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Liu Q, Zhu W, Wen X, Da Y. The Role of Platelet-Neutrophil Interactions in Driving Autoimmune Diseases. Immunology 2025; 175:1-15. [PMID: 39825744 DOI: 10.1111/imm.13901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 12/17/2024] [Accepted: 01/07/2025] [Indexed: 01/20/2025] Open
Abstract
Platelets and neutrophils are among the most abundant cell types in peripheral blood. Beyond their traditional roles in thrombosis and haemostasis, they also play an active role in modulating immune responses. Current knowledge on the role of platelet-neutrophil interactions in the immune system has been rapidly expanding. Notably, circulating platelet-neutrophil complexes (PNCs) have been widely detected in various inflammatory diseases and infections, closely associated with inflammatory processes affecting multiple organs. These findings emphasise the critical role of platelet-neutrophil interactions in driving and sustaining inflammatory responses. In this review, we elucidate the mechanisms by which neutrophils and platelets physically interact, leading to mutual activation. Additionally, activated platelets release pro-inflammatory factors that further modulate neutrophil effector functions, enhancing their immune response capabilities. We highlight the role of platelets in promoting the formation of neutrophil extracellular traps (NETs), which, in turn, promote local platelet activation, thereby exacerbating the immune response and sustaining chronic inflammation. Furthermore, we review current evidence on the role of platelet-neutrophil interactions in common autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and rheumatoid arthritis (RA). Finally, we identify gaps in understanding the mechanisms of these interactions in the context of other autoimmune diseases and underscore the potential of targeting platelets and neutrophils as a therapeutic strategy for these conditions.
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Affiliation(s)
- Qinyao Liu
- Department of Neurology, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Wenjia Zhu
- Department of Neurology, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Xinmei Wen
- Department of Neurology, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Yuwei Da
- Department of Neurology, Xuanwu Hospital Capital Medical University, Beijing, China
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2
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Chen H, Lin X, Pan X, Xu H, Zhang X, Liang G, Qiu J, Zhang X, Gao Y, Tan X, Li N, Cai H, Cang X, Qi J, Li W, Li S, Zheng Y, Zhao L, Jin S. Development and validation of a blood routine-based extent and severity clinical decision support tool for ulcerative colitis. Sci Rep 2023; 13:21368. [PMID: 38049548 PMCID: PMC10696009 DOI: 10.1038/s41598-023-48569-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 11/28/2023] [Indexed: 12/06/2023] Open
Abstract
Monitoring extent and severity is vital in the ulcerative colitis (UC) follow-up, however, current assessment is complex and low cost-effectiveness. We aimed to develop a routine blood-based clinical decision support tool, Jin's model, to investigate the extent and severity of UC. The multicentre retrospective cohort study recruited 975 adult UC inpatients and sub-grouped into training, internal validation and external validation set. Model was developed by logistics regression for the extent via Montreal classification and for the severity via Mayo score, Truelove and Witts score (TWS), Mayo endoscopic score (MES) and Degree of Ulcerative colitis Burden of Luminal Inflammation (DUBLIN) score. In Montreal classification, left-sided and extensive versus proctitis model achieved area under the receiver operating characteristic curve (AUROC) of 0.78 and 0.81 retrospectively. For severity, Mayo score model, TWS model, MES model and DUBLIN score model achieved an AUROC of 0.81, 0.70, 0.74 and 0.70 retrospectively. The models also were evaluated with satisfactory calibration and clinical unity. Jin's model was free with open access at http://jinmodel.com:3000/ . Jin's model is a noninvasive, convenient, and efficient approach to assess the extent and severity of UC.
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Affiliation(s)
- Hongliang Chen
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China
| | - Xindi Lin
- Department of Statistics, University of Wisconsin, Madison, WI, USA
| | - Xinyue Pan
- School of Economics and Finance, Xi'an Jiaotong University, Xi'an, China
| | - Hongyu Xu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xuemei Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Guoying Liang
- Department of Liver, Spleen and Stomach Diseases, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jiawei Qiu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China
| | - Xueyan Zhang
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China
| | - Yang Gao
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China
| | - Xin Tan
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ning Li
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China
| | - Huimin Cai
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China
| | - Xueyu Cang
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China
| | - Jihan Qi
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China
| | - Wei Li
- Department of Gastroenterology, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Shuang Li
- Department of Gastroenterology, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Yutong Zheng
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China
| | - Lei Zhao
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China
| | - Shizhu Jin
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China.
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3
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Dorken-Gallastegi A, Lee Y, Li G, Li H, Naar L, Li X, Ye T, Van Cott E, Rosovsky R, Gregory D, Tompkins R, Karniadakis G, Kaafarani HMA, Velmahos GC, Lee J, Frydman GH. Circulating cellular clusters are associated with thrombotic complications and clinical outcomes in COVID-19. iScience 2023; 26:107202. [PMID: 37485375 PMCID: PMC10290732 DOI: 10.1016/j.isci.2023.107202] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/28/2023] [Accepted: 06/20/2023] [Indexed: 07/25/2023] Open
Abstract
We sought to study the role of circulating cellular clusters (CCC) -such as circulating leukocyte clusters (CLCs), platelet-leukocyte aggregates (PLA), and platelet-erythrocyte aggregates (PEA)- in the immunothrombotic state induced by COVID-19. Forty-six blood samples from 37 COVID-19 patients and 12 samples from healthy controls were analyzed with imaging flow cytometry. Patients with COVID-19 had significantly higher levels of PEAs (p value<0.001) and PLAs (p value = 0.015) compared to healthy controls. Among COVID-19 patients, CLCs were correlated with thrombotic complications (p value = 0.016), vasopressor need (p value = 0.033), acute kidney injury (p value = 0.027), and pneumonia (p value = 0.036), whereas PEAs were associated with positive bacterial cultures (p value = 0.033). In predictive in silico simulations, CLCs were more likely to result in microcirculatory obstruction at low flow velocities (≤1 mm/s) and at higher branching angles. Further studies on the cellular component of hyperinflammatory prothrombotic states may lead to the identification of novel biomarkers and drug targets for inflammation-related thrombosis.
