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Hollis R, Tenet M, Aziz M, Wang P. Anti-DAMP therapies for acute inflammation. Front Immunol 2025; 16:1579954. [PMID: 40406124 PMCID: PMC12094975 DOI: 10.3389/fimmu.2025.1579954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Accepted: 04/15/2025] [Indexed: 05/26/2025] Open
Abstract
Shock, affecting a third of intensive care patients, remains a highly fatal condition despite advances in critical care, irrespective of its etiology. Cellular injury, central to shock pathophysiology, triggers the release of damage-associated molecular patterns (DAMPs), such as extracellular cold-inducible RNA-binding protein (eCIRP), high-mobility group box 1 (HMGB1), histones 3 and 4, and adenosine triphosphate (ATP). These molecules are confined within cells under normal conditions and perform essential physiological functions. However, upon their extracellular release during cellular injury, they act as alarmins, engaging pattern recognition receptors (PRRs) on immune cells. This interaction triggers a robust inflammatory response, propagating systemic inflammation and exacerbating tissue damage. Excessive DAMP-mediated inflammation is increasingly recognized as a major contributor to morbidity and mortality in a wide range of critical illnesses, including trauma, hemorrhagic shock, sepsis, and organ ischemia/reperfusion (I/R) injury. These pathologies are characterized by uncontrolled inflammatory cascades driven by the deleterious effects of DAMPs, underscoring the urgent need for targeted therapeutic interventions. This review explores the pivotal role of DAMPs in the pathogenesis of acute inflammation and shock, highlighting cutting-edge therapeutic strategies aimed at mitigating their effects. Emerging approaches include monoclonal antibodies, decoy receptors, small molecule inhibitors, and scavengers designed to neutralize or inhibit DAMP activity. The discussion also delves into the potential clinical applications of these interventions, offering insights into how targeting DAMPs could transform the management of shock and improve patient outcomes.
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Affiliation(s)
- Russell Hollis
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
- Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, United States
| | - Megan Tenet
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
- Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, United States
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
- Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, United States
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Xia Y, Chen K, Wang Y, Jiang Q, Du Y, Luo D, Li X, Li S. Importance of Selenoprotein O in Regulating Hmgb1: A New Direction for Modulating ROS-Dependent NETs Formation to Aggravate the Progression of Acute Liver Inflammation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:9382-9397. [PMID: 40189811 DOI: 10.1021/acs.jafc.5c01956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Selenoproteins (Sels) are a class of essential biomolecules that play critical roles in cellular homeostasis. SelO was identified as the preferential source of selenium in the liver, implying its potential as a key regulatory factor in hepatic pathophysiology. Bioinformatics analysis of data from GEO data sets revealed marked downregulation of SelO in liver injury. However, its function and regulatory mechanisms in the liver remain unclear. To address this, we investigated the effect of SelO ablation on acute liver inflammation, focusing on its association with inflammation and neutrophil extracellular traps (NETs) formation. Wild-type (WT) and SelO-knockout mice were used to establish a lipopolysaccharide (LPS) exposure model and a coculture model (AML12 cells and neutrophils) in vitro. Our findings revealed that LPS stimulation significantly reduced SelO expression in the WT mouse liver. SelO deletion promoted the expression of Hmgb1 and marker cytokines for chemokines, NETs generation, pyroptosis and inflammation, and induced an imbalance in redox homeostasis. Immunofluorescence, SYTOX staining, and scanning electron microscopy confirmed that SelO silencing promoted reactive oxygen species (ROS)-dependent NETs formation. Moreover, the coculture model demonstrated that excessive NETs formation exacerbated SelO-ablation-induced hepatic inflammation. Importantly, we confirmed the significant involvement of the Hmgb1/ROS axis in the development of acute liver inflammation in the absence of SelO. Our results demonstrated that SelO ablation promoted neutrophil recruitment and enhanced ROS-dependent NETs formation by increasing Hmgb1 expression levels, thereby aggravating LPS-induced pyroptosis and inflammation. This study not only uncovered the crucial biological functions of SelO, but also shed light on its regulatory implications in the inflammatory process.
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Affiliation(s)
- Yu Xia
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
- Animal Science College, Hebei North University, Zhangjiakou 075000, China
| | - Kai Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Yidan Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Qihang Jiang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Yongzhen Du
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Dongliu Luo
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Xiang Li
- National Selenium-Rich Product Quality Supervision and Inspection Center, Enshi 445000, China
| | - Shu Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
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Swetha K, Indumathi MC, Kishan R, Siddappa S, Chen CH, Marathe GK. Selenium Mitigates Caerulein and LPS-induced Severe Acute Pancreatitis by Inhibiting MAPK, NF-κB, and STAT3 Signaling via the Nrf2/HO-1 Pathway. Biol Trace Elem Res 2025:10.1007/s12011-025-04531-2. [PMID: 39907886 DOI: 10.1007/s12011-025-04531-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 01/20/2025] [Indexed: 02/06/2025]
Abstract
Severe acute pancreatitis (SAP) leads to systemic inflammation, resulting in multiorgan damage. Acute lung injury and acute respiratory distress syndrome develop in one-third of SAP patients, with a high mortality rate of 60% due to secondary complications. Patients with pancreatitis often have selenium deficiency, and selenium supplements may provide beneficial effects. This study examined the protective role of selenium in a model of SAP induced by caerulein + lipopolysaccharide (cae + LPS). Mice were administered selenium (1 mg/kg) before being challenged with caerulein (6 injections of 50 μg/kg) and LPS (10 mg/kg). At 3 h after the last caerulein injection, blood was collected for estimating pancreatic enzymes and cytokine levels, and the mice were euthanized. We performed morphological and histological studies, measured levels of protease and oxidative stress markers and conducted western blot, ELISA, and RT-qPCR analyses. We examined lung tissue histologically and estimated myeloperoxidase levels. Selenium pretreatment significantly reduced pancreatic enzyme levels such as amylase, lipase, and proteases (specifically MMPs) and reversed tissue injury in the pancreas and lungs caused by cae + LPS. In addition, selenium-treated mice showed decreased levels of inflammatory markers and chemokines. Examination of the downstream inflammatory pathways confirmed the protective effect of selenium, which mediates its anti-inflammatory and antioxidant action by inhibiting the major inflammatory signaling pathways (MAPKs, NF-κB, and STAT3) and activating the phosphorylation of Nrf2 via Nrf2/HO-1 pathways. These findings suggest that selenium may be a potential therapeutic option for treating SAP-associated secondary complications.
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Affiliation(s)
- Kamatam Swetha
- Department of Studies in Biochemistry, University of Mysore, Manasagangotri Mysore, 570006, India
| | | | - Raju Kishan
- Department of Studies in Molecular Biology, University of Mysore, Manasagangotri Mysore, 570006, India
| | - Shiva Siddappa
- Division of Biochemistry, School of Life Sciences, JSS Academy of Higher Education and Research, Mysore, 570015, India
| | - Chu-Huang Chen
- Vascular and Medicinal Research, The Texas Heart Institute, Houston, TX, 77030, USA
| | - Gopal K Marathe
- Department of Studies in Biochemistry, University of Mysore, Manasagangotri Mysore, 570006, India.
- Department of Studies in Molecular Biology, University of Mysore, Manasagangotri Mysore, 570006, India.
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Tsomidis I, Voumvouraki A, Kouroumalis E. The Pathogenesis of Pancreatitis and the Role of Autophagy. GASTROENTEROLOGY INSIGHTS 2024; 15:303-341. [DOI: 10.3390/gastroent15020022] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The pathogenesis of acute and chronic pancreatitis has recently evolved as new findings demonstrate a complex mechanism operating through various pathways. In this review, the current evidence indicating that several mechanisms act in concert to induce and perpetuate pancreatitis were presented. As autophagy is now considered a fundamental mechanism in the pathophysiology of both acute and chronic pancreatitis, the fundamentals of the autophagy pathway were discussed to allow for a better understanding of the pathophysiological mechanisms of pancreatitis. The various aspects of pathogenesis, including trypsinogen activation, ER stress and mitochondrial dysfunction, the implications of inflammation, and macrophage involvement in innate immunity, as well as the significance of pancreatic stellate cells in the development of fibrosis, were also analyzed. Recent findings on exosomes and the miRNA regulatory role were also presented. Finally, the role of autophagy in the protection and aggravation of pancreatitis and possible therapeutic implications were reviewed.
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Affiliation(s)
- Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
| | - Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
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Oikonomou P, Nikolaou C, Papachristou F, Sovatzidis A, Lambropoulou M, Giouleka C, Kontaxis V, Linardoutsos D, Papalois A, Pitiakoudis M, Tsaroucha A. Eugenol Reduced ΜPO, CD45 and HMGB1 Expression and Attenuated the Expression of Leukocyte Infiltration Markers in the Intestinal Tissue in Biliopancreatic Duct Ligation-Induced Pancreatitis in Rats. MEDICINA (KAUNAS, LITHUANIA) 2023; 60:74. [PMID: 38256335 PMCID: PMC10820626 DOI: 10.3390/medicina60010074] [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: 10/26/2023] [Revised: 11/30/2023] [Accepted: 12/26/2023] [Indexed: 01/24/2024]
Abstract
Background and Objectives: Inflammation and dysregulation in the intestinal barrier function in acute pancreatitis (AP) trigger pancreatic lesions, systemic inflammatory response, and multiple organ dysfunction. Eugenol, as the main component of clove (Syzygium aromaticum), is known for its antioxidant and anti-inflammatory properties. We studied the potentially beneficial effect of eugenol in a rodent model of biliopancreatic duct ligation-induced AP. Materials and Methods: Rats were randomly divided into three groups: Sham, AP, and AP + eugenol (15 mg/kg/day). Serum TNFα, IL-6, IL-18, and resistin levels, as well as IL-6, TNFα, MPO, HMGB1, and CD45 tissue expression, were determined at various timepoints after the induction of AP. Results: Eugenol attenuated hyperemia and inflammatory cell infiltration in the intestinal mucosal, submucosal, and muscular layers. IL-6 and resistin serum levels were significantly reduced in the AP + eugenol group, while serum TNFα and IL-18 levels remained unaffected overall. TNFα pancreatic and intestinal expression was attenuated by eugenol at 72 h, while IL-6 expression was affected only in the pancreas. MPO, CD45, and HMGB1 intestinal expression was significantly reduced in eugenol-treated rats. Conclusions: Eugenol managed to attenuate the inflammatory response in the intestine in duct ligation-induced AP in rats.
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Affiliation(s)
- Panagoula Oikonomou
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
| | - Christina Nikolaou
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
| | - Fotini Papachristou
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
| | - Apostolos Sovatzidis
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Maria Lambropoulou
- Laboratory of Histology-Embryology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Charikleia Giouleka
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Vasileios Kontaxis
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Dimitrios Linardoutsos
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Apostolos Papalois
- Experimental Research Center, ELPEN Pharmaceuticals, Pikermi, 19009 Athens, Greece;
| | - Michael Pitiakoudis
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Alexandra Tsaroucha
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
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Venkatesh K, Glenn H, Delaney A, Andersen CR, Sasson SC. Fire in the belly: A scoping review of the immunopathological mechanisms of acute pancreatitis. Front Immunol 2023; 13:1077414. [PMID: 36713404 PMCID: PMC9874226 DOI: 10.3389/fimmu.2022.1077414] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 12/21/2022] [Indexed: 01/13/2023] Open
Abstract
Introduction Acute pancreatitis (AP) is characterised by an inflammatory response that in its most severe form can cause a systemic dysregulated immune response and progression to acute multi-organ dysfunction. The pathobiology of the disease is unclear and as a result no targeted, disease-modifying therapies exist. We performed a scoping review of data pertaining to the human immunology of AP to summarise the current field and to identify future research opportunities. Methods A scoping review of all clinical studies of AP immunology was performed across multiple databases. Studies were included if they were human studies of AP with an immunological outcome or intervention. Results 205 studies met the inclusion criteria for the review. Severe AP is characterised by significant immune dysregulation compared to the milder form of the disease. Broadly, this immune dysfunction was categorised into: innate immune responses (including profound release of damage-associated molecular patterns and heightened activity of pattern recognition receptors), cytokine profile dysregulation (particularly IL-1, 6, 10 and TNF-α), lymphocyte abnormalities, paradoxical immunosuppression (including HLA-DR suppression and increased co-inhibitory molecule expression), and failure of the intestinal barrier function. Studies including interventions were also included. Several limitations in the existing literature have been identified; consolidation and consistency across studies is required if progress is to be made in our understanding of this disease. Conclusions AP, particularly the more severe spectrum of the disease, is characterised by a multifaceted immune response that drives tissue injury and contributes to the associated morbidity and mortality. Significant work is required to develop our understanding of the immunopathology of this disease if disease-modifying therapies are to be established.
