phagocytes can be useful for the prediction of septic complications in SAP patients.
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Affiliation(s)
- Yaroslav M Susak
- Department of Surgery, O.O. Bogomolet's National Medical University, 13/7 Tarasa Shevchenko Boulevard, Kyiv, 01601, Ukraine
- Department of Surgery N2, Kyiv City Clinical Emergency Hospital, 3, Bratyslavska Str., Kyiv, 02000, Ukraine
| | - Olexandr O Dirda
- Department of Surgery N2, Kyiv City Clinical Emergency Hospital, 3, Bratyslavska Str., Kyiv, 02000, Ukraine
| | - Olexandr G Fedorchuk
- Laboratory of Molecular and Cellular Mechanisms of Metastasis, R. E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NASU, 45, Vasylkivska Str., Kyiv, 03022, Ukraine
| | - Olekcandr A Tkachenko
- Department of Surgery N2, Kyiv City Clinical Emergency Hospital, 3, Bratyslavska Str., Kyiv, 02000, Ukraine
| | - Larysa M Skivka
- Department of Microbiology and Immunology, ESC "Institute of Biology and Medicine", Taras Shevchenko National University of Kyiv, 64, Volodymirska Str., Kyiv, 01033, Ukraine.
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Percutaneous Catheter Drainage of Pancreatic Fluid Collections in Patients With Acute Pancreatitis. Indian J Surg 2020. [DOI: 10.1007/s12262-020-02187-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Hu J, Kang H, Chen H, Yao J, Yi X, Tang W, Wan M. Targeting neutrophil extracellular traps in severe acute pancreatitis treatment. Therap Adv Gastroenterol 2020; 13:1756284820974913. [PMID: 33281940 PMCID: PMC7692350 DOI: 10.1177/1756284820974913] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 10/26/2020] [Indexed: 02/05/2023] Open
Abstract
Severe acute pancreatitis (SAP) is a critical abdominal disease associated with high death rates. A systemic inflammatory response promotes disease progression, resulting in multiple organ dysfunction. The functions of neutrophils in the pathology of SAP have been presumed traditionally to be activation of chemokine and cytokine cascades accompanying the inflammatory process. Recently, since their discovery, a new type of antimicrobial mechanism, neutrophil extracellular traps (NETs), and their role in SAP, has attracted widespread attention from the scientific community. Significantly different from phagocytosis and degranulation, NETs kill extracellular microorganisms by releasing DNA fibers decorated with granular proteins. In addition to their strong antimicrobial functions, NETs participate in the pathophysiological process of many noninfectious diseases. In SAP, NETs injure normal tissues under inflammatory stress, which is associated with the activation of inflammatory cells, to cause an inflammatory cascade, and SAP products also trigger NET formation. Thus, due to the interaction between NET generation and SAP, a treatment targeting NETs might become a key point in SAP therapy. In this review, we summarize the mechanism of NETs in protecting the host from pathogen invasion, the stimulus that triggers NET formation, organ injury associated with SAP involving NETs, methods to interrupt the harmful effects of NETs, and different therapeutic strategies to preserve the organ function of patients with SAP by targeting NETs.
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Affiliation(s)
| | | | - Huan Chen
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Jiaqi Yao
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaolin Yi
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Wenfu Tang
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
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Zhang X, Zhu M, Jiang XL, Liu X, Liu X, Liu P, Wu XX, Yang ZW, Qin T. P-selectin glycoprotein ligand 1 deficiency prevents development of acute pancreatitis by attenuating leukocyte infiltration. World J Gastroenterol 2020; 26:6361-6377. [PMID: 33244198 PMCID: PMC7656215 DOI: 10.3748/wjg.v26.i41.6361] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 07/13/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute pancreatitis (AP) is rapid-onset pancreatic inflammation that causes local and systemic inflammatory response syndrome (SIRS) with high morbidity and mortality, but no approved therapies are currently available. P-selectin glycoprotein ligand 1 (PSGL-1) is a transmembrane glycoprotein to initiate inflammatory responses. We hypothesized that PSGL-1 may be involved in the development of AP and would be a new target for the treatment of AP.
AIM To investigate the role and mechanism of PSGL-1 in the development of AP.
METHODS The PSGL-1 expression on leukocytes was detected in peripheral blood of AP patients and volunteers. Pancreatic injury, inflammatory cytokines expression, and inflammatory cell infiltration was measured in AP mouse models induced with PSGL-1 knockout (PSGL-1-/-) and wild-type (PSGL-1+/+) mice. Leukocyte-endothelial cell adhesion was measured in a peripheral blood mononuclear cell (PBMC)-endothelial cell coculture system.
RESULTS The expression of PSGL-1 on monocytes and neutrophils was significantly increased in AP patients. Compared with PSGL-1+/+ mice, PSGL-1-/- AP mice induced by caerulein exhibited lower serum amylase, less Interleukin-1beta (IL-1beta) and Interleukin-6 (IL-6) expression, less neutrophil and macrophage infiltration, and reduced peripheral neutrophil and monocyte accounts. PSGL-1 deficiency alleviated leukocyte-endothelial cell adhesion via IL-6 but not IL-1beta.
CONCLUSION PSGL-1 deficiency effectively inhibits the development of AP by preventing leukocyte-endothelial cell adhesion via IL-6 stimulation and may become a potential therapeutic target for treating AP.
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Affiliation(s)
- Xu Zhang
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450003, Henan Province, China
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Ming Zhu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510000, Guangdong Province, China
| | - Xiao-Liang Jiang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical Collage (PUMC), Beijing 100021, China
| | - Xing Liu
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical Collage (PUMC), Beijing 100021, China
| | - Xue Liu
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical Collage (PUMC), Beijing 100021, China
| | - Pan Liu
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Xian-Xian Wu
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical Collage (PUMC), Beijing 100021, China
| | - Zhi-Wei Yang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical Collage (PUMC), Beijing 100021, China
| | - Tao Qin
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450003, Henan Province, China
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
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