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Affiliation(s)
- Ander Dorken-Gallastegi
- Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Yao Lee
- Center for Biomedical Engineering & Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02039, USA
| | - Guansheng Li
- Division of Applied Mathematics, Brown University, Providence, RI 02912, USA
| | - He Li
- Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI 02912, USA
| | - Leon Naar
- Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Xuejin Li
- Department of Engineering Mechanics, Zhejiang University, Hangzhou, China
| | - Ting Ye
- Information and Computational Mathematics, Ji Lin University, Changchun, China
| | - Elizabeth Van Cott
- Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Rachel Rosovsky
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - David Gregory
- Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Ronald Tompkins
- Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | - George Karniadakis
- Division of Applied Mathematics, Brown University, Providence, RI 02912, USA
- School of Engineering, Brown University, Providence, RI 02912, USA
| | - Haytham MA. Kaafarani
- Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA
| | - George C. Velmahos
- Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Jarone Lee
- Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Galit H. Frydman
- Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA
- Center for Biomedical Engineering & Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02039, USA
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Granja TF, Köhler D, Leiss V, Eggstein C, Nürnberg B, Rosenberger P, Beer-Hammer S. Platelets and the Cybernetic Regulation of Ischemic Inflammatory Responses through PNC Formation Regulated by Extracellular Nucleotide Metabolism and Signaling. Cells 2022; 11:cells11193009. [PMID: 36230973 PMCID: PMC9561997 DOI: 10.3390/cells11193009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 09/12/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
Ischemic events are associated with severe inflammation and are here referred to as ischemic inflammatory response (IIR). Recent studies identified the formation of platelet–neutrophil complexes (PNC) as key players in IIR. We investigated the role of extracellular platelet nucleotide signaling in the context of IIR and defined a cybernetic circle, including description of feedback loops. Cybernetic circles seek to integrate different levels of information to understand how biological systems function. Our study specifies the components of the cybernetic system of platelets in IIR and describes the theoretical progression of IIR passing the cybernetic cycle with positive and negative feedback loops based on nucleotide-dependent signaling and functional regulation. The cybernetic components and feedback loops were explored by cytometry, immunohistological staining, functional blocking antibodies, and ADP/ATP measurements. Using several ex vivo and in vivo approaches we confirmed cybernetic parameters, such as controller, sensor, and effector (VASP phosphorylation, P2Y12, ADORAs and GPIIb/IIIa activity), as well as set points (ADP, adenosine) and interfering control and disturbance variables (ischemia). We demonstrate the impact of the regulated platelet–neutrophil complex (PNC) formation in blood and the resulting damage to the affected inflamed tissue. Taken together, extracellular nucleotide signaling, PNC formation, and tissue damage in IIR can be integrated in a controlled cybernetic circle of platelet function, as introduced through this study.
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Affiliation(s)
- Tiago F. Granja
- Lusófona’s Research Center for Biosciences & Health Technologies, CBIOS–Universidade, Campo Grande 376, 1749-024 Lisboa, Portugal
- Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Wilhelmstrasse 56, D-72074 Tübingen, Germany
| | - David Köhler
- Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Wilhelmstrasse 56, D-72074 Tübingen, Germany
| | - Veronika Leiss
- Department of Pharmacology and Experimental Therapy and Toxicology and Interfaculty Center of Pharmacogenomics and Drug Research (ICePhA), Tübingen University Hospital, Wilhelmstrasse 56, D-72074 Tübingen, Germany
| | - Claudia Eggstein
- Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Wilhelmstrasse 56, D-72074 Tübingen, Germany
| | - Bernd Nürnberg
- Department of Pharmacology and Experimental Therapy and Toxicology and Interfaculty Center of Pharmacogenomics and Drug Research (ICePhA), Tübingen University Hospital, Wilhelmstrasse 56, D-72074 Tübingen, Germany
| | - Peter Rosenberger
- Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Wilhelmstrasse 56, D-72074 Tübingen, Germany
| | - Sandra Beer-Hammer
- Department of Pharmacology and Experimental Therapy and Toxicology and Interfaculty Center of Pharmacogenomics and Drug Research (ICePhA), Tübingen University Hospital, Wilhelmstrasse 56, D-72074 Tübingen, Germany
- Correspondence: ; Tel.: +49-7071-29-74594
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5
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Izzi B, Gianfagna F, Yang WY, Cludts K, De Curtis A, Verhamme P, Di Castelnuovo A, Cerletti C, Donati MB, de Gaetano G, Staessen JA, Hoylaerts MF, Iacoviello L. Variation of PEAR1 DNA methylation influences platelet and leukocyte function. Clin Epigenetics 2019; 11:151. [PMID: 31665082 PMCID: PMC6820903 DOI: 10.1186/s13148-019-0744-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 09/22/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Platelet-endothelial aggregation receptor 1 (PEAR-1) is a transmembrane receptor involved in platelet activation and megakaryopoiesis whose expression is driven by DNA methylation. PEAR1 variants were associated with differential platelet response to activation and cardiovascular outcomes. We aimed at investigating the link between PEAR1 methylation and platelet and leukocyte function markers in a family-based population. RESULTS We measured PEAR1 methylation in 605 Moli-family participants with available blood counts, plasma P-selectin and C-reactive protein, whole blood platelet P-selectin, and platelet-leukocyte mixed conjugate measurements. We performed principal component analysis (PCA) to identify groups of highly correlated CpG sites. We used linear mixed regression models (using age, gender, BMI, smoking, alcohol drinking, being a proband for family recruitment, being a member of myocardial infarction (MI) family as fixed effects, and family as a random effect) to evaluate associations between PEAR1 methylation and phenotypes. PEAR1 methylation Factor2, characterized by the previously identified megakaryocyte-specific CpG sites, was inversely associated with platelet-monocyte conjugates, P-selectin, and WBC counts, while positively associated with the platelet distribution width (PDW) and with leukocyte CD11b and L-selectin. Moreover, PEAR1 Factor2 methylation was negatively associated with INFLAscore, a low-grade inflammation score. The latter was partially mediated by the PEAR1 methylation effect on platelet variables. PEAR1 methylation association with WBC measurements and INFLAscore was confirmed in the independent cohort FLEMENGHO. CONCLUSIONS We report a significant link between epigenetic signatures in a platelet functional gene and inflammation-dependent platelet function variability measured in two independent cohorts.