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Affiliation(s)
- Karthik Venkatesh
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
| | - Hannah Glenn
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Anthony Delaney
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- Division of Critical Care, The George Institute for Global Health, Newtown, NSW, Australia
| | - Christopher R. Andersen
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
- Division of Critical Care, The George Institute for Global Health, Newtown, NSW, Australia
| | - Sarah C. Sasson
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
- Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW, Australia
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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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Dynamics of HMBG1 (High Mobility Group Box 1) during radiochemotherapy correlate with outcome of HNSCC patients. Strahlenther Onkol 2021; 198:194-200. [PMID: 34671818 PMCID: PMC8789630 DOI: 10.1007/s00066-021-01860-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 09/19/2021] [Indexed: 11/30/2022]
Abstract
Purpose High Mobility Group Box 1 (HMGB1) protein has been described as a consensus marker for immunogenic cell death (ICD) in cancer. To personalize treatments, there is a need for biomarkers to adapt dose prescription, concomitant chemotherapy, and follow-up in radiation oncology. Thus, we investigated the levels of HMGB1 in plasma of patients with head and neck squamous cell carcinoma (HNSCC) during the course of radiochemotherapy and follow-up in correlation with oncologic outcome and clinical confounders. Methods In our pilot study, 11 patients with advanced HNSCC were treated with definitive radiochemotherapy. Blood samples were taken weekly during treatment and frequently at follow-up visits. HMGB1 levels as well as routine laboratory values were measured and clinical information was collected including tumor volume, infections, toxicity, and follow-up data. Results In total, 85 samples were analyzed. In eight patients, HMGB1 levels (baseline vs. last available sample during treatment) were increasing and in three patients HMGB1 values were decreasing toward the end of treatment. All three patients with decreasing values developed tumor recurrence. By contrast, no relapse occurred in patients that showed increasing HMGB1 levels during therapy. Moreover, a positive correlation of HMGB1 levels with tumor volumes, C‑reactive protein (CRP) levels, infections, and grade three toxicity (RTOG) was observed. Conclusion HMGB1 might be a promising marker to monitor ICD in HNSCC during the course of radiochemotherapy. However, HMGB1 seems to reflect complex and diverse immunogenic responses and potential confounders. Infections and treatment-associated toxicity should be considered when interpreting the dynamics of HMGB1.
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Song Y, Zhang Z, Yu Z, Xia G, Wang Y, Wang L, Peng C, Jiang B, Liu S. Wip1 Aggravates the Cerulein-Induced Cell Autophagy and Inflammatory Injury by Targeting STING/TBK1/IRF3 in Acute Pancreatitis. Inflammation 2021; 44:1175-1183. [PMID: 33417178 DOI: 10.1007/s10753-021-01412-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 12/22/2020] [Accepted: 01/02/2021] [Indexed: 10/22/2022]
Abstract
Acute pancreatitis (AP) is an inflammatory reaction of pancreatic tissue self-digestion, edema, hemorrhage, and even necrosis after the activation of pancreatic enzymes in the pancreas caused by a variety of etiologies. This study was aimed to explore the functions and mechanism of Wip1 in AP. Twenty male SD rats were randomly assigned into 2 groups (control group: saline treatment; AP group: cerulein treatment). And cerulein-treated AR42J cells were conducted as AP model in vitro. The levels of amylase were detected by using the Beckman biochemical analyzer. The levels of IFNβ and TNFα were analyzed by ELISA. The autophagosomes were observed by transmission electron microscopy. The Wip1-specific shRNAs were transfected to AR42J cells to silence the expression of Wip1. The levels of Wip1 were measured by qRT-PCR and Western blot. The levels of STING/TBK1/IRF3 and LC3 were measured by Western blot. The AP model was successfully constructed by cerulein administration. Wip1 was notably upregulated in AP models. Autophagy and STING pathway activation were involved in the development of AP. Wip1 inhibition counteracts the promotion effect on inflammatory response induced by cerulein in AR42J Cells. Wip1 inhibition inhibited the activity of the STING/TBK1/IRF3 and reduced LC3 levels in AP. This study preliminarily explored that Wip1 could regulate autophagy and participate in the development of AP through the STING/TBK1/IRF3 signaling pathway.
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Affiliation(s)
- Yinghui Song
- Department of Hepatobiliary Surgery, Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
- Biliary Disease Research Laboratory of Hunan Provincial People's Hospital, Key Laboratory of Hunan Normal University, Changsha, Hunan Province, China
- Clinical Medical Technology Research Center of Hunan Provincial for Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
| | - Zhihua Zhang
- Department of Hepatobiliary Surgery, Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
- Biliary Disease Research Laboratory of Hunan Provincial People's Hospital, Key Laboratory of Hunan Normal University, Changsha, Hunan Province, China
- Clinical Medical Technology Research Center of Hunan Provincial for Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
| | - Zhangtao Yu
- Department of Hepatobiliary Surgery, Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
- Biliary Disease Research Laboratory of Hunan Provincial People's Hospital, Key Laboratory of Hunan Normal University, Changsha, Hunan Province, China
- Clinical Medical Technology Research Center of Hunan Provincial for Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
| | - Guoyi Xia
- Department of Hepatobiliary Surgery, Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
- Biliary Disease Research Laboratory of Hunan Provincial People's Hospital, Key Laboratory of Hunan Normal University, Changsha, Hunan Province, China
- Clinical Medical Technology Research Center of Hunan Provincial for Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
| | - Yizhi Wang
- Department of Hepatobiliary Surgery, Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
- Biliary Disease Research Laboratory of Hunan Provincial People's Hospital, Key Laboratory of Hunan Normal University, Changsha, Hunan Province, China
- Clinical Medical Technology Research Center of Hunan Provincial for Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
| | - Le Wang
- Department of Hepatobiliary Surgery, Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
- Biliary Disease Research Laboratory of Hunan Provincial People's Hospital, Key Laboratory of Hunan Normal University, Changsha, Hunan Province, China
- Clinical Medical Technology Research Center of Hunan Provincial for Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
| | - Chuang Peng
- Department of Hepatobiliary Surgery, Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
- Biliary Disease Research Laboratory of Hunan Provincial People's Hospital, Key Laboratory of Hunan Normal University, Changsha, Hunan Province, China
- Clinical Medical Technology Research Center of Hunan Provincial for Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
| | - Bo Jiang
- Department of Hepatobiliary Surgery, Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
- Biliary Disease Research Laboratory of Hunan Provincial People's Hospital, Key Laboratory of Hunan Normal University, Changsha, Hunan Province, China
- Clinical Medical Technology Research Center of Hunan Provincial for Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
| | - Sulai Liu
- Department of Hepatobiliary Surgery, Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China.
- Biliary Disease Research Laboratory of Hunan Provincial People's Hospital, Key Laboratory of Hunan Normal University, Changsha, Hunan Province, China.
- Clinical Medical Technology Research Center of Hunan Provincial for Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China.
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10
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Gao P, Ding N, Lv J, Ramzan MN, Wen Q. α-Cyperone inhibitory effects on tumor-derived DNA trigger microglia by STING pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 264:113246. [PMID: 32781257 DOI: 10.1016/j.jep.2020.113246] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/21/2020] [Accepted: 08/02/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cyperus rotundus L. (Cyperaceae) is a widespread herbal in China and widely used in Traditional Chinese Medicine for multiple effects such as anti-arthritic, anti-genotoxic, anti-mutagenic, anti-bacterial effects, and analgesic. α-Cyperone is an active compound in Cyperus rotundus and has analgesic effects, but the exact molecular mechanisms require further investigations. MATERIALS AND METHODS Tumor-derived DNA isolated from Lewis cell lines was transfected into microglia, and analyzed for stimulator of interferon genes (STING) effects. The downstream protein, such as interferon regulatory factor 3 (IRF3) and p65 nuclear factor-κB (NF-κB) were treated with STING siRNA and 5,6-dimethyllxanthenone-4-acetic acid (DMXAA) in microglia. The α-Cyperone effect on microglia was also investigated. RESULTS Tumor-derived DNA activate microglia by upregulation of STING and downstream proteins. STING siRNA was reduced to its downstream expression and neuroinflammation inhibition was caused by tumor-derived DNA. However, DMXAA reversed the STING siRNA effect and increased neuroinflammation. α-Cyperone takes inhibitory effects on tumor-derived DNA that trigger microglia by STING pathway. CONCLUSIONS α-Cyperone inhibition by tumor-derived DNA activated microglial to neuroinflammation in STING signaling pathway.
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Affiliation(s)
- Peng Gao
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
| | - Ning Ding
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
| | - Jiaxin Lv
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
| | - Muhammad Noman Ramzan
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, 116044, China.
| | - Qingping Wen
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China; Department of Anesthesiology, Dalian Medical University, Dalian, 116044, China.
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11
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Barreto SG, Habtezion A, Gukovskaya A, Lugea A, Jeon C, Yadav D, Hegyi P, Venglovecz V, Sutton R, Pandol SJ. Critical thresholds: key to unlocking the door to the prevention and specific treatments for acute pancreatitis. Gut 2021; 70:194-203. [PMID: 32973069 PMCID: PMC7816970 DOI: 10.1136/gutjnl-2020-322163] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/01/2020] [Accepted: 08/19/2020] [Indexed: 12/11/2022]
Abstract
Acute pancreatitis (AP), an acute inflammatory disorder of the exocrine pancreas, is one of the most common gastrointestinal diseases encountered in emergency departments with no specific treatments. Laboratory-based research has formed the cornerstone of endeavours to decipher the pathophysiology of AP, because of the limitations of such study in human beings. While this has provided us with substantial understanding, we cannot answer several pressing questions. These are: (a) Why is it that only a minority of individuals with gallstones, or who drink alcohol excessively, or are exposed to other causative factors develop AP? (b) Why do only some develop more severe manifestations of AP with necrosis and/or organ failure? (c) Why have we been unable to find an effective therapeutic for AP? This manuscript provides a state-of-the-art review of our current understanding of the pathophysiology of AP providing insights into the unanswered clinical questions. We describe multiple protective factors operating in most people, and multiple stressors that in a minority induce AP, independently or together, via amplification loops. We present testable hypotheses aimed at halting progression of severity for the development of effective treatments for this common unpredictable disease.
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Affiliation(s)
- Savio George Barreto
- Division of Surgery and Perioperative Medicine, Flinders Medical Center, Bedford Park, Adelaide, South Australia, Australia
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Anna Gukovskaya
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
- Department of Medicine, West Los Angeles VA Healthcare Center, Los Angeles, California, USA
| | - Aurelia Lugea
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Christie Jeon
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dhiraj Yadav
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Peter Hegyi
- First Department of Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary
- Institute for Translational Medicine and First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
- Szentágothai Research Center, University of Pécs, Pécs, Hungary
| | - Viktória Venglovecz
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
| | - Robert Sutton
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Stephen J Pandol
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California, USA
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12
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Ferrero-Andrés A, Panisello-Roselló A, Roselló-Catafau J, Folch-Puy E. NLRP3 Inflammasome-Mediated Inflammation in Acute Pancreatitis. Int J Mol Sci 2020; 21:5386. [PMID: 32751171 PMCID: PMC7432368 DOI: 10.3390/ijms21155386] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/17/2020] [Accepted: 07/28/2020] [Indexed: 12/11/2022] Open
Abstract
The discovery of inflammasomes has enriched our knowledge in the pathogenesis of multiple inflammatory diseases. The NLR pyrin domain-containing protein 3 (NLRP3) has emerged as the most versatile and well-characterized inflammasome, consisting of an intracellular multi-protein complex that acts as a central driver of inflammation. Its activation depends on a tightly regulated two-step process, which includes a wide variety of unrelated stimuli. It is therefore not surprising that the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Inflammasome-mediated inflammation has become increasingly important in acute pancreatitis, an inflammatory disorder of the pancreas that is one of the fatal diseases of the gastrointestinal tract. This review presents an update on the progress of research into the contribution of the NLRP3 inflammasome to acute pancreatic injury, examining the mechanisms of NLRP3 activation by multiple signaling events, the downstream interleukin 1 family of cytokines involved and the current state of the literature on NLRP3 inflammasome-specific inhibitors.