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Affiliation(s)
- Benedetta Izzi
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy.
| | - Francesco Gianfagna
- Mediterranea Cardiocentro, Naples, Italy.,Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Wen-Yi Yang
- Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
| | - Katrien Cludts
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
| | - Amalia De Curtis
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Peter Verhamme
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
| | | | - Chiara Cerletti
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Maria Benedetta Donati
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Giovanni de Gaetano
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Jan A Staessen
- Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
| | - Marc F Hoylaerts
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
| | - Licia Iacoviello
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy.,Department of Medicine and Surgery, University of Insubria, Varese, Italy
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6
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Steiger T, Foltan M, Philipp A, Mueller T, Gruber M, Bredthauer A, Krenkel L, Birkenmaier C, Lehle K. Accumulations of von Willebrand factor within ECMO oxygenators: Potential indicator of coagulation abnormalities in critically ill patients? Artif Organs 2019; 43:1065-1076. [PMID: 31192471 PMCID: PMC6899554 DOI: 10.1111/aor.13513] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 06/05/2019] [Accepted: 06/06/2019] [Indexed: 12/13/2022]
Abstract
Clot formation within membrane oxygenators (MOs) remains a critical problem during extracorporeal membrane oxygenation (ECMO). The composition of the clots-in particular, the presence of von Willebrand factor (vWF)-may be an indicator for prevalent nonphysiological flow conditions, foreign body reactions, or coagulation abnormalities in critically ill patients. Mats of interwoven gas exchange fibers from randomly collected MOs (PLS, Maquet, Rastatt, Germany) of 21 patients were stained with antibodies (anti-vWF and anti-P-selectin) and counterstained with 4',6-diamidino-2-phenylindole. The extent of vWF-loading was correlated with patient and technical data. While 12 MOs showed low vWF-loadings, 9 MOs showed high vWF-loading with highest accumulations close to crossing points of adjacent gas fibers. The presence and the extent of vWF-fibers/"cobwebs," leukocytes, platelet-leukocyte aggregates (PLAs), and P-selectin-positive platelet aggregates were independent of the extent of vWF-loading. However, the highly loaded MOs were obtained from patients with a significantly elevated SOFA score, severe thrombocytopenia, and persistent liver dysfunction. The coagulation abnormalities of these critically ill patients may cause an accumulation of the highly thrombogenic and elongated high-molecular-weight vWF multimers in the plasma which will be trapped in the MOs during the ECMO therapy.
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Affiliation(s)
- Tamara Steiger
- Department of Cardiothoracic Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Maik Foltan
- Department of Cardiothoracic Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Alois Philipp
- Department of Cardiothoracic Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Thomas Mueller
- Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany
| | - Michael Gruber
- Department of Anesthesiology, University Medical Center Regensburg, Regensburg, Germany
| | - Andre Bredthauer
- Department of Anesthesiology, University Medical Center Regensburg, Regensburg, Germany
| | - Lars Krenkel
- Regensburg Center of Biomedical Engineering, Ostbayerische Technische Hochschule, Regensburg, Germany
| | - Clemens Birkenmaier
- Regensburg Center of Biomedical Engineering, Ostbayerische Technische Hochschule, Regensburg, Germany
| | - Karla Lehle
- Department of Cardiothoracic Surgery, University Medical Center Regensburg, Regensburg, Germany
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Al‐Kishali HA, Abd El Fattah MA, Mohammad WA, El‐Abhar HS. Cilostazol against 2,4,6‐trinitrobenzene sulfonic acid‐induced colitis: Effect on tight junction, inflammation, and apoptosis. JGH Open 2019; 3:281-289. [PMID: 31406920 PMCID: PMC6684512 DOI: 10.1002/jgh3.12148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 12/13/2018] [Accepted: 12/29/2018] [Indexed: 11/07/2022]
Abstract
Background Aim Methods Results Conclusion
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Affiliation(s)
- Hiba A Al‐Kishali
- Department of Pharmacology and Toxicology, Faculty of PharmacyCairo UniversityCairoEgypt
| | - Mai A Abd El Fattah
- Department of Pharmacology and Toxicology, Faculty of PharmacyCairo UniversityCairoEgypt
| | | | - Hanan S El‐Abhar
- Department of Pharmacology and Toxicology, Faculty of PharmacyCairo UniversityCairoEgypt
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8
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Finsterbusch M, Norman MU, Hall P, Kitching AR, Hickey MJ. Platelet retention in inflamed glomeruli occurs via selective prolongation of interactions with immune cells. Kidney Int 2018; 95:363-374. [PMID: 30522769 DOI: 10.1016/j.kint.2018.08.042] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 08/13/2018] [Accepted: 08/30/2018] [Indexed: 01/16/2023]
Abstract
Platelet-leukocyte interactions promote acute glomerulonephritis. However, neither the nature of the interactions between platelets and immune cells nor the capacity of platelets to promote leukocyte activation has been characterized in this condition. We used confocal intravital microscopy to define the interactions of platelets with neutrophils, monocytes, and endothelial cells in glomerular capillaries in mice. In the absence of inflammation, platelets underwent rapid on/off interactions with immune cells. During glomerulonephritis induced by in situ immune complex formation, platelets that interacted with neutrophils or monocytes, but not with other intraglomerular cells, were retained in the glomerulus for prolonged durations. Depletion of platelets inhibited both neutrophil recruitment and activation. Inhibition of platelet activating factor reduced neutrophil recruitment without impacting reactive oxygen species generation, while blocking CXC chemokine ligand 7 (CXCL7) reduced both responses. In contrast, inhibition of the adenosine diphosphate and thromboxane A2 pathways inhibited neutrophil reactive oxygen species generation without affecting neutrophil adhesion. Thus, platelet retention in glomerular capillaries following immune complex deposition stems from prolongation of platelet interactions with immune cells but not other substrates. Pro-inflammatory mediators play divergent roles in promoting neutrophil retention and activation in glomerular capillaries.
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Affiliation(s)
- Michaela Finsterbusch
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia
| | - M Ursula Norman
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia
| | - Pam Hall
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia
| | - A Richard Kitching
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia; Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia; Department of Paediatric Nephrology, Monash Medical Centre, Clayton, Victoria, Australia
| | - Michael J Hickey
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
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9
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Gadolinium chloride attenuates acetic acid-evoked colitis in mice by reducing neutrophil infiltration and pro-oxidative enzyme activity. Naunyn Schmiedebergs Arch Pharmacol 2018; 392:299-311. [PMID: 30483861 DOI: 10.1007/s00210-018-1592-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 11/22/2018] [Indexed: 12/19/2022]
Abstract
This study investigated the potential of gadolinium chloride (GdCl3), an inhibitor of kupffer cells on the myeloperoxidase (MPO) function, both in vivo on colon inflammation model and in vitro on thioglycollate-elicited peritoneal neutrophils. Colon inflammation was induced in mice (n = 7) by 4% acetic acid (AA) enema. GdCl3 (10 mg/kg) treatment was given 24 h before AA challenge. Clinical changes during the protocol were scored. Colons were segmented into distal and proximal parts for histological and biochemical assessment. Furthermore, myeloperoxidase (MPO) enzymes were extracted and analyzed by western blot. Short-term GdCl3 treatment inhibited dose-dependently superoxide anion (O2·-), alkaline phosphatase (ALP), and MPO release and promoted neutrophil apoptosis. In vivo, low-dose GdCl3 improved colitis scores and inhibited acute phagocyte recruitment and colon damage within the mucosa as revealed by the decrease in MPO, nitric oxide (NO), and malondialdehyde (MDA) levels. At the same time, GdCl3 restored catalase (CAT), superoxide dismutase (SOD) activities, and reduced glutathione (GSH) levels, thus reversing the MDA/GSH ratio in both distal and proximal colons. Compared to proximal, distal colon was more altered and displayed higher pathological manifestations. Lastly, the induction of apoptosis and regulation of the major nitrosative and oxidative functions of neutrophils by GdCl3 suggests its consideration as a beneficial tool in attenuating colon inflammation.
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10
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Finsterbusch M, Schrottmaier WC, Kral-Pointner JB, Salzmann M, Assinger A. Measuring and interpreting platelet-leukocyte aggregates. Platelets 2018; 29:677-685. [PMID: 29461910 PMCID: PMC6178087 DOI: 10.1080/09537104.2018.1430358] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Platelets, besides their specialised role in haemostasis and atherothrombosis, actively modulate innate and adaptive immune responses with crucial roles in immune surveillance, inflammation and host defence during infection. An important prerequisite for platelet-mediated changes of immune functions involves direct engagement with different types of leukocytes. Indeed, increased platelet-leukocyte aggregates (PLAs) within the circulation and/or locally at the site of inflammation represent markers of many thrombo-inflammatory diseases, such as cardiovascular diseases, acute lung injury, renal and cerebral inflammation. Therefore, measurement of PLAs could provide an attractive and easily accessible prognostic and/or diagnostic tool for many diseases. To measure PLAs in different (patho-)physiological settings in human and animal models flow cytometric and microscopic approaches have been applied. These techniques represent complementary tools to study different aspects relating to the involvement of leukocyte subtypes and molecules, as well as location of PLAs within tissues, dynamics of their interactions and/or dynamic changes in leukocyte and platelet behaviour. This review summarises various approaches to measure and interpret PLAs and discusses potential experimental factors influencing platelet binding to leukocytes. Furthermore, we summarise insights gained from studies regarding the underlying mechanism of platelet-leukocyte interactions and discuss implications of these interactions in health and disease.
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Affiliation(s)
- Michaela Finsterbusch
- a Department for Vascular Biology and Thrombosis Research , Centre for Physiology and Pharmacology, Medical University of Vienna , Vienna , Austria
| | - Waltraud C Schrottmaier
- a Department for Vascular Biology and Thrombosis Research , Centre for Physiology and Pharmacology, Medical University of Vienna , Vienna , Austria
| | - Julia B Kral-Pointner
- a Department for Vascular Biology and Thrombosis Research , Centre for Physiology and Pharmacology, Medical University of Vienna , Vienna , Austria
| | - Manuel Salzmann
- a Department for Vascular Biology and Thrombosis Research , Centre for Physiology and Pharmacology, Medical University of Vienna , Vienna , Austria
| | - Alice Assinger
- a Department for Vascular Biology and Thrombosis Research , Centre for Physiology and Pharmacology, Medical University of Vienna , Vienna , Austria
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11
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Olsson AK, Cedervall J. NETosis in Cancer - Platelet-Neutrophil Crosstalk Promotes Tumor-Associated Pathology. Front Immunol 2016; 7:373. [PMID: 27708646 PMCID: PMC5030622 DOI: 10.3389/fimmu.2016.00373] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 09/07/2016] [Indexed: 01/13/2023] Open
Abstract
It has become increasingly clear that circulating immune cells in the body have a major impact on cancer development, progression, and outcome. The role of both platelets and neutrophils as independent regulators of various processes in cancer has been known for long, but it has quite recently emerged that the platelet-neutrophil interplay is yet a critical component to take into account during malignant disease. It was reported a few years ago that neutrophils in mice with cancer have increased propensity to form neutrophil extracellular traps (NETs) - web-like structures formed by externalized chromatin and secreted proteases. The initial finding describing this as a cell death-associated process has been followed by reports of additional mechanisms for NET formation (NETosis), and it has been shown that similar structures can be formed also without lysis and neutrophil cell death as a consequence. Furthermore, presence of NETs in humans with cancer has been verified in a few recent studies, indicating that tumor-induced NETosis is clinically relevant. Several reports have also described that NETs contribute to cancer-associated pathology, by promoting processes responsible for cancer-related death such as thrombosis, systemic inflammation, and relapse of the disease. This review summarizes current knowledge about NETosis in cancer, including the role of platelets as regulators of tumor-induced NETosis. It has been shown that platelets can serve as inducers of NETosis, and the platelet-neutrophil interface can therefore be an important issue to consider when designing therapies targeting cancer-associated pathology in the future.
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Affiliation(s)
- Anna-Karin Olsson
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University , Uppsala , Sweden
| | - Jessica Cedervall
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University , Uppsala , Sweden
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12
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Mauler M, Seyfert J, Haenel D, Seeba H, Guenther J, Stallmann D, Schoenichen C, Hilgendorf I, Bode C, Ahrens I, Duerschmied D. Platelet-neutrophil complex formation-a detailed in vitro analysis of murine and human blood samples. J Leukoc Biol 2015; 99:781-9. [PMID: 26578648 DOI: 10.1189/jlb.3ta0315-082r] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 10/28/2015] [Indexed: 12/13/2022] Open
Abstract
Platelets form complexes with neutrophils during inflammatory processes. These aggregates migrate into affected tissues and also circulate within the organism. Several studies have evaluated platelet-neutrophil complexes as a marker of cardiovascular diseases in human and mouse. Although multiple publications have reported platelet-neutrophil complex counts, we noticed that different methods were used to analyze platelet-neutrophil complex formation, resulting in significant differences, even in baseline values. We established a protocol for platelet-neutrophil complex measurement with flow cytometry in murine and human whole blood samples. In vitro platelet-neutrophil complex formation was stimulated with ADP or PMA. We tested the effect of different sample preparation steps and cytometer settings on platelet-neutrophil complex detection and noticed false-positive counts with increasing acquisition speed. Platelet-neutrophil complex formation depends on platelet P-selectin expression, and antibody blocking of P-selectin consequently prevented ADP-induced platelet-neutrophil complex formation. These findings may help generating more comparable data among different research groups that examine platelet-neutrophil complexes as a marker for cardiovascular disease and novel therapeutic interventions.