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Affiliation(s)
- Ana Ferrero-Andrés
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain; (A.F.-A.); (A.P.-R.)
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain; (A.F.-A.); (A.P.-R.)
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036 Catalonia, Spain;
| | - Emma Folch-Puy
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036 Catalonia, Spain;
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13
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Böhme R, Becker C, Keil B, Damm M, Rasch S, Beer S, Schneider R, Kovacs P, Bugert P, Riedel J, Griesmann H, Ruffert C, Kaune T, Michl P, Hesselbarth N, Rosendahl J. Serum levels of advanced glycation end products and their receptors sRAGE and Galectin-3 in chronic pancreatitis. Pancreatology 2020; 20:187-192. [PMID: 31870801 DOI: 10.1016/j.pan.2019.12.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 12/09/2019] [Accepted: 12/16/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND /Objectives: AGE and their receptors like RAGE and Galectin-3 can activate inflammatory pathways and have been associated with chronic inflammatory diseases. Several studies investigated the role of AGE, Galectin-3 and sRAGE in pancreatic diseases, whereas no comprehensive data for chronic pancreatitis (CP) are available. METHODS Serum samples from CP patients without an active inflammatory process (85 ACP; 26 NACP patients) and 40 healthy controls were collected. Levels of AGE, sRAGE and Galectin-3 were measured by ELISA. To exclude potential influences of previously described RAGE SNPs on detected serum levels, we analyzed variants rs207128, rs207060, rs1800625, and rs1800624 by melting curve technique in 378 CP patients and 338 controls. RESULTS AGE and Galectin-3 serum levels were significantly elevated in both ACP and NACP patients compared to controls (AGE: 56.61 ± 3.043 vs. 31.71 ± 2.308 ng/mL; p < 0.001; Galectin-3: 16.63 ± 0.6297 vs. 10.81 ± 0.4835 ng/mL; p < 0.001). In contrast, mean serum sRAGE levels were significantly reduced in CP patients compared to controls (sRAGE: 829.7 ± 37.10 vs. 1135 ± 55.74 ng/mL; p < 0.001). All results were consistent after correction for gender, age and diabetes mellitus. No genetic association with CP was found. CONCLUSIONS Our extensive analysis demonstrated the importance of aging related pathways in the pathogenesis of CP. As the results were consistent in ACP and NACP, both entities most likely share common pathomechanisms. Most probably the involved pathways are a general hallmark of an inflammatory state in CP that is even present in symptom-free intervals.
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Affiliation(s)
- Richard Böhme
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Carla Becker
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Bettina Keil
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Marko Damm
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Sebastian Rasch
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675, München, Germany
| | - Sebastian Beer
- Department for Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany
| | - Rick Schneider
- Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, 06120, Halle (Saale), Germany
| | - Peter Kovacs
- Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany; Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, 04103, Germany
| | - Peter Bugert
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg, Mannheim, Germany
| | - Jan Riedel
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Heidi Griesmann
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Claudia Ruffert
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Tom Kaune
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Patrick Michl
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Nico Hesselbarth
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Jonas Rosendahl
- Department of Internal Medicine I, Martin Luther University, Halle, Germany.
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Habtezion A, Gukovskaya AS, Pandol SJ. Acute Pancreatitis: A Multifaceted Set of Organelle and Cellular Interactions. Gastroenterology 2019; 156:1941-1950. [PMID: 30660726 PMCID: PMC6613790 DOI: 10.1053/j.gastro.2018.11.082] [Citation(s) in RCA: 189] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 10/29/2018] [Accepted: 11/15/2018] [Indexed: 12/15/2022]
Abstract
Acute pancreatitis is an inflammatory disorder of the exocrine pancreas associated with tissue injury and necrosis. The disease can be mild, involving only the pancreas, and resolve spontaneously within days or severe, with systemic inflammatory response syndrome-associated extrapancreatic organ failure and even death. Importantly, there are no therapeutic agents currently in use that can alter the course of the disease. This article emphasizes emerging findings that stressors (environmental and genetic) that cause acute pancreatitis initially cause injury to organelles of the acinar cell (endoplasmic reticulum, mitochondria, and endolysosomal-autophagy system), and that disorders in the functions of the organelles lead to inappropriate intracellular activation of trypsinogen and inflammatory pathways. We also review emerging work on the role of damage-associated molecular patterns in mediating the local and systemic inflammatory response in addition to known cytokines and chemokine pathways. In the review, we provide considerations for correction of organelle functions in acute pancreatitis to create a discussion for clinical trial treatment and design options.
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Affiliation(s)
- Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Anna S. Gukovskaya
- Division of Gastroenterology, Department of Medicine, Department of Veterans Affairs and David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California
| | - Stephen J. Pandol
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Cedars Sinai Medical Center, Los Angeles, California
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15
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Yang R, Tonnesseen TI. DAMPs and sterile inflammation in drug hepatotoxicity. Hepatol Int 2018; 13:42-50. [PMID: 30474802 DOI: 10.1007/s12072-018-9911-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 11/02/2018] [Indexed: 12/15/2022]
Abstract
Drug hepatotoxicity is the leading cause of acute liver failure (ALF) in the developed countries. The early diagnosis and treatment are still problematic, and one important reason is the lack of reliable mechanistic biomarkers and therapeutic targets; therefore, searching for new biomarkers and therapeutic targets is urgent. Drug hepatotoxicity induces severe liver cells damage and death. Dead and damaged cells release endogenous damage-associated molecular patterns (DAMPs). Increased circulating levels of DAMPs (HMGB1, histones and DNA) can reflect the severity of drug hepatotoxicity. Elevated plasma HMGB1 concentrations can serve as early and sensitive mechanistic biomarker for clinical acetaminophen hepatotoxicity. DAMPS significantly contribute to liver injury and inhibiting the release of DAMPs ameliorates experimental hepatotoxicity. In addition, HMGB1 mediates 80% of gut bacterial translocation (BT) during acetaminophen toxicity. Gut BT triggers systemic inflammation, leading to multiple organ injury and mortality. Moreover, DAMPs can trigger and extend sterile inflammation, which contributes to early phase liver injury but improves liver regeneration at the late phase of acetaminophen overdose, because anti-inflammatory treatment reduces liver injury at early phase but impairs liver regeneration at late phase of acetaminophen toxicity, whereas pro-inflammatory therapy improves late phase liver regeneration. DAMPs are promising mechanistic biomarkers and could also be the potential therapeutic targets for drug hepatotoxicity. DAMPs-triggered sterile inflammation contributes to liver injury at early phase but improves liver regeneration at later phase of acetaminophen hepatotoxicity; therefore, anti-inflammatory therapy would be beneficial at early phase but should be avoided at the late phase of acetaminophen overdose.
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Affiliation(s)
- Runkuan Yang
- Department of Emergencies and Critical Care, Oslo University Hospital, Nydalen, PO Box 4950, 0424, Oslo, Norway. .,Department of Critical Care Medicine, University of Pittsburgh Medical School, 3550 Terrace Street, Pittsburgh, PA, 15261, USA.
| | - Tor Inge Tonnesseen
- Department of Emergencies and Critical Care, Oslo University Hospital, Nydalen, PO Box 4950, 0424, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Blindern, 0316, Oslo, Norway
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16
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Arriaga-Pizano L, Boscó-Gárate I, Martínez-Ordaz JL, Wong-Baeza I, Gutiérrez-Mendoza M, Sánchez-Fernandez P, López-Macías C, Isibasi A, Pelaez-Luna M, Cérbulo-Vázquez A, Torres-González R, Ferat-Osorio E. High Serum Levels of High-Mobility Group Box 1 (HMGB1) and Low Levels of Heat Shock Protein 70 (Hsp70) are Associated with Poor Prognosis in Patients with Acute Pancreatitis. Arch Med Res 2018; 49:504-511. [PMID: 30947809 DOI: 10.1016/j.arcmed.2019.02.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 02/03/2019] [Accepted: 02/18/2019] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Cell damage in Acute Pancreatitis (AP) lead to release of cytokines and HMGB1 and Hsp70. While Hsp70 plays a role in cytoprotection, when released to extracellular milieu constitutes, as HMGB1, a danger signal and trigger pro-inflammatory responses. These molecules seem to be related to the clinical progression; but because no evidence exists about them as molecular network in AP development, we quantify HSP70, HMGB1, and cytokines in patients with AP and search for correlations with severity and prognosis. METHODS Fifteen patients with AP were included. The average age was 52 years. Six patients had mild pancreatitis, 4 were moderately severe and 5 with a severe form. Blood samples were taken within the first 24 h, at 3d and 7d from the start. Serum HMGB1 and Hsp70 were determined using ELISA; TNF-α, IL-1β, IL-6, IL-8, IL-10 and IL-12p70 were determined by bead based immuassay. RESULTS Of all 15 patients recruited, 4 were women. Eight patients had APACHEII score higher than 8. Two patients died from AP related complications. Increase in serum HMGB1 and decrease of Hsp70 were associated with the severity and mortality. TNF-α, IL-6 and IL-8 were higher in patients that did not survive, in those with an APACHE II >8, and in those with severe AP. CONCLUSIONS High HMGB1 and low Hsp70 were associated with poor prognosis. Hsp70 might play a protective role in AP. TNF-α, IL-6, IL-8, HMGB1 and Hsp70 during hospital admissions might serve to evaluate risk of death due to AP.
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Affiliation(s)
- Lourdes Arriaga-Pizano
- Unidad de Investigación Médica en Inmunoquímica, Unidad Médica de Alta Especialidad, Hospital de Especialidades, Dr. Bernardo Sepúlveda Gutiérrez, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Ilka Boscó-Gárate
- Unidad de Investigación Médica en Inmunoquímica, Unidad Médica de Alta Especialidad, Hospital de Especialidades, Dr. Bernardo Sepúlveda Gutiérrez, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - José Luis Martínez-Ordaz
- Servicio de Cirugía Gastrointestinal, Unidad Médica de Alta Especialidad, Hospital de Especialidades Dr. Bernardo Sepúlveda Gutiérrez, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Isabel Wong-Baeza
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México, México
| | - Mireille Gutiérrez-Mendoza
- Unidad de Investigación Médica en Inmunoquímica, Unidad Médica de Alta Especialidad, Hospital de Especialidades, Dr. Bernardo Sepúlveda Gutiérrez, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Patricio Sánchez-Fernandez
- Servicio de Cirugía Gastrointestinal, Unidad Médica de Alta Especialidad, Hospital de Especialidades Dr. Bernardo Sepúlveda Gutiérrez, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Constantino López-Macías
- Unidad de Investigación Médica en Inmunoquímica, Unidad Médica de Alta Especialidad, Hospital de Especialidades, Dr. Bernardo Sepúlveda Gutiérrez, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Armando Isibasi
- Unidad de Investigación Médica en Inmunoquímica, Unidad Médica de Alta Especialidad, Hospital de Especialidades, Dr. Bernardo Sepúlveda Gutiérrez, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Mario Pelaez-Luna
- Laboratorio de Hígado, Páncreas y Motilidad Intestinal, Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Cuidad de México, México
| | - Arturo Cérbulo-Vázquez
- Programa de Estudios Combinados en Medicina, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, México
| | - Rubén Torres-González
- Dirección de Educación e Investigación en Salud, Hospital de Traumatología y Ortopedia, Dr. Victorio de la Fuente Narváez, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Eduardo Ferat-Osorio
- Unidad de Investigación Médica en Inmunoquímica, Unidad Médica de Alta Especialidad, Hospital de Especialidades, Dr. Bernardo Sepúlveda Gutiérrez, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México; Servicio de Cirugía Gastrointestinal, Unidad Médica de Alta Especialidad, Hospital de Especialidades Dr. Bernardo Sepúlveda Gutiérrez, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México.
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Zhao Q, Wei Y, Pandol SJ, Li L, Habtezion A. STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis. Gastroenterology 2018; 154:1822-1835.e2. [PMID: 29425920 PMCID: PMC6112120 DOI: 10.1053/j.gastro.2018.01.065] [Citation(s) in RCA: 164] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Revised: 01/13/2018] [Accepted: 01/29/2018] [Indexed: 01/08/2023]
Abstract
BACKGROUND & AIMS Acute pancreatitis (AP) is characterized by severe inflammation and acinar cell death. Transmembrane protein 173 (TMEM173 or STING) is a DNA sensor adaptor protein on immune cells that recognizes cytosolic nucleic acids and transmits signals that activate production of interferons and the innate immune response. We investigated whether leukocyte STING signaling mediates inflammation in mice with AP. METHODS We induced AP in C57BL/6J mice (control) and C57BL/6J-Tmem173gt/J mice (STING-knockout mice) by injection of cerulein or placement on choline-deficient DL-ethionine supplemented diet. In some mice, STING signaling was induced by administration of a pharmacologic agonist. AP was also induced in C57BL/6J mice with bone marrow transplants from control or STING-knockout mice and in mice with disruption of the cyclic GMP-AMP synthase (Cgas) gene. Pancreata were collected, analyzed by histology, and acini were isolated and analyzed by flow cytometry, quantitative polymerase chain reaction, immunoblots, and enzyme-linked immunosorbent assay. Bone-marrow-derived macrophages were collected from mice and tested for their ability to detect DNA from dying acinar cells in the presence and absence of deoxyribonuclease (DNaseI). RESULTS STING signaling was activated in pancreata from mice with AP but not mice without AP. STING-knockout mice developed less severe AP (less edema, inflammation, and markers of pancreatic injury) than control mice, whereas mice given a STING agonist developed more severe AP than controls. In immune cells collected from pancreata, STING was expressed predominantly in macrophages. Levels of cGAS were increased in mice with vs without AP, and cGAS-knockout mice had decreased edema, inflammation, and other markers of pancreatic injury upon induction of AP than control mice. Wild-type mice given bone marrow transplants from STING-knockout mice had less pancreatic injury and lower serum levels of lipase and pancreatic trypsin activity following induction of AP than mice given wild-type bone marrow. DNA from dying acinar cells activated STING signaling in macrophages, which was inhibited by addition of DNaseI. CONCLUSIONS In mice with AP, STING senses acinar cell death (by detecting DNA from dying acinar cells) and activates a signaling pathway that promotes inflammation. Macrophages express STING and activate pancreatic inflammation in AP.
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Affiliation(s)
- Qinglan Zhao
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Yi Wei
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Stephen J. Pandol
- Cedars-Sinai Medical Center and Department of Veterans Affairs, Los Angeles, California
| | - Lingyin Li
- Biochemistry Department and the ChEM-H institute, Stanford University, Stanford, California
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California.
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18
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Kim ID, Lee H, Kim SW, Lee HK, Choi J, Han PL, Lee JK. Alarmin HMGB1 induces systemic and brain inflammatory exacerbation in post-stroke infection rat model. Cell Death Dis 2018; 9:426. [PMID: 29555931 PMCID: PMC5859283 DOI: 10.1038/s41419-018-0438-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 01/13/2018] [Accepted: 02/21/2018] [Indexed: 12/21/2022]
Abstract
Post-stroke infection (PSI) is known to worsen functional outcomes of stroke patients and accounts to one-third of stroke-related deaths in hospital. In our previous reports, we demonstrated that massive release of high-mobility group box protein 1 (HMGB1), an endogenous danger signal molecule, is promoted by N-methyl-D-aspartic acid-induced acute damage in the postischemic brain, exacerbating neuronal damage by triggering delayed inflammatory processes. Moreover, augmentation of proinflammatory function of lipopolysaccharides (LPS) by HMGB1 via direct interaction has been reported. The aim of this study was to investigate the role of HMGB1 in aggravating inflammation in the PSI by exacerbating the function of LPS. PSI animal model was produced by administrating a low-dose LPS at 24 h post-middle cerebral artery occlusion (MCAO). Profound aggravations of inflammation, deterioration of behavioral outcomes, and infarct expansion were observed in LPS-injected MCAO animals, in which serum HMGB1 surge, especially disulfide type, occurred immediately after LPS administration and aggravated brain and systemic inflammations probably by acting in synergy with LPS. Importantly, blockage of HMGB1 function by delayed administrations of therapeutic peptides known to inhibit HMGB1 (HMGB1 A box, HPep1) or by treatment with LPS after preincubation with HMGB1 A box significantly ameliorated damages observed in the rat PSI model, demonstrating that HMGB1 plays a crucial role. Furthermore, administration of Rhodobacter sphaeroides LPS, a selective toll-like receptor 4 antagonist not only failed to exert these effects but blocked the effects of LPS, indicating its TLR4 dependence. Together, these results indicated that alarmin HMGB1 mediates potentiation of LPS function, exacerbating TLR4-dependent systemic and brain inflammation in a rat PSI model and there is a positive-feedback loop between augmentation of LPS function by HMGB1 and subsequent HMGB1 release/serum. Therefore, HMGB1 might be a valuable therapeutic target for preventing post-stroke infection.
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Affiliation(s)
- Il-Doo Kim
- Department of Anatomy, Inha University School of Medicine, Inchon, Republic of Korea.,Medical Research Center, Inha University School of Medicine, Inchon, Republic of Korea
| | - Hahnbie Lee
- Department of Anatomy, Inha University School of Medicine, Inchon, Republic of Korea.,Medical Research Center, Inha University School of Medicine, Inchon, Republic of Korea
| | - Seung-Woo Kim
- Medical Research Center, Inha University School of Medicine, Inchon, Republic of Korea.,Department of Biomedical Sciences, Inha University School of Medicine, Inchon, Republic of Korea
| | - Hye-Kyung Lee
- Medical Research Center, Inha University School of Medicine, Inchon, Republic of Korea.,Department of Biomedical Sciences, Inha University School of Medicine, Inchon, Republic of Korea
| | - Juli Choi
- Department of Brain and Cognitive Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Pyung-Lim Han
- Department of Brain and Cognitive Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Ja-Kyeong Lee
- Medical Research Center, Inha University School of Medicine, Inchon, Republic of Korea. .,Department of Biomedical Sciences, Inha University School of Medicine, Inchon, Republic of Korea.
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19
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Yang R, Zhu S, Pischke SE, Haugaa H, Zou X, Tonnessen TI. Bile and circulating HMGB1 contributes to systemic inflammation in obstructive jaundice. J Surg Res 2018; 228:14-19. [PMID: 29907203 DOI: 10.1016/j.jss.2018.02.049] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 02/08/2018] [Accepted: 02/22/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Obstructive jaundice (OJ) patients with cholangitis are prone to sepsis; however, the underlying mechanisms are still not clear and need to be clarified. METHODS Analyzing all available published data related to the title of this article. RESULTS OJ leads to absence of gut luminal bile and accumulation of hepatic and circulating bile acids. Absence of gut luminal bile deprives the gut from its antiinflammatory, endotoxin-binding, bacteriostatic, mucosal-trophic, epithelial tight-junction maintaining, and gut motility-regulating effects, leading to gut bacterial overgrowth, mucosal atrophy, mucosal tight-junction loss, and gut motility dysfunction. These alterations promote intestinal endotoxin and bacterial translocation (BT) into portal and systemic circulation. Gut BT triggers systemic inflammation, which can lead to multiple organ dysfunctions in OJ. The accumulation of hepatic and circulating bile acids kills/damages hepatocyte and Kupffer cells, and it also significantly decreases the number of liver natural killer T-cells in OJ. This results in impaired hepatic and systemic immune function, which facilitates BT. In addition, neutralizing bile HMGB1 can reverse endotoxemic bile-induced gut BT and mucosal injury in mice, suggesting that bile HMGB1 in OJ patients can be responsible for internal drainage-related clinical complications. Moreover, the elevated circulating HMGB1 level may contribute to multiple organ injuries, and it might also mediate gut BT in OJ. CONCLUSIONS HMGB1 may significantly contribute to systemic inflammation and multiple organ dysfunctions in OJ.
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Affiliation(s)
- Runkuan Yang
- Department of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway; Department of Critical Care Medicine, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania.
| | - Shengtao Zhu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Soeren Erik Pischke
- Department of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
| | - Hakon Haugaa
- Department of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway; Lovisenberg Diaconal University College, Oslo, Norway
| | - Xiaoping Zou
- Department of Gastroenterology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Tor Inge Tonnessen
- Department of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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20
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Kanak MA, Shindo Y, SaiKumar P, Naziruddin B. Role of Inflammasomes in the Development of Gastrointestinal Diseases. EXPERIENTIA SUPPLEMENTUM (2012) 2018; 108:235-268. [PMID: 30536174 DOI: 10.1007/978-3-319-89390-7_10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Many diseases of the gastrointestinal tract have been attributed to chronic inflammation, and a few have identified the role of inflammasomes in their pathogenesis. Inflammasomes are a group of protein complexes comprising of several intracellular proteins that link the sensing of microbial products and metabolic stress to the proteolytic activation of the proinflammatory cytokines. Recent studies have implicated activation of several families of NOD-like receptors (NLRs) which are major components of inflammasomes in the development and exacerbation of many diseases of human systems. In this chapter, we discuss the role of inflammasomes in some of the most prevalent diseases of the gastrointestinal tract and highlight potential targets for treatment.
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Affiliation(s)
- Mazhar A Kanak
- Division of Transplantation, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, VA, USA
| | - Yoshitaro Shindo
- Division of Transplantation, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, VA, USA
| | | | - Bashoo Naziruddin
- Sammons Cancer Center, Baylor Simmons Transplant Institute, Dallas, TX, USA.
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21
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A novel synthetic derivative of squamosamide FLZ inhibits the high mobility group box 1 protein-mediated neuroinflammatory responses in murine BV2 microglial cells. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2017; 390:643-650. [PMID: 28280849 DOI: 10.1007/s00210-017-1363-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2016] [Accepted: 02/20/2017] [Indexed: 10/20/2022]
Abstract
High mobility group box 1 (HMGB1) is a critical pro-inflammatory cytokine that contributes to the pathogenesis of various human diseases. FLZ, a squamosamide derivative, has been demonstrated to have neuroprotective effects in Parkinson's disease models and shows strong anti-inflammatory activity, while the precise mechanism remains unclear. Here, we investigated the anti-inflammatory mechanism of FLZ on HMGB1-mediated inflammatory responses. The effects of FLZ on HMGB1 release from microglial cells induced by lipopolysaccharide were first explored by Western blot assay and ELISA. Then, co-immunoprecipition was used to study FLZ's effect on the interaction between HMGB1 and its receptor TLR4. Finally, we employed HMGB1 to simulate pro-inflammatory responses and then studied the inhibitory effects of FLZ on its bioactivity. FLZ has a significant inhibitory effect on HMGB1 release while it exerts no inhibitory effect on the binding between HMGB1 and TLR4. After the recognition of HMGB1 by TLR4, NF-κB signaling pathway is activated. FLZ could efficaciously alleviate HMGB1-induced inflammatory responses via the suppression of TLR4/MyD88/NF-κB signaling pathway. FLZ could inhibit HMGB1 release as well as HMGB1-induced inflammatory responses, HMGB1 might be one of the FLZ anti-inflammatory targets, and interfering at this inflammatory mediator may have benefit effects on neurodegenerative disorders, such as Parkinson's disease.
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22
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HMGB1 and Histones Play a Significant Role in Inducing Systemic Inflammation and Multiple Organ Dysfunctions in Severe Acute Pancreatitis. Int J Inflam 2017; 2017:1817564. [PMID: 28316860 PMCID: PMC5339498 DOI: 10.1155/2017/1817564] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 11/13/2016] [Indexed: 01/01/2023] Open
Abstract
Severe acute pancreatitis (SAP) starts as a local inflammation of pancreatic tissue that induces the development of multiple extrapancreatic organs dysfunction; however, the underlying mechanisms are still not clear. Ischemia-reperfusion, circulating inflammatory cytokines, and possible bile cytokines significantly contribute to gut mucosal injury and intestinal bacterial translocation (BT) during SAP. Circulating HMGB1 level is significantly increased in SAP patients and HMGB1 is an important factor that mediates (at least partly) gut BT during SAP. Gut BT plays a critical role in triggering/inducing systemic inflammation/sepsis in critical illness, and profound systemic inflammatory response syndrome (SIRS) can lead to multiple organ dysfunction syndrome (MODS) during SAP, and systemic inflammation with multiorgan dysfunction is the cause of death in experimental SAP. Therefore, HMGB1 is an important factor that links gut BT and systemic inflammation. Furthermore, HMGB1 significantly contributes to multiple organ injuries. The SAP patients also have significantly increased circulating histones and cell-free DNAs levels, which can reflect the disease severity and contribute to multiple organ injuries in SAP. Hepatic Kupffer cells (KCs) are the predominant source of circulating inflammatory cytokines in SAP, and new evidence indicates that hepatocyte is another important source of circulating HMGB1 in SAP; therefore, treating the liver injury is important in SAP.