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Affiliation(s)
- Maximilian Mauler
- Faculty of Biology, Heart Center, University of Freiburg, Germany and Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany
| | - Julia Seyfert
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany
| | - David Haenel
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany
| | - Hannah Seeba
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany
| | - Janine Guenther
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany
| | - Daniela Stallmann
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany
| | - Claudia Schoenichen
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany
| | - Ingo Hilgendorf
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany
| | - Christoph Bode
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany
| | - Ingo Ahrens
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany
| | - Daniel Duerschmied
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany
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13
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Theodoratou E, Campbell H, Ventham NT, Kolarich D, Pučić-Baković M, Zoldoš V, Fernandes D, Pemberton IK, Rudan I, Kennedy NA, Wuhrer M, Nimmo E, Annese V, McGovern DPB, Satsangi J, Lauc G. The role of glycosylation in IBD. Nat Rev Gastroenterol Hepatol 2014; 11:588-600. [PMID: 24912389 DOI: 10.1038/nrgastro.2014.78] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A number of genetic and immunological studies give impetus for investigating the role of glycosylation in IBD. Experimental mouse models have helped to delineate the role of glycosylation in intestinal mucins and to explore the putative pathogenic role of glycosylation in colitis. These experiments have been extended to human studies investigating the glycosylation patterns of intestinal mucins as well as levels of glycans of serum glycoproteins and expression of glycan receptors. These early human studies have generated interesting hypotheses regarding the pathogenic role of glycans in IBD, but have generally been restricted to fairly small underpowered studies. Decreased glycosylation has been observed in the intestinal mucus of patients with IBD, suggesting that a defective inner mucus layer might lead to increased bacterial contact with the epithelium, potentially triggering inflammation. In sera, decreased galactosylation of IgG has been suggested as a diagnostic marker for IBD. Advances in glycoprofiling technology make it technically feasible and affordable to perform high-throughput glycan pattern analyses and to build on previous work investigating a much wider range of glycan parameters in large numbers of patients.
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Affiliation(s)
- Evropi Theodoratou
- Centre for Population Health Sciences, University of Edinburgh, Teviot Place, EH8 9AG, Edinburgh, UK
| | - Harry Campbell
- Centre for Population Health Sciences, University of Edinburgh, Teviot Place, EH8 9AG, Edinburgh, UK
| | - Nicholas T Ventham
- Centre for Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Edinburgh, UK
| | - Daniel Kolarich
- Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1 OT Golm, 14476, Potsdam, Germany
| | | | - Vlatka Zoldoš
- University of Zagreb, Faculty of Science, Horvatovac 102a, 10000 Zagreb, Croatia
| | | | - Iain K Pemberton
- IP Research Consulting SAS, 34 Rue Carnot, 93160 Noisy-le-Grand, Paris, France
| | - Igor Rudan
- Centre for Population Health Sciences, University of Edinburgh, Teviot Place, EH8 9AG, Edinburgh, UK
| | - Nicholas A Kennedy
- Centre for Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Edinburgh, UK
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands
| | - Elaine Nimmo
- Centre for Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Edinburgh, UK
| | - Vito Annese
- Department of Medical and Surgical Specialities, Division of Gastroenterology, AOU Careggi University Hospital, Largo Brambilla 13, 50139 Florence, Italy
| | - Dermot P B McGovern
- F.Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Suite D4063, Los Angeles, CA 90048, USA
| | - Jack Satsangi
- Centre for Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Edinburgh, UK
| | - Gordan Lauc
- Department of Biochemistry and Molecular Biology, University of Zagreb Faculty of Pharmacy and Biochemistry, Trg maršala Tita 14, 10000 Zagreb, Croatia
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14
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Schmid W, Vogelsang H, Papay P, Primas C, Eser A, Gratzer C, Handler M, Novacek G, Panzer S. Increased responsiveness to thrombin through protease-activated receptors (PAR)-1 and -4 in active Crohn's disease. J Crohns Colitis 2014; 8:495-503. [PMID: 24291018 DOI: 10.1016/j.crohns.2013.11.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Revised: 10/03/2013] [Accepted: 11/02/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Platelets are essential in hemostasis and inflammation, thereby linking coagulation with inflammation. Abundant thrombin generation in association with inflammation is considered a major reason for the increased risk for thromboembolic events. We therefore investigated platelet responsiveness to thrombin. METHODS In this case-control study 85 patients with Crohn's disease (active CD 42, remission 43) and 30 sex- and age-matched controls were enrolled. Clinical disease activity (Harvey-Bradshaw-Index) was assessed and CD-related data were determined by chart review. Platelets' response to protease activated receptor-1 and -4 (PAR-1, -4) was assessed by whole blood platelet aggregometry (MEA), levels of platelets adhering to monocytes (PMA), and platelet surface P-selectin. RESULTS Platelets' aggregation after activation with the specific PAR-1 agonist (SFLLRN) and PAR-4 agonist (AYPGKF) was higher in patients with active CD compared to patients in remission and controls (p=0.0068 and p=0.0023 for SFLLRN, p=0.0019 and 0.0003 for AYPGKF). Likewise, levels of PMA after activation with PAR-1 and PAR-4 receptor agonists were higher in patients with active CD compared to patients in remission and controls (p=0.0001 and p<0.0001 for SFLLRN, p=0.0329 and p=0.0125 for AYPGKF). However, P-selectin expression on human platelets showed heterogeneous results. Only PAR-1 activation of platelets resulted in significant differences between CD patients and controls (p=0.0001 and p=0.0022 for active and inactive CD versus controls, respectively). CONCLUSIONS Our data suggest a new mechanism of platelet activation which has the potential to increase risk for thromboembolism in patients with active CD which might be due to platelets poised for thrombin-inducible activation.