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23
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Lui G, Wong CK, Ip M, Chu YJ, Yung IMH, Cheung CSK, Zheng L, Lam JSY, Wong KT, Sin WWY, Choi KW, Lee N. HMGB1/RAGE Signaling and Pro-Inflammatory Cytokine Responses in Non-HIV Adults with Active Pulmonary Tuberculosis. PLoS One 2016; 11:e0159132. [PMID: 27434276 PMCID: PMC4951129 DOI: 10.1371/journal.pone.0159132] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 06/28/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND We aimed to study the pathogenic roles of High-Mobility Group Box 1 (HMGB1) / Receptor-for-Advanced-Glycation-End-products (RAGE) signaling and pro-inflammatory cytokines in patients with active pulmonary tuberculosis (PTB). METHODS A prospective study was conducted among non-HIV adults newly-diagnosed with active PTB at two acute-care hospitals (n = 80); age-and-sex matched asymptomatic individuals (tested for latent TB) were used for comparison (n = 45). Plasma concentrations of 8 cytokines/chemokines, HMGB1, soluble-RAGE, and transmembrane-RAGE expressed on monocytes/dendritic cells, were measured. Gene expression (mRNA) of HMGB1, RAGE, and inflammasome-NALP3 was quantified. Patients' PBMCs were stimulated with recombinant-HMGB1 and MTB-antigen (lipoarabinomannan) for cytokine induction ex vivo. RESULTS In active PTB, plasma IL-8/CXCL8 [median(IQR), 6.0(3.6-15.1) vs 3.6(3.6-3.6) pg/ml, P<0.001] and IL-6 were elevated, which significantly correlated with mycobacterial load, extent of lung consolidation (rs +0.509, P<0.001), severity-score (rs +0.317, P = 0.004), and fever and hospitalization durations (rs +0.407, P<0.001). IL-18 and sTNFR1 also increased. Plasma IL-8/CXCL8 (adjusted OR 1.12, 95%CI 1.02-1.23 per unit increase, P = 0.021) and HMGB1 (adjusted OR 1.42 per unit increase, 95%CI 1.08-1.87, P = 0.012) concentrations were independent predictors for respiratory failure, as well as for ICU admission/death. Gene expression of HMGB1, RAGE, and inflammasome-NALP3 were upregulated (1.2-2.8 fold). Transmembrane-RAGE was increased, whereas the decoy soluble-RAGE was significantly depleted. RAGE and HMGB1 gene expressions positively correlated with cytokine levels (IL-8/CXCL8, IL-6, sTNFR1) and clinico-/radiographical severity (e.g. extent of consolidation rs +0.240, P = 0.034). Ex vivo, recombinant-HMGB1 potentiated cytokine release (e.g. TNF-α) when combined with lipoarabinomannan. CONCLUSION In patients with active PTB, HMGB1/RAGE signaling and pro-inflammatory cytokines may play important roles in pathogenesis and disease manifestations. Our clinico-immunological data can provide basis for the development of new strategies for disease monitoring, management and control.
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Affiliation(s)
- Grace Lui
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China
| | - Chun Kwok Wong
- Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Margaret Ip
- Department of Microbiology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yi Jun Chu
- Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Irene M. H. Yung
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China
| | | | - Lin Zheng
- Department of Microbiology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Judy S. Y. Lam
- Department of Imaging and Interventional Radiology, Prince of Wales Hospital, Hong Kong SAR, China
| | - Ka Tak Wong
- Department of Imaging and Interventional Radiology, Prince of Wales Hospital, Hong Kong SAR, China
| | - Winnie W. Y. Sin
- Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong SAR, China
| | - Kin Wing Choi
- Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong SAR, China
| | - Nelson Lee
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China
- Stanley Ho Center for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong SAR, China
- * E-mail:
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Regulation of autophagy by systemic admission of microRNA-141 to target HMGB1 in l-arginine-induced acute pancreatitis in vivo. Pancreatology 2016; 16:337-46. [PMID: 27017485 DOI: 10.1016/j.pan.2016.03.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 02/22/2016] [Accepted: 03/04/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS MicroRNAs are endogenous, non-coding RNAs of approximately 20-22 nucleotides that regulate gene expression by binding to the 3' untranslated region (UTR) of target mRNAs and can be applied in gene therapy. Acute pancreatitis is an inflammatory pancreatic disease that carries considerable morbidity and mortality. The purpose of this study was to explore the therapeutic potential of microRNA-141 (miR-141) for acute pancreatitis in vivo. METHODS AP was induced by two hourly intra-peritoneal (i.p.) injections of l-arginine (200mg × 2/100 g.BW). Control mice received normal saline injections. In a separate group, normal saline, empty adenoviral vector and miR-141 adenoviral vector were given to the mice via tail vein hydrodynamically at 72 h before the first l-arginine injection. All the mice were euthanized at 24 h after the last l-arginine injection, and the pancreatic tissues were assessed by qRT-PCR, Western blotting and electron microscopy. RESULTS miR-141 directly inhibited HMGB1 expression in mouse hepal-6 cell. Furthermore, systemic administration of the miR-141 knock-down the expression of HMGB1 protein and further antagonized the downstream protein Beclin-1, leading to the reduction of autophagosomes and autolysosomes, blockade of the LC3-II level and the increased levels of p62 protein after injection of l-arginine. In addition, the level of Lamp-2 was not significantly different. CONCLUSIONS For the first time miR-141 was applied in acute pancreatitis treatment in vivo. Inhibition of HMGB1 by miR-141 may block the process of autophagosome formation through the HMGB1/Beclin-1 pathway. The miR-141 appears to be a promising candidate for the gene therapy of acute pancreatitis.
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25
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Penttilä AK, Rouhiainen A, Kylänpää L, Mustonen H, Puolakkainen P, Rauvala H, Repo H. Circulating nucleosomes as predictive markers of severe acute pancreatitis. J Intensive Care 2016; 4:14. [PMID: 26893906 PMCID: PMC4758106 DOI: 10.1186/s40560-016-0135-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 02/03/2016] [Indexed: 01/26/2023] Open
Abstract
Background The components of nucleosomes, which contain DNA and histones, are released into the circulation from damaged cells and can promote inflammation. We studied whether the on-admission levels of circulating nucleosomes predict the development of severe acute pancreatitis (AP), in particular among the patients who present without clinical signs of organ dysfunction. Methods This is a prospective study of 74 AP patients admitted to Helsinki University Hospital from 2003 to 2007. Twenty-three patients had mild, 27 moderately severe, and 24 severe AP as defined by the revised Atlanta criteria. 14/24 severe AP patients had no sign of organ dysfunction on admission (modified marshall score <2). Blood samples were obtained on admission and the plasma levels of nucleosomes were measured using enzyme-linked immunosorbent assay. Results The on-admission levels of nucleosomes were significantly higher in severe AP than in mild or moderately severe AP (p < 0.001 for all), higher in non-survivors (n = 8) than in survivors (p = 0.019), and correlated with the on-admission levels of C-reactive protein (p < 0.001) and creatinine (p < 0.001). Among the AP patients who presented without organ dysfunction, the on-admission nucleosome level was an independent predictor of severe AP (p = 0.038, gender-adjusted forward-stepping logistic regression). Conclusions Circulating nucleosome levels may be helpful in identifying, on admission to hospital, the AP patients who present without clinical signs of organ dysfunction, and, yet, are bound to develop organ dysfunction during hospitalization.
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Affiliation(s)
- Anne K Penttilä
- Department of Surgery, Helsinki University Hospital, P.O. Box 340, 00029 HUS Helsinki, Finland
| | - Ari Rouhiainen
- Neuroscience Center, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.,Department of Biosciences, University of Helsinki, P.O. Box 65, 00014 Helsinki, Finland
| | - Leena Kylänpää
- Department of Surgery, Helsinki University Hospital, P.O. Box 340, 00029 HUS Helsinki, Finland
| | - Harri Mustonen
- Department of Surgery, Helsinki University Hospital, P.O. Box 340, 00029 HUS Helsinki, Finland
| | - Pauli Puolakkainen
- Department of Surgery, Helsinki University Hospital, P.O. Box 340, 00029 HUS Helsinki, Finland.,Institute of Clinical Medicine, University of Helsinki, P.O. Box 340, 00029 HUS Helsinki, Finland
| | - Heikki Rauvala
- Neuroscience Center, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland
| | - Heikki Repo
- Department of Bacteriology and Immunology, University of Helsinki, The Haartman Institute, P.O. Box 21, 00014 Helsinki, Finland
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Abstract
The intestinal symbiotic microbes and the human body depend on each other to form the intestinal microecology system of the human body. Symbiotic microorganisms play an important role in many diseases through the interaction between pathogens and host pattern recognition receptors. Pathogen-associated molecular pattern (PAMPs) and damage-associated molecular patterns (DAMPs) are involved in the progression of pancreatitis. Intestinal microecology plays an important role in the pathogenesis of pancreatitis. Acute pancreatitis, which is associated with intestinal barrier dysfunction and bacterial translocation, increases the risk of pancreatic infection and death. Infection with intestinal bacteria is related to the development of chronic pancreatitis, and it may induce autoimmune pancreatitis (AIP) by molecular modeling. Understanding the relationship between intestinal microecology and pancreatitis will provide guidance and direction for the diagnosis and treatment of pancreatitis.
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Abstract
OBJECTIVES Extracellular histones are rapidly cleared by the liver and rarely detectable in the circulation unless there is extensive cell death, as in severe trauma and sepsis. This study investigated whether circulating histones are elevated in experimental acute pancreatitis models and correlate to disease severity. METHODS Acute pancreatitis was induced in mice by: (1) 4 or (2) 12 intraperitoneal injections of cerulein (50 μg/kg) at 1 hour apart; (3) retrograde infusion of 3.5% sodium taurocholate into the biliopancreatic duct. Mice were sacrificed at various time points to collect blood and tissues. Severity of pancreatitis was assessed by biochemical markers and histopathology. Circulating histones were determined by Western blotting. RESULTS Four cerulein injections induced edematous pancreatitis, whereas 12 cerulein injections and ductal taurocholate infusion caused necrotizing pancreatitis. Circulating histones were barely detectable in the blood of animals with edematous pancreatitis but significantly increased in necrotizing pancreatitis. The levels of circulating histones were strongly correlated to histopathological scores of necrosis of the pancreas. CONCLUSIONS Circulating histones increased significantly in necrotizing pancreatitis due to extensive pancreatic acinar cell death. Levels of circulating histones may have translational potential as a biomarker of disease severity.
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Abstract
PURPOSE OF REVIEW This report reviews recent animal model and human studies associated with inflammatory responses in acute and chronic pancreatitis. RECENT FINDINGS Animal model and limited human acute and chronic pancreatitis studies unravel the dynamic nature of the inflammatory processes and the ability of the immune cells to sense danger and environmental signals. In acute pancreatitis, such molecules include pathogen-associated molecular pattern recognition receptors such as toll-like receptors, and the more recently appreciated damage-associated molecular pattern molecules or 'alarmin' high mobility group box 1 and IL-33. In chronic pancreatitis, a recent understanding of a critical role for macrophage-pancreatic stellate cell interaction offers a potential targetable pathway that can alter fibrogenesis. Microbiome research in pancreatitis is a new field gaining interest but will require further investigation. SUMMARY Immune cell contribution to the pathogenesis of acute and chronic pancreatitis is gaining more appreciation and further understanding in immune signaling presents potential therapeutic targets that can alter disease progression.
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HMGB1-binding heptamer suppresses the synergistic effect of HMGB1 and LPS by interacting directly with HMGB1. Neurosci Lett 2015; 593:40-4. [DOI: 10.1016/j.neulet.2015.03.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 02/18/2015] [Accepted: 03/06/2015] [Indexed: 11/17/2022]
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Shen X, Li WQ. High-mobility group box 1 protein and its role in severe acute pancreatitis. World J Gastroenterol 2015; 21:1424-1435. [PMID: 25663762 PMCID: PMC4316085 DOI: 10.3748/wjg.v21.i5.1424] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2014] [Revised: 10/07/2014] [Accepted: 11/11/2014] [Indexed: 02/06/2023] Open
Abstract
The high mobility group box 1 (HMGB1), which belongs to the subfamily of HMG-1/-2, is a highly conserved single peptide chain consisting of 215 amino acid residues with a molecular weight of approximately 24894 Da. HMGB1 is a ubiquitous nuclear protein in mammals and plays a vital role in inflammatory diseases. Acute pancreatitis is one of the most common causes of acute abdominal pain with a poor prognosis. Acute pancreatitis is an acute inflammatory process of the pancreas (duration of less than six months), for which the severe form is called severe acute pancreatitis (SAP). More and more studies have shown that HMGB1 has a bidirectional effect in the pathogenesis of SAP. Extracellular HMGB1 can aggravate the pancreatic inflammatory process, whereas intracellular HMGB1 has a protective effect against pancreatitis. The mechanism of HMGB1 is multiple, mainly through the nuclear factor-κB pathway. Receptors for advanced glycation end-products and toll-like receptors (TLR), especially TLR-2 and TLR-4, are two major types of receptors mediating the inflammatory process triggered by HMGB1 and may be also the main mediators in the pathogenesis of SAP. HMGB1 inhibitors, such as ethyl pyruvate, pyrrolidine dithiocarbamate and Scolopendra subspinipes mutilans, can decrease the level of extracellular HMGB1 and are the promising targets in the treatment of SAP.
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Correlation between serum levels of high mobility group box-1 protein and pancreatitis: a meta-analysis. BIOMED RESEARCH INTERNATIONAL 2015; 2015:430185. [PMID: 25695079 PMCID: PMC4324490 DOI: 10.1155/2015/430185] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 10/30/2014] [Indexed: 12/12/2022]
Abstract
Background. Aberrant expression of high mobility group box-1 protein (HMGB1) contributes to the progression of various inflammatory diseases. This meta-analysis focused on the clinical significance of serum HMGB1 levels in pancreatitis patients, with the goal of building a novel diagnostic score model. Method. We conducted a meta-analysis by searching in the PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine (CBM), and China National Knowledge Infrastructure (CNKI) databases without any language restrictions. Studies were pooled and standard mean difference (SMD) and its corresponding 95% confidence intervals (95% CIs) were calculated. Version 12.0 STATA software was used for statistical analysis. Results. We performed a final analysis of 841 subjects from 12 clinical case-control studies. The meta-analysis results showed a positive association between serum HMGB1 levels and the progression of pancreatitis. In the subgroup analysis by country, high serum level of HMGB1 may be related to pancreatitis progression in China, Korea, Hungary, and Japan populations (all P < 0.05). Conclusion. The present meta-analysis indicated that serum HMGB1 level was statistically elevated in patients with pancreatitis, and thus serum levels of HMGB1 could be determined to be a useful biomarker for pancreatitis patients.
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32
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Leal-Lopes C, Velloso FJ, Campopiano JC, Sogayar MC, Correa RG. Roles of Commensal Microbiota in Pancreas Homeostasis and Pancreatic Pathologies. J Diabetes Res 2015; 2015:284680. [PMID: 26347203 PMCID: PMC4544440 DOI: 10.1155/2015/284680] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2015] [Accepted: 07/09/2015] [Indexed: 12/12/2022] Open
Abstract
The pancreas plays a central role in metabolism, allowing ingested food to be converted and used as fuel by the cells throughout the body. On the other hand, the pancreas may be affected by devastating diseases, such as pancreatitis, pancreatic adenocarcinoma (PAC), and diabetes mellitus (DM), which generally results in a wide metabolic imbalance. The causes for the development and progression of these diseases are still controversial; therefore it is essential to better understand the underlying mechanisms which compromise the pancreatic homeostasis. The interest in the study of the commensal microbiome increased extensively in recent years, when many discoveries have illustrated its central role in both human physiology and maintenance of homeostasis. Further understanding of the involvement of the microbiome during the development of pathological conditions is critical for the improvement of new diagnostic and therapeutic approaches. In the present review, we discuss recent findings on the behavior and functions played by the microbiota in major pancreatic diseases and provide further insights into its potential roles in the maintenance of pancreatic steady-state activities.
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Affiliation(s)
- Camila Leal-Lopes
- Department of Biochemistry, Chemistry Institute, University of São Paulo, 05508-000 São Paulo, SP, Brazil
- Cell and Molecular Therapy Center (NUCEL-NETCEM), School of Medicine, University of São Paulo, 05360-130 São Paulo, SP, Brazil
| | - Fernando J. Velloso
- Cell and Molecular Therapy Center (NUCEL-NETCEM), School of Medicine, University of São Paulo, 05360-130 São Paulo, SP, Brazil
| | - Julia C. Campopiano
- Cell and Molecular Therapy Center (NUCEL-NETCEM), School of Medicine, University of São Paulo, 05360-130 São Paulo, SP, Brazil
| | - Mari C. Sogayar
- Department of Biochemistry, Chemistry Institute, University of São Paulo, 05508-000 São Paulo, SP, Brazil
- Cell and Molecular Therapy Center (NUCEL-NETCEM), School of Medicine, University of São Paulo, 05360-130 São Paulo, SP, Brazil
| | - Ricardo G. Correa
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
- *Ricardo G. Correa:
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Lv JC, Wang G, Pan SH, Bai XW, Sun B. Lycopene protects pancreatic acinar cells against severe acute pancreatitis by abating the oxidative stress through JNK pathway. Free Radic Res 2014; 49:151-63. [PMID: 25410533 DOI: 10.3109/10715762.2014.988150] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This study investigated the anti-oxidative and anti-inflammatory effects of lycopene on severe acute pancreatitis (SAP) in both in vivo and in vitro models. Utilizing a rat model, we found that lycopene administration protected against SAP, as indicated by the decreased levels of serum amylase and C-reactive protein. Pathological changes were alleviated by pretreatment with lycopene. The serum levels of tumor necrosis factor-α, interleukin-6, macrophage inflammatory protein-1α, and monocyte chemotactic protein-1 were decreased by lycopene. The decreased reactive oxygen species (ROS) content in the pancreatic tissues of the lycopene-treated group were indirectly evaluated by measuring the levels of myeloperoxidase, lipid peroxidase, and superoxide dismutase. Lycopene protected acinar cells against necrosis and apoptosis by relieving the mitochondrial and endoplasmic stress caused by ROS which was shown in electron microscopy and immunohistochemistry staining of active nuclear factor-κB p65. The protective effect was also observed in a simulated SAP model in a rat acinar cell line. ROS and apoptotic staining were compared between groups. Lycopene exerts protective effects against SAP in rats that may be related to its anti-inflammatory property through inhibiting the expression of damage-associated molecular patterns, and anti-oxidative property which can thus maintain cellular homeostasis and prevent the phosphorylation of JNK pathway.
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Affiliation(s)
- J C Lv
- Department of Pancreatic and Biliary Surgery, the First Affiliated Hospital of Harbin Medical University , Harbin, Heilongjiang , P. R. China
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Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, Sun X, Wang H, Wang Q, Tsung A, Billiar TR, Zeh HJ, Lotze MT, Tang D. HMGB1 in health and disease. Mol Aspects Med 2014; 40:1-116. [PMID: 25010388 PMCID: PMC4254084 DOI: 10.1016/j.mam.2014.05.001] [Citation(s) in RCA: 740] [Impact Index Per Article: 67.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 05/05/2014] [Indexed: 12/22/2022]
Abstract
Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed high-mobility group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhibitors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localization, structure, post-translational modification, and identification of additional partners will undoubtedly uncover additional secrets regarding HMGB1's multiple functions.
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Affiliation(s)
- Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
| | - Ruochan Chen
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Qiuhong Zhang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Wen Hou
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Sha Wu
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Lizhi Cao
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Jin Huang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yan Yu
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xue-Gong Fan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhengwen Yan
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA; Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Xiaofang Sun
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Experimental Department of Institute of Gynecology and Obstetrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Haichao Wang
- Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA
| | - Qingde Wang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Allan Tsung
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Herbert J Zeh
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Michael T Lotze
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
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Abstract
High-mobility group box 1 (HMGB1) was originally defined as a ubiquitous nuclear protein, but it was later determined that the protein has different roles both inside and outside of cells. Nuclear HMGB1 regulates chromatin structure and gene transcription, whereas cytosolic HMGB1 is involved in inflammasome activation and autophagy. Extracellular HMGB1 has drawn attention because it can bind to related cell signalling transduction receptors, such as the receptor for advanced glycation end products, Toll-like receptor (TLR)2, TLR4 and TLR9. It also participates in the development and progression of a variety of diseases. HMGB1 is actively secreted by stimulation of the innate immune system, and it is passively released by ischaemia or cell injury. This review focuses on the important role of HMGB1 in the pathogenesis of acute and chronic sterile inflammatory conditions. Strategies that target HMGB1 have been shown to significantly decrease inflammation in several disease models of sterile inflammation, and this may represent a promising clinical approach for treatment of certain conditions associated with sterile inflammation.
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Affiliation(s)
- A Tsung
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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Yanai H, Taniguchi T. Nucleic acid sensing and beyond: virtues and vices of high-mobility group box 1. J Intern Med 2014; 276:444-53. [PMID: 25041239 DOI: 10.1111/joim.12285] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
High-mobility group box 1 (HMGB1) was first described as an architectural chromatin-binding protein. Today, a wealth of evidence indicates that this protein is very versatile and serves an amazing assortment of roles in the nucleus, cytoplasm and extracellular milieu. As a result, HMGB1 is fast becoming recognized as a key regulator of protective and pathological immune responses. Whilst acknowledging the many functions of HMGB1 and its family members, we focus this review on their role as broad effectors of immune responses mediated by nucleic acids. In addition, we touch upon the recent progress in determining the in vivo role of HMGB1 as revealed by the study of mice conditionally null for the Hmgb1 gene.
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Affiliation(s)
- H Yanai
- Department of Molecular Immunology, Institute of Industrial Science, Max Planck-The University of Tokyo Center for Integrative Inflammology, The University of Tokyo, Tokyo, Japan; Core Research for Evolution Science and Technology, Japan Science and Technology Agency, Tokyo, Japan
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Kang R, Lotze MT, Zeh HJ, Billiar TR, Tang D. Cell death and DAMPs in acute pancreatitis. Mol Med 2014; 20:466-77. [PMID: 25105302 PMCID: PMC4277549 DOI: 10.2119/molmed.2014.00117] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Accepted: 08/04/2014] [Indexed: 12/18/2022] Open
Abstract
Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (for example, high mobility group box 1, DNA, histones and adenosine triphosphate) provides significant protection against experimental AP. Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis and management of AP. DAMPs might be an attractive therapeutic target in AP.