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Affiliation(s)
- Werner Schmid
- Department of Anesthesiology, General Intensive Care and Pain Medicine, Division of Cardiothoracic and Vascular Anesthesia and Intensive Care, Medical University of Vienna, Vienna, Austria
| | - Harald Vogelsang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Pavol Papay
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Christian Primas
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Alexander Eser
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Cornelia Gratzer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Handler
- Department of Anesthesiology, General Intensive Care and Pain Medicine, Division of Cardiothoracic and Vascular Anesthesia and Intensive Care, Medical University of Vienna, Vienna, Austria
| | - Gottfried Novacek
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Simon Panzer
- Department for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
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15
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Voudoukis E, Karmiris K, Koutroubakis IE. Multipotent role of platelets in inflammatory bowel diseases: A clinical approach. World J Gastroenterol 2014; 20:3180-3190. [PMID: 24696603 PMCID: PMC3964390 DOI: 10.3748/wjg.v20.i12.3180] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
There is evidence that inflammatory bowel diseases (IBD) combine both inflammation and coagulation in their pathogenesis and clinical manifestations. Although platelets (PLT) are well known for their role in hemostasis, there are a rising number of studies supporting their considerable role as inflammatory amplifiers in chronic inflammatory conditions. IBD are associated with several alterations of PLT, including number, shape, and function, and these abnormalities are mainly attributed to the highly activated state of circulating PLT in IBD patients. When PLT activate, they increase in size, release a great variety of bio-active inflammatory and procoagulant molecules/particles, and express a variety of inflammatory receptors. These inflammatory products may represent a part of the missing link between coagulation and inflammation, and can be considered as possible IBD pathogenesis instigators. In clinical practice, thrombocytosis is associated both with disease activity and iron deficiency anemia. Controlling inflammation and iron replacement in anemic patients usually leads to a normalization of PLT count. The aim of this review is to update the role of PLT in IBD and present recent data revealing the possible therapeutic implications of anti-PLT agents in future IBD remedies.
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16
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Effects of modified Sanhuang decoction () enema on serum tumor necrosis factor-α and colonic mucosa interleukin-1β, interleukin-6 levels in ulcerative colitis rats. Chin J Integr Med 2013; 20:865-9. [PMID: 24126972 DOI: 10.1007/s11655-013-1538-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2011] [Indexed: 02/08/2023]
Abstract
OBJECTIVE To investigate the effects of Modified Sanhuang Decoction (, MSD) enema on the serum tumor necrosis factor alpha (TNF-α) and colonic mucosa interleukin-1β (IL-1β), interleukin-6 (IL-6) levels in experimental ulcerative colitis (UC) rats. METHODS Forty-five male Wistar rats were randomly divided into 4 groups: normal group (n=12), model group (n=11), salazosulfapyridine (SASP) group (n=11) and MSD group (n=11). The UC model was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS)/ethanol solution. Rats in the normal group and model group were clystered with 0.9% normal saline, while in the SASP group and MSD group were clystered with SASP and MSD enema, respectively. After drug administration (10 mL/kg body weight, for 7 days), colonic gross changes and colonic mucosa histology were observed, serum TNF-α and colonic mucosa IL-1β, IL-6 levels were tested by enzyme linked immunosorbent assay and radioimmunoassay, respectively. RESULTS As compared with the normal group, the experimental UC rats, the colonic mucosal damage index scores (CMDIs), histopathological scores (HS) and the serum TNF-α and colonic mucosa IL-1β, IL-6 levels significantly increased (P<0.05 or P<0.01). In the MSD and SASP groups, the ulcer area significantly reduced, and edema disappeared. The CMDIs, HS, the serum TNF-α and colonic mucosa IL-1β, IL-6 levels in the MSD and SASP groups significantly decreased (P<0.05 or P<0.01) compared with the model group. The CMDIs in the MSD group were lower than that in the SASP group (P<0.05), but there were no significant differences in HS, serum TNF-α or colonic mucosa IL-1β, IL-6 levels between the MSD and SASP groups. CONCLUSION MSD enema can improve colonic mucosa impairment and decrease serum TNF-α and colonic mucosa IL-1β, IL-6 levels in experimental UC.
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17
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Page C, Pitchford S. Neutrophil and platelet complexes and their relevance to neutrophil recruitment and activation. Int Immunopharmacol 2013; 17:1176-84. [PMID: 23810443 DOI: 10.1016/j.intimp.2013.06.004] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2012] [Revised: 09/20/2012] [Accepted: 06/09/2013] [Indexed: 12/29/2022]
Abstract
The manifestation of platelet 'satallitism' around neutrophils in whole blood is a long acknowledged phenomenon [1]. Circulating platelet-neutrophil complexes (PNC) occur in a diverse range of inflammatory disorders and infections that affect numerous organs of the body. Animal models have revealed that the formation of PNC is required for the recruitment of neutrophils to inflamed tissue, since platelets 'prime' neutrophils for efficient adhesion to vascular endothelium via the up-regulation of integrins and enhanced responsiveness to chemokines (Fig. 1). Perhaps surprisingly, the surface contact between platelets and neutrophils additionally enhances other neutrophil functions, such as chemotaxis that is required for migration into tissues, trans-cellular production of eicosanoids, phagocytosis and trapping of pathogens, increased respiratory burst leading to the production of reactive oxygen species (ROS), and modulation of neutrophil apoptosis (Fig. 1). Platelet P-selectin appears to have a particular role in enhancing the majority of these activities, and the influence of platelet P-selectin is not therefore confined to the initial rolling events in the process of neutrophil extravasation.
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Affiliation(s)
- Clive Page
- Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, Kings College London, London SE1 9NH, UK
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18
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Dircks BH, Mischke R, Schuberth HJ. Platelet-neutrophil aggregate formation in blood samples from dogs with systemic inflammatory disorders. Am J Vet Res 2012; 73:939-45. [PMID: 22738043 DOI: 10.2460/ajvr.73.7.939] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To evaluate platelet-neutrophil aggregate (PNA) formation and neutrophil shape as indicators of neutrophil activation in dogs with systemic inflammatory diseases and after blood sample incubation with various platelet and neutrophil agonists. ANIMALS 20 dogs with systemic inflammatory response syndrome (SIRS) and 10 healthy Beagles. PROCEDURES Neutrophils were isolated from blood samples directly after blood sample collection and after incubation of blood samples with phorbol myristate acetate, collagen, adenosine diphosphate, epinephrine, or various concentrations of lipopolysaccharide or arachidonic acid. CD61+ neutrophils as an indicator of PNA formation were evaluated, and neutrophil size and granularity were assessed via flow cytometry. RESULTS Dogs with SIRS had more PNA formation, larger neutrophil size, and less granularity relative to control dogs, but no differences were evident when these dogs were grouped by whether they had sepsis (n = 6) or disseminated intravascular coagulation (12). A significant increase in PNA formation occurred after neutrophil incubation with all agonists, and incubation with phorbol myristate acetate elicited the strongest response. Neutrophils increased in size and decreased in granularity after incubation with all agonists except epinephrine. Incubation with lipopolysaccharide or arachidonic acid resulted in a dose-dependent effect on PNA formation and neutrophil shape. CONCLUSIONS AND CLINICAL RELEVANCE SIRS appeared to increase the degree of PNA formation and neutrophil shape change. Similar changes after neutrophil incubation with platelet agonists suggested that platelet activation has a role in PNA formation. Additional studies are necessary to determine the clinical importance and diagnostic value of PNA formation in dogs with SIRS and sepsis.