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Affiliation(s)
- Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Michael T Lotze
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Herbert J Zeh
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
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Palmiere C, Augsburger M, Mangin P. High-mobility group box-1 protein determination in postmortem samples. Forensic Sci Int 2014; 239:103-6. [DOI: 10.1016/j.forsciint.2014.03.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Revised: 02/13/2014] [Accepted: 03/24/2014] [Indexed: 12/27/2022]
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Kang R, Zhang Q, Hou W, Yan Z, Chen R, Bonaroti J, Bansal P, Billiar TR, Tsung A, Wang Q, Bartlett DL, Whitcomb DC, Chang EB, Zhu X, Wang H, Lu B, Tracey KJ, Cao L, Fan XG, Lotze MT, Zeh HJ, Tang D. Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice. Gastroenterology 2014; 146:1097-107. [PMID: 24361123 PMCID: PMC3965592 DOI: 10.1053/j.gastro.2013.12.015] [Citation(s) in RCA: 255] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 12/08/2013] [Accepted: 12/09/2013] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS High mobility group box 1 (HMGB1) is an abundant protein that regulates chromosome architecture and also functions as a damage-associated molecular pattern molecule. Little is known about its intracellular roles in response to tissue injury or during subsequent local and systemic inflammatory responses. We investigated the function of Hmgb1 in mice after induction of acute pancreatitis. METHODS We utilized a Cre/LoxP system to create mice with pancreas-specific disruption in Hmbg1 (Pdx1-Cre; HMGB1(flox/flox) mice). Acute pancreatitis was induced in these mice (HMGB1(flox/flox) mice served as controls) after injection of l-arginine or cerulein. Pancreatic tissues and acinar cells were collected and analyzed by histologic, immunoblot, and immunohistochemical analyses. RESULTS After injection of l-arginine or cerulein, Pdx1-Cre; HMGB1(flox/flox) mice developed acute pancreatitis more rapidly than controls, with increased mortality. Pancreatic tissues of these mice also had higher levels of serum amylase, acinar cell death, leukocyte infiltration, and interstitial edema than controls. Pancreatic tissues and acinar cells collected from the Pdx1-Cre; HMGB1(flox/flox) mice after l-arginine or cerulein injection demonstrated nuclear catastrophe with greater nucleosome release when compared with controls, along with increased phosphorylation/activation of RELA nuclear factor κB, degradation of inhibitor of κB, and phosphorylation of mitogen-activated protein kinase. Inhibitors of reactive oxygen species (N-acetyl-l-cysteine) blocked l-arginine-induced DNA damage, necrosis, apoptosis, release of nucleosomes, and activation of nuclear factor κB in pancreatic tissues and acinar cells from Pdx1-Cre; HMGB1(flox/flox) and control mice. Exogenous genomic DNA and recombinant histone H3 proteins significantly induced release of HMGB1 from mouse macrophages; administration of antibodies against H3 to mice reduced serum levels of HMGB1 and increased survival after l-arginine injection. CONCLUSIONS In 2 mouse models of acute pancreatitis, intracellular HMGB1 appeared to prevent nuclear catastrophe and release of inflammatory nucleosomes to block inflammation. These findings indicate a role for the innate immune response in tissue damage.
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Affiliation(s)
- Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
| | - Qiuhong Zhang
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Wen Hou
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Zhenwen Yan
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA, Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Ruochan Chen
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Jillian Bonaroti
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Preeti Bansal
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Timothy R. Billiar
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Allan Tsung
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Qingde Wang
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - David L. Bartlett
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - David C Whitcomb
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Eugene B. Chang
- Department of Medicine, University of Chicago; Chicago, IL 60637, USA
| | - Xiaorong Zhu
- Department of Medicine, University of Chicago; Chicago, IL 60637, USA
| | - Haichao Wang
- Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York 11030, USA
| | - Ben Lu
- Laboratory of Biomedical Science, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA
| | - Kevin J. Tracey
- Laboratory of Biomedical Science, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA
| | - Lizhi Cao
- Department of Pediatrics Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xue-Gong Fan
- Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Michael T. Lotze
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA,Correspondence should be directed to Dr. Daolin Tang (), Dr. Rui Kang (), Dr. Michael T. Lotze (), or Dr. Herbert J. Zeh ()
| | - Herbert J. Zeh
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA,Correspondence should be directed to Dr. Daolin Tang (), Dr. Rui Kang (), Dr. Michael T. Lotze (), or Dr. Herbert J. Zeh ()
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Kim ID, Lee JK. HMGB1-Binding Heptamer Confers Anti-Inflammatory Effects in Primary Microglia Culture. Exp Neurobiol 2013; 22:301-7. [PMID: 24465145 PMCID: PMC3897691 DOI: 10.5607/en.2013.22.4.301] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 12/17/2013] [Accepted: 12/17/2013] [Indexed: 11/19/2022] Open
Abstract
High mobility group box 1 (HMGB1) is an endogenous danger signal molecule. In the postischemic brain, HMGB1 is massively released during NMDA-induced acute damage and triggers inflammatory processes. In a previous study, we demonstrated that intranasally delivered HMGB1 binding heptamer peptide (HBHP; HMSKPVQ) affords robust neuroprotective effects in the ischemic brain after middle cerebral artery occlusion (MCAO, 60 minutes). In the present study, we investigated HBHP-induced anti-inflammatory effects on microglia activation. In LPS-treated primary microglia culture, HMGB1 was rapidly released and accumulated in culture media. Furthermore, LPS-conditioned media collected from primary microglia cultures (LCM) activated naïve microglia and markedly induced NO and proinflammatory cytokines. However, the suppression of HMGB1 by siRNA-HMGB1, HMGB1 A box, or anti-HMGB1 antibody significantly attenuated LCM-induced microglial activation, suggesting that HMGB1 plays a critical role in this process. A pull-down assay using biotin-labeled HBHP showed that HBHP binds directly to HMGB1 (more specifically to HMGB1 A box) in LCM. In addition, HBHP consistently inhibited LCM-induced microglial activation and suppressed the inductions of iNOS and proinflammatory cytokines. Together these results suggest that HBHP confers anti-inflammatory effects in activated microglia cultures by forming a complex with HMGB1.
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Affiliation(s)
- Il-Doo Kim
- Department of Anatomy, Inha University School of Medicine, Incheon 400-712, Korea
| | - Ja-Kyeong Lee
- Department of Anatomy, Inha University School of Medicine, Incheon 400-712, Korea
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Xue J, Habtezion A. Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition. J Clin Invest 2013; 124:437-47. [PMID: 24334457 DOI: 10.1172/jci71362] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 10/11/2013] [Indexed: 12/14/2022] Open
Abstract
The protective role of hemeoxygenase-1 (HO-1) in various inflammatory conditions is mediated in part by its products, carbon monoxide (CO) and biliverdin. Here we investigated a therapeutic role for CO and CO-primed cells in acute pancreatitis (AP). In a mouse model of AP, treatment with CO-releasing molecule-2 (CORM-2) decreased mortality, pancreatic damage, and lung injury. CORM-2 decreased systemic inflammatory cytokines, suppressed systemic and pancreatic macrophage TNF-α secretion, and inhibited macrophage TLR4 receptor complex expression. In both human and mouse cells, CORM-2 inhibited endogenous and exogenous ligand-dependent TLR4 activation, which indicates that CORM-2 could be therapeutic for both early and late stages of AP, which involve sterile- and endotoxin-mediated inflammation, respectively. Mice engrafted with TLR4-deficient hematopoietic cells were protected against caerulein-induced AP. In the absence of leukocyte TLR4 expression, CORM-2 did not confer additional protection, which indicates that CORM-2-dependent effects are mediated via suppression of macrophage TLR4 activation. We determined that CO was directly responsible for the protective effects of CORM-2 in AP, as inactive forms of CORM-2 were ineffective. Importantly, adoptive transfer of CORM-2-primed cells reduced AP. Such a therapeutic approach would translate the beneficial effects of CO-based therapies, avoiding CO- or CO-RM-mediated toxicities in AP and a wide range of diseases.
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Andrades MÉ, Lorenzi R, Nagai R, Moreira JCF, Ritter C, Dal-Pizzol F. Plasma glycation levels are associated with severity in sepsis. Eur J Clin Invest 2012; 42:1055-60. [PMID: 22625221 DOI: 10.1111/j.1365-2362.2012.02694.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Advanced glycation end-products (AGE) have been involved in inflammatory diseases and may have an important role in the progression of symptoms. However, few studies have analysed the levels of glycated proteins in sepsis. In this study, we evaluated the levels of the well-known AGE (N(ε) -(carboxymethyl)lysine (CML) and N(ε) -(carboxyethyl)lysine (CEL)) in the plasma of septic patients. MATERIAL AND METHODS Plasma from 36 patients admitted to an adult intensive care unit and 6 healthy controls had the levels of CML/CEL measured by ELISA. RESULTS The level of AGE in plasma decreased with the increase of severity (1·40±0·46 nmol/mg of protein in sepsis, 0·58±0·23 nmol/mg of protein in severe sepsis and 0·31±0·12 nmol/mg of protein in septic shock). Control plasma presented low AGE concentration (0·06±0·01 nmol/mg protein). Also, we found a decrease in plasma AGE in those patients that died at the end of 28 days follow-up (0·80±0·50 nmol/mg of protein in survivors vs. 0·31±0·10 nmol/mg of protein in nonsurvivors), being associated with the renal component of sequential organ failure assessment (SOFA) score. In the same line, there was a decrease in plasma AGE with the increase in SOFA. CONCLUSIONS Our data demonstrate that plasma AGE levels are inversely associated with the severity of sepsis and may be associated with kidney dysfunction.
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Affiliation(s)
- Michael Éverton Andrades
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
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Breitbach S, Tug S, Simon P. Circulating cell-free DNA: an up-coming molecular marker in exercise physiology. Sports Med 2012; 42:565-86. [PMID: 22694348 DOI: 10.2165/11631380-000000000-00000] [Citation(s) in RCA: 157] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The phenomenon of circulating cell-free DNA (cfDNA) concentrations is of importance for many biomedical disciplines including the field of exercise physiology. Increases of cfDNA due to exercise are described to be a potential hallmark for the overtraining syndrome and might be related to, or trigger adaptations of, immune function induced by strenuous exercise. At the same time, exercise provides a practicable model for studying the phenomenon of cfDNA that is described to be of pathophysiological relevance for different topics in clinical medicine like autoimmune diseases and cancer. In this review, we are summarizing the current knowledge of exercise-based acute and chronic alterations in cfDNA levels and their physiological significance. The effects of acute exercise on cfDNA concentrations have been investigated in resistance exercises and in continuous, stepwise and interval endurance exercises of different durations. cfDNA concentrations peaked immediately after acute exercise and showed a rapid return to baseline levels. Typical markers of skeletal muscle damage (creatine kinase, uric acid, C-reactive protein) show delayed kinetics compared with the cfDNA peak response. Exercise parameters such as intensity, duration or average energy expenditure do not explain the extent of increasing cfDNA concentrations after strenuous exercise. This could be due to complex processes inside the human organism during and after physical activity. Therefore, we hypothesize composite effects of different physiological stress parameters that come along with exercise to be responsible for increasing cfDNA concentrations. We suggest that due to acute stress, cfDNA levels increase rapidly by a spontaneous active or passive release mechanism that is not yet known. As a result of the rapid and parallel increase of cfDNA and lactate in an incremental treadmill test leading to exhaustion within 15-20 minutes, it is unlikely that cfDNA is released into the plasma by typical necrosis or apoptosis of cells in acute exercise settings. Recently, rapid DNA release mechanisms of activated immune-competent cells like NETosis (pathogen-induced cell death including the release of neutrophil extracellular traps [NETs]) have been discovered. cfDNA accumulations might comprise a similar kind of cell death including trap formation or an active release of cfDNA. Just like chronic diseases, chronic high-intensity resistance training protocols induced persistent increases of cfDNA levels. Chronic, strenuous exercise protocols, either long-duration endurance exercise or regular high-intensity workouts, induce chronic inflammation that might lead to a slow, constant release of DNA. This could be due to mechanisms of cell death like apoptosis or necrosis. Yet, it has neither been implicated nor proven sufficiently whether cfDNA can serve as a marker for overtraining. The relevance of cfDNA with regard to overtraining status, performance level, and the degree of physical exhaustion still remains unclear. Longitudinal studies are required that take into account standardized and controlled exercise, serial blood sampling, and large and homogeneous cohorts of different athletic achievement. Furthermore, it is important to establish standardized laboratory procedures for the measurement of genomic cfDNA concentrations by quantitative real-time polymerase chain reaction (PCR). We introduce a new hypothesis based on acute exercise and chronic exposure to stress, and rapid active and passive chronic release of cfDNA fragments into the circulation.