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Lapchak PH, Kannan L, Rani P, Pamuk ON, Ioannou A, Dalle Lucca JJ, Pine P, Tsokos GC. Inhibition of Syk activity by R788 in platelets prevents remote lung tissue damage after mesenteric ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 2012; 302:G1416-22. [PMID: 22492694 DOI: 10.1152/ajpgi.00026.2012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Tissue injury following ischemia-reperfusion (I/R) occurs as a consequence of actions of soluble factors and immune cells. Growing evidence supports a role for platelets in the manifestation of tissue damage following I/R. Spleen tyrosine kinase has been well documented to be important in lymphocyte activation and more recently in platelet activation. We performed experiments to evaluate whether inhibition of platelet activation through inhibition of spleen tyrosine kinase prevents tissue damage after mesenteric I/R injury. Platelets isolated from C57BL/6J mice fed with R788 for 10 days were transfused into C57BL/6J mice depleted of platelets 2 days before mesenteric I/R injury. Platelet-depleted mice transfused with platelets from R788-treated mice before mesenteric I/R displayed a significant reduction in the degree of remote lung damage, but with little change in the degree of local intestinal damage compared with control I/R mice. Transfusion of R788-treated platelets also decreased platelet sequestration, C3 deposition, and immunoglobulin deposition in lung, but not in the intestine, compared with control groups. These findings demonstrate that platelet activation is a requisite for sequestration in the pulmonary vasculature to mediate remote tissue injury after mesenteric I/R. The use of small-molecule inhibitors may be valuable to prevent tissue damage in remote organs following I/R injury.
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Affiliation(s)
- Peter H Lapchak
- Rheumatology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA
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20
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Lapchak PH, Kannan L, Ioannou A, Rani P, Karian P, Dalle Lucca JJ, Tsokos GC. Platelets orchestrate remote tissue damage after mesenteric ischemia-reperfusion. Am J Physiol Gastrointest Liver Physiol 2012; 302:G888-97. [PMID: 22301111 DOI: 10.1152/ajpgi.00499.2011] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Ischemia-reperfusion (I/R) injury is a leading cause of morbidity and mortality. A functional role for platelets in tissue damage after mesenteric I/R is largely unknown. The hypothesis that mesenteric I/R local and remote injury are platelet dependent was tested. Using a murine mesenteric I/R model, we demonstrate that platelets orchestrate remote lung tissue damage that follows mesenteric I/R injury and also contribute, albeit to a lesser degree, to local villi damage. While lung damage is delayed compared with villi damage, it increased over time and was characterized by accumulation of platelets in the pulmonary vasculature early, followed by alveolar capillaries and extravasation into the pulmonary space. Both villi and lung tissues displayed complement deposition. We demonstrate that villi and lung damage are reduced in mice made platelet deficient before I/R injury and that platelet transfusion into previously platelet-depleted mice before I/R increased both villi and lung tissue damage. Increased C3 deposition accompanied platelet sequestration in the lung, which was mostly absent in platelet-depleted mice. In contrast, C3 deposition was only minimally reduced on villi of platelet-depleted mice. Our findings position platelets alongside complement as a significant early upstream component that orchestrates remote lung tissue damage after mesenteric I/R and strongly suggest that reperfusion injury mitigating modalities should consider the contribution of platelets.
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Affiliation(s)
- Peter H Lapchak
- Rheumatology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
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21
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Lapchak PH, Ioannou A, Kannan L, Rani P, Dalle Lucca JJ, Tsokos GC. Platelet-associated CD40/CD154 mediates remote tissue damage after mesenteric ischemia/reperfusion injury. PLoS One 2012; 7:e32260. [PMID: 22384195 PMCID: PMC3288090 DOI: 10.1371/journal.pone.0032260] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Accepted: 01/21/2012] [Indexed: 01/08/2023] Open
Abstract
Several innate and adaptive immune cell types participate in ischemia/reperfusion induced tissue injury. Amongst them, platelets have received little attention as contributors in the process of tissue damage after ischemia reperfusion (I/R) injury. It is currently unknown whether platelets participate through the immunologically important molecules including, CD40 and when activated, CD154 (CD40L), in the pathogenesis of I/R injury. We hypothesized that constitutive expression of CD40 and activation-induced expression of CD154 on platelets mediate local mesenteric and remote lung tissue damage after I/R injury. Wild type (WT; C57BL/6J), CD40 and CD154 deficient mice underwent mesenteric ischemia for 30 minutes followed by reperfusion for 3 hours. WT mice subjected to mesenteric I/R injury displayed both local intestinal and remote lung damage. In contrast, there was significantly less intestinal damage and no remote lung injury in CD40 and CD154 deficient mice when compared to WT mice. Platelet-depleted WT mice transfused with platelets from CD40 or CD154 deficient mice failed to reconstitute remote lung damage. In contrast, when CD40 or CD154 deficient mice were transfused with WT platelets lung tissue damage was re-established. Together, these findings suggest that multiple mechanisms are involved in local and remote tissue injury and also identify platelet-expressed CD40 and/or CD154 as mediators of remote tissue damage.
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Affiliation(s)
- Peter H. Lapchak
- Rheumatology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Antonis Ioannou
- Rheumatology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (GCT); (AI)
| | - Lakshmi Kannan
- Rheumatology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Poonam Rani
- Rheumatology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Jurandir J. Dalle Lucca
- The United States Army Institute of Surgical Research, San Antonio, Texas, United States of America
| | - George C. Tsokos
- Rheumatology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (GCT); (AI)
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22
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Amison R, Page C, Pitchford S. Pharmacological modulation of the inflammatory actions of platelets. Handb Exp Pharmacol 2012:447-468. [PMID: 22918742 DOI: 10.1007/978-3-642-29423-5_18] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Patients with inflammatory diseases often exhibit a change in platelet function, with these alterations being clearly distinct from the well-characterized role of platelets in haemostasis and thrombosis. It has recently been revealed that platelets can behave as innate inflammatory cells in immune responses with roles in leukocyte recruitment, migration into tissues, release of cytotoxic mediators, and in tissue remodelling following injury.Platelets exhibit a wide range of receptors for mediators involved in the inflammatory pathway and the immune response (Fig. 1). These include purinergic receptors, selectins, integrins, toll-like receptors, immunoglobulins, and chemokine receptors, but the precise role platelets play in the inflammatory process is still under investigation. Nevertheless, given that many of these receptors are distinct from those involved in thrombosis and haemostasis, this raises the real possibility of targeting these receptors to regulate inflammatory diseases without compromising haemostasis.
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Affiliation(s)
- Richard Amison
- Sackler Institute of Pulmonary Pharmacology, King's College London, 150 Stamford Street, Room 5.44, 5th Floor, Franklin-Wilkins Building, Waterloo Campus, London, SE1 9NH, UK
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23
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Huang X, Lv B, Jin HF, Zhang S. A meta-analysis of the therapeutic effects of tumor necrosis factor-α blockers on ulcerative colitis. Eur J Clin Pharmacol 2011; 67:759-66. [DOI: 10.1007/s00228-011-1079-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2011] [Accepted: 05/31/2011] [Indexed: 01/04/2023]
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Jackson CS, Fryer J, Danese S, Vanagunas A, Polensky S, Buchman AL. Mesenteric vascular thromboembolism in inflammatory bowel disease: a single center experience. J Gastrointest Surg 2011; 15:97-100. [PMID: 20824370 DOI: 10.1007/s11605-010-1336-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2010] [Accepted: 08/12/2010] [Indexed: 01/31/2023]
Abstract
BACKGROUND Vascular thrombotic complications in inflammatory bowel disease (IBD) are well recognized, although mesenteric vascular thrombotic disease is rare. METHODS We describe nine patients in a tertiary care center with IBD that developed thrombosis of the mesenteric arterial or venous vasculature (e.g., mesenteric thrombosis, MT). RESULTS Eight subjects developed mesenteric venous thrombosis (five located in the superior mesenteric vein and three located in a branch of the portal vein) and one had a mesenteric arterial embolus, located in the splenic artery. Five subjects had Crohn's disease (CD), and four had ulcerative colitis. The one subject diagnosed with an arterial thrombosis had CD. Mean time from diagnosis of IBD to diagnosis of thrombosis was 24.6 ± 13.5 years. Five of the nine subjects developed mesenteric venous thrombosis while their IBD was clinically in remission. Seven of nine subjects were symptomatic from the development of MT, including bowel infarction that led to development of short bowel syndrome. CONCLUSION Mesenteric thrombosis is a rare complication of IBD and may develop during clinical remission, suggesting a potential role for factors other than clinically significant inflammation in its pathogenesis.
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Affiliation(s)
- Christian S Jackson
- Section of Gastroenterology, Loma Linda VA Healthcare System, Loma Linda University Medical Center, Loma Linda, CA, USA
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Miele LF, Turhan A, Lee GS, Lin M, Ravnic D, Tsuda A, Konerding MA, Mentzer SJ. Blood flow patterns spatially associated with platelet aggregates in murine colitis. Anat Rec (Hoboken) 2009; 292:1143-53. [PMID: 19645018 DOI: 10.1002/ar.20954] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
In the normal murine mucosal plexus, blood flow is generally smooth and continuous. In inflammatory conditions, such as chemically-induced murine colitis, the mucosal plexus demonstrates markedly abnormal flow patterns. The inflamed mucosal plexus is associated with widely variable blood flow velocity as well as discontinuous and even bidirectional flow. To investigate the mechanisms responsible for these blood flow patterns, we used intravital microscopic examination of blood flow within the murine mucosal plexus during dextran sodium sulphate-and trinitrobenzenesulfonic acid-induced colitis. The blood flow patterns within the mucosal plexus demonstrated flow exclusion in 18% of the vessel segments (P < 0.01). Associated with these segmental exclusions was significant variation in neighboring flow velocities. Intravascular injection of fluorescent platelets demonstrated platelet incorporation into both fixed and rolling platelet aggregates. Rolling platelet aggregates (mean velocity 113 microm/sec; range, 14-186 microm/sec) were associated with reversible occlusions and flow variations within the mucosal plexus. Gene expression profiles of microdissected mucosal plexus demonstrated enhanced expression of genes for CCL3, CXCL1, CCL2, CXCL5, CCL7, CCL8, and Il-1b (P < 0.01), and decreased expression of CCL6 (P < 0.01). These results suggest that platelet aggregation, activated by the inflammatory mileau, contributes to the complex flow dynamics observed in acute murine colitis.
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Affiliation(s)
- Lino F Miele
- Laboratory of Adaptive and Regenerative Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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Menezes GB, McAvoy EF, Kubes P. Hyaluronan, platelets, and monocytes: a novel pro-inflammatory triad. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 174:1993-5. [PMID: 19435789 DOI: 10.2353/ajpath.2009.081138] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This commentary reports on the role of platelets and hyaluronan in activating monocytes.
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Affiliation(s)
- Gustavo B Menezes
- Immunology Research Group, Department of Physiologyand Biophysics, Institute of Infection, Immunity andInflammation, University of Calgary, Alberta, Canada
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Schreiber O, Petersson J, Phillipson M, Perry M, Roos S, Holm L. Lactobacillus reuteri prevents colitis by reducing P-selectin-associated leukocyte- and platelet-endothelial cell interactions. Am J Physiol Gastrointest Liver Physiol 2009; 296:G534-42. [PMID: 19147805 DOI: 10.1152/ajpgi.90470.2008] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Recent findings indicate that dextran sodium sulfate (DSS)-induced colitis is associated with a prothrombogenic phenotype, with P-selectin playing a major role in platelet recruitment. It has been suggested that probiotics may ameliorate colonic inflammation. We therefore investigated how treatment with Lactobacillus reuteri influenced P-selectin expression, leukocyte and platelet endothelial cell interactions, and colitis severity in DSS-treated rats. Rats were divided into the following four groups: nontreated, DSS treated (5% in drinking water for 9 days), L. reuteri, and L. reuteri and DSS treated. The rats were anesthetized with Inactin (120 mg/kg ip), and the dual radiolabeled monoclonal antibody technique was used to quantify P-selectin expression. Leukocyte-endothelial and platelet-endothelial cell interactions were studied in colonic venules with intravital microscopy. Colitis severity was assessed using a disease activity index. Disease activity index increased, as did the expression of P-selectin in the entire colon after DSS treatment, but both were reduced to control levels with L. reuteri pretreatment. The increased platelet- and leukocyte-endothelial cell interactions after DSS treatment were abolished by pretreatment with L. reuteri. L. reuteri protects against DSS-induced colitis in rats. The protection is associated with reduced P-selectin expression and a decrease in leukocyte- and platelet-endothelial cell interactions.
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Affiliation(s)
- O Schreiber
- Department of Medical Cell Biology, Biomedical Center, Uppsala University, Box 571, Husarg. 3, 751 23 Uppsala, Sweden.
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