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Affiliation(s)
- Sarah Breitbach
- Department of Sports Medicine, Faculty of Social Science, Media and Sport, Johannes Gutenberg-University, Mainz, Germany
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Kim SW, Jin Y, Shin JH, Kim ID, Lee HK, Park S, Han PL, Lee JK. Glycyrrhizic acid affords robust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibiting HMGB1 phosphorylation and secretion. Neurobiol Dis 2012; 46:147-56. [DOI: 10.1016/j.nbd.2011.12.056] [Citation(s) in RCA: 186] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2011] [Revised: 12/22/2011] [Accepted: 12/31/2011] [Indexed: 02/02/2023] Open
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Abstract
The initial injury in acute pancreatitis is characteristically sterile and results in acinar cells necrosis. Intracellular contents released from damaged cells into the extracellular space serve as damage-associated molecular patterns (DAMPs) that trigger inflammation. There is increasing evidence that this sterile inflammatory response mediated through DAMPs released from necrotic acinar cells is a key determinant of further pancreatic injury, remote organ injury, and disease resolution in experimental models. A number of DAMPS, including high-mobility group box protein 1, DNA, adenosine triphosphate and heat shock protein 70, have been shown to have a role in experimental pancreatitis. Many of these DAMPs are also detectable in the human pancreatitis. Genetic deletion and pharmacologic antagonism demonstrate that specific DAMP receptors, including Toll-like receptor (TLR) 4, TLR9, and P2X7, are also required for inflammation in experimental acute pancreatitis. Downstream DAMP-sensing components include nod-like receptor protein 3, caspase 1, interleukin-1β (IL-1), IL-18, and IL-1 receptor, and also are required for full experimental pancreatitis. These DAMP-mediated pathways provide novel therapeutic targets using antagonists of TLRs and other receptors.
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Affiliation(s)
- Rafaz Hoque
- Section of Digestive Diseases, Yale University, New Haven, CT, USA
| | - Ahsan Malik
- Section of Digestive Diseases, Yale University, New Haven, CT, USA
| | - Fred Gorelick
- Section of Digestive Diseases, Yale University, New Haven, CT, USA
| | - Wajahat Mehal
- Section of Digestive Diseases, Yale University, New Haven, CT, USA
- Department of Immunobiology, Yale University, New Haven, CT, USA
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Elder ASF, Saccone GTP, Bersten AD, Dixon DL. Evaluation of lung injury and respiratory mechanics in a rat model of acute pancreatitis complicated with endotoxin. Pancreatology 2012; 12:240-7. [PMID: 22687380 DOI: 10.1016/j.pan.2012.03.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Revised: 02/19/2012] [Accepted: 03/05/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Acute lung injury (ALI) is a common complication of acute pancreatitis (AP) and contributes to the majority of AP-associated deaths, particularly in the setting of secondary infection. This 'two-hit' model mimics clinical cases where the presentation of AP is associated with mild lung injury that, following a secondary direct lung infection, can result in respiratory dysfunction and death. We therefore aimed to characterize lung injury in a clinically-relevant 'two-hit' rat model of caerulein-induced AP combined with intratracheal endotoxin. METHODS Rats received 7 hourly intraperitoneal injections of caerulein (50 μg/kg). Twenty four hours following the first caerulein injection, rats were anaesthetised and LPS (15 mg/kg) was instilled intratracheally. Following LPS instillation, rats were ventilated for a total of 2 h. RESULTS In the present study, AP results in mild pulmonary injury indicated by increased lung myeloperoxidase (MPO) activity and edema, but with no alteration of respiratory function, while intratracheal instillation of LPS results in more substantial pulmonary injury. The induction of AP challenged with secondary intratracheal LPS results in an exacerbation of lung damage indicated by further increased lung edema, plasma and bronchoalveolar (BAL) CINC-1 concentration, lung damage histology score, and lung tissue resistance and elastance, compared with LPS alone. CONCLUSIONS In conclusion, the addition of instilled LPS acted as a "second-hit" and exacerbated caerulein-induced AP, compared with the induction of AP alone or the instillation of LPS alone. Given its clinical relevance, this model could prove useful for examination of therapeutic interventions for ALI following secondary infection.
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Affiliation(s)
- Alison S F Elder
- Department of Critical Care Medicine, Flinders University, Adelaide, Australia.
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Okkonen M, Lakkisto P, Korhonen AM, Parviai-nen I, Reinikainen M, Varpula T, Pettilä V. Plasma cell-free DNA in patients needing mechanical ventilation. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2011; 15:R196. [PMID: 21838858 PMCID: PMC3387638 DOI: 10.1186/cc10357] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Revised: 07/08/2011] [Accepted: 08/12/2011] [Indexed: 01/05/2023]
Abstract
Introduction Concentrations of plasma cell-free DNA are increased in various diseases and have shown some prognostic value in many patient groups, including critically ill patients. Pathophysiological processes behind the need for mechanical ventilation and the treatment itself could raise plasma levels of cell-free DNA. We evaluated levels of plasma cell-free DNA and their prognostic value in patients needing mechanical ventilation. Methods We studied prospectively 580 mechanically ventilated critically ill patients. Blood samples were taken at study admission (Day 0) and on Day 2. Plasma cell-free DNA concentrations were measured by real-time quantitative PCR assay for the β-globin gene and are expressed as genome equivalents (GE)/ml. Results Median (interquartile range, IQR) plasma cell-free DNA concentration was 11,853 GE/ml (5,304 to 24,620 GE/mL) at study admission, and 11,610 GE/mL (6,411 to 21,558 GE/mL) on Day 2. Concentrations at admission were significantly higher in 90-day non-survivors than survivors, 16,936 GE/mL (7,262 to 46,866 GE/mL) versus 10,026 GE/mL (4,870 to 19,820 GE/mL), P < 0.001. In a multivariate logistic regression analysis plasma cell-free DNA concentration over 16,000 GE/ml remained an independent predictor of 90-day mortality (adjusted odds ratio 2.16, 95% confidence interval CI 1.37 to 3.40). Positive likelihood ratio of plasma cell-free DNA at admission for the prediction of 90-day mortality was 1.72 (95% CI 1.40 to 2.11). Conclusions Plasma levels of cell-free DNA were significantly higher in non-survivors than survivors. Plasma DNA level at baseline was an independent predictor of 90-day mortality. However, its clinical benefit as a prognostic marker seems to be limited.
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Affiliation(s)
- Marjatta Okkonen
- Division of Anaesthesia and Intensive Care Medicine, Department of Surgery, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 340, 00029 HUS, Helsinki, Finland.
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Mándi Y, Vécsei L. The kynurenine system and immunoregulation. J Neural Transm (Vienna) 2011; 119:197-209. [PMID: 21744051 DOI: 10.1007/s00702-011-0681-y] [Citation(s) in RCA: 288] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Accepted: 06/21/2011] [Indexed: 12/15/2022]
Abstract
There is developing interest in the role of the kynurenines in the immune function. A considerable amount of evidence has accumulated as concerns interactions between the kynurenine pathway, cytokines and the nervous system. Indoleamine 2,3-dioxygenase (IDO) occupies a key position connecting the immune system and the kynurenine pathway. There are evidences of the immunosuppressive effect of IDO. Following the interferon (IFN)-mediated activation of antigen presenting cells, the induction of IDO and the kynurenine system exerts a counter-regulating effect, maintaining the homeostasis. Inhibition of T cell functions, activation of the regulatory T cells, and the inhibition of Natural Killer cells are among the important factors in the immunosuppressive effects of IDO and kynurenines. There is a close connection between cytokines (IFN-α, IFN-γ, TNF-α, TGF-β, IL-4 and IL-23) and the kynurenine system, and an imbalance in the TH1/TH2 cytokine profile may possibly lead to neurologic or psychiatric disorders. As the tryptophan metabolic pathway is activated by pro-inflammatory stimuli, the anti-inflammatory effect of kynurenic acid provides a further feedback mechanism in modulating the immune responses.
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Affiliation(s)
- Yvette Mándi
- Department of Medical Microbiology and Immunobiology, University of Szeged, Dóm tér 10, 6720, Szeged, Hungary.
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Hoque R, Sohail M, Malik A, Sarwar S, Luo Y, Shah A, Barrat F, Flavell R, Gorelick F, Husain S, Mehal W. TLR9 and the NLRP3 inflammasome link acinar cell death with inflammation in acute pancreatitis. Gastroenterology 2011; 141:358-69. [PMID: 21439959 PMCID: PMC3129497 DOI: 10.1053/j.gastro.2011.03.041] [Citation(s) in RCA: 235] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2010] [Revised: 03/02/2011] [Accepted: 03/08/2011] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Acute pancreatitis is characterized by early activation of intracellular proteases followed by acinar cell death and inflammation. Activation of damage-associated molecular pattern (DAMP) receptors and a cytosolic complex termed the inflammasome initiate forms of inflammation. In this study, we examined whether DAMP-receptors and the inflammasome provide the link between cell death and the initiation of inflammation in pancreatitis. METHODS Acute pancreatitis was induced by caerulein stimulation in wild-type mice and mice deficient in components of the inflammasome (apoptosis-associated speck-like protein containing a caspase recruitment domain [ASC], NLRP3, caspase-1), Toll-like receptor 9 (TLR9), or the purinergic receptor P2X(7). Resident and infiltrating immune cell populations and pro-interleukin-1β expression were characterized in control and caerulein-treated adult murine pancreas. TLR9 expression was quantified in pancreatic cell populations. Additionally, wild-type mice were pretreated with a TLR9 antagonist before induction of acute pancreatitis by caerulein or retrograde bile duct infusion of taurolithocholic acid 3-sulfate. RESULTS Caspase-1, ASC, and NLRP3 were required for inflammation in acute pancreatitis. Genetic deletion of Tlr9 reduced pancreatic edema, inflammation, and pro-IL-1β expression in pancreatitis. TLR9 was expressed in resident immune cells of the pancreas, which are predominantly macrophages. Pretreatment with the TLR9 antagonist IRS954 reduced pancreatic edema, inflammatory infiltrate, and apoptosis. Pretreatment with IRS954 reduced pancreatic necrosis and lung inflammation in taurolithocholic acid 3-sulfate-induced acute pancreatitis. CONCLUSIONS Components of the inflammasome, ASC, caspase-1, and NLRP3, are required for the development of inflammation in acute pancreatitis. TLR9 and P2X(7) are important DAMP receptors upstream of inflammasome activation, and their antagonism could provide a new therapeutic strategy for treating acute pancreatitis.
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Affiliation(s)
- Rafaz Hoque
- Section of Digestive Diseases, Yale University, New Haven, CT, USA
| | - Muhammad Sohail
- Section of Digestive Diseases, Yale University, New Haven, CT, USA
| | - Ahsan Malik
- Section of Digestive Diseases, Yale University, New Haven, CT, USA
| | - Sherhayar Sarwar
- Section of Gastroenterology, Department of Pediatrics, Yale University, New Haven, CT, USA
| | - Yuhuan Luo
- Section of Gastroenterology, Department of Pediatrics, Yale University, New Haven, CT, USA
| | - Ahsan Shah
- Section of Gastroenterology, Department of Pediatrics, Yale University, New Haven, CT, USA
| | - Franck Barrat
- Dynavax Technologies Corporation, Berkeley, CA 94710, USA
| | - Richard Flavell
- Department of Immunobiology, Yale University, New Haven, CT, USA
| | - Fred Gorelick
- Section of Digestive Diseases, Yale University, New Haven, CT, USA
| | - Sohail Husain
- Section of Gastroenterology, Department of Pediatrics, Yale University, New Haven, CT, USA
| | - Wajahat Mehal
- Section of Digestive Diseases, Yale University, New Haven, CT, USA
- Department of Immunobiology, Yale University, New Haven, CT, USA
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Abstract
A key question in immunology concerns how sterile injury activates innate immunity to mediate damaging inflammation in the absence of foreign invaders. The discovery that HMGB1, a ubiquitous nuclear protein, mediates the activation of innate immune responses led directly to the understanding that HMGB1 plays a critical role at the intersection of the host inflammatory response to sterile and infectious threat. HMGB1 is actively released by stimulation of the innate immune system with exogenous pathogen-derived molecules and is passively released by ischemia or cell injury in the absence of invasion. Established molecular mechanisms of HMGB1 binding and signaling through TLR4 reveal signaling pathways that mediate cytokine release and tissue damage. Experimental strategies that selectively target HMGB1 and TLR4 effectively reverse and prevent activation of innate immunity and significantly attenuate damage in diverse models of sterile and infection-induced threat.
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Affiliation(s)
- Ulf Andersson
- Department of Women's and Children's Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
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