| 1. |
- Du, Feifei, et al.
(författare)
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Microvascular Mechanisms of Polyphosphate-Induced Neutrophil-Endothelial Cell Interactions in vivo
- 2019
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Ingår i: European Surgical Research. - : S. Karger AG. - 0014-312X .- 1421-9921. ; 60:1-2, s. 53-62
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Tidskriftsartikel (refereegranskat)abstract
- Background: Polyphosphates (PolyPs) have been reported to exert pro-inflammatory effects. However, the molecular mechanisms regulating PolyP-provoked tissue accumulation of leukocytes are not known. The aim of the present investigation was to determine the role of specific adhesion molecules in PolyP-mediated leukocyte recruitment. Methods: PolyPs and TNF-α were intrascrotally administered, and anti-P-selectin, anti-E-selectin, anti-P-selectin glycoprotein ligand-1 (PSGL-1), anti-membrane-activated complex-1 (Mac-1), anti-lymphocyte function antigen-1 (LFA-1), and neutrophil depletion antibodies were injected intravenously or intraperitoneally. Intravital microscopy of the mouse cremaster microcirculation was used to examine leukocyte-endothelium interactions and recruitment in vivo. Results: Intrascrotal injection of PolyPs increased leukocyte accumulation. Depletion of neutrophils abolished PolyP-induced leukocyte-endothelium interactions, indicating that neutrophils were the main leukocyte subtype responding to PolyP challenge. Immunoneutralization of P-selectin and PSGL-1 abolished PolyP-provoked neutrophil rolling, adhesion, and emigration. Moreover, immunoneutralization of Mac-1 and LFA-1 had no impact on neutrophil rolling but markedly reduced neutrophil adhesion and emigration evoked by PolyPs. Conclusion: These results suggest that P-selectin and PSGL-1 exert important roles in PolyP-induced inflammatory cell recruitment by mediating neutrophil rolling. In addition, our data show that Mac-1 and LFA-1 are necessary for supporting PolyP-triggered firm adhesion of neutrophils to microvascular endothelium. These novel findings define specific molecules as potential targets for pharmacological intervention in PolyP-dependent inflammatory diseases. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
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| 2. |
- Hawez, Avin, et al.
(författare)
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MiR-155 Regulates PAD4-Dependent Formation of Neutrophil Extracellular Traps
- 2019
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating data suggest that neutrophil extracellular traps (NETs) exert a key function in several diseases. Peptidylarginine deiminase 4 (PAD4) regulates NET formation via citrullination of histones. The aim of this study was to examine the role of miR-155 in controlling PAD4-dependent generation of NETs. Bone marrow neutrophils were stimulated with PMA and MIP-2. Pre-incubation of neutrophils with translational inhibitors (cycloheximide or puromycin) markedly decreased NET formation induced by PMA or MIP-2. Neutrophil transfection with a mimic miR-155 increased PMA-induced PAD4 mRNA expression and NET formation. In contrast, transfection with an antagomiR-155 decreased induction of PAD4 mRNA and NETs in response to PMA challenge. Bioinformatical examination of PAD4 revealed a potential binding site in AU-rich elements at the 3′-UTR region. MiR-155 binding to PAD4 was examined by use of target site blockers and RNA immunoprecipitation, revealing that miR-155 regulation of PAD4 mRNA is mediated via AU-rich elements in the 3′-UTR region. In conclusion, our findings demonstrate that miR-155 positively regulates neutrophil expression of PAD4 and expulsion of extracellular traps. Thus, our novel results indicate that targeting miR-155 might be useful to inhibit exaggerated NET generation in inflammatory diseases.
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| 3. |
- Madhi, Raed, et al.
(författare)
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c-Abl kinase regulates neutrophil extracellular trap formation, inflammation, and tissue damage in severe acute pancreatitis
- 2019
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Ingår i: Journal of Leukocyte Biology. - 0741-5400. ; 106:2, s. 455-466
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil extracellular traps (NETs) are involved in acute pancreatitis (AP) but mechanisms controlling NET expulsion in AP are incompletely understood. Herein, we examined the role of c-Abelson (c-Abl) kinase in NET formation and tissue damage in severe AP. AP was induced by taurocholate infusion into pancreatic duct or intraperitoneal administration of l-arginine in mice. Pancreatic, lung, and blood samples were collected and levels of phosphorylated c-Abl kinase, citrullinated histone 3, DNA-histone complexes, myeloperoxidase, amylase, cytokines, and CXC chemokines were quantified. Citrullinated histone 3, reactive oxygen species (ROS), and NET formation were determined in bone marrow neutrophils. Taurocholate challenge increased phosphorylation of c-Abl kinase and levels of citrullinated histone 3 in the pancreas as well as DNA-histone complexes in the plasma. Administration of the c-Abl kinase inhibitor GZD824 not only abolished activation of c-Abl kinase but also decreased levels of citrullinated histone 3 in the pancreas and DNA-histone complexes in the plasma of animals with AP. Moreover, GZD824 decreased plasma levels of amylase, IL-6, and MMP-9 as well as edema, acinar cell necrosis, hemorrhage, CXC chemokine formation, and neutrophil infiltration in the inflamed pancreas. A beneficial effect of c-Abl kinase inhibition was confirmed in l-arginine-induced pancreatitis. In vitro, inhibition of c-Abl kinase reduced TNF-α-induced formation of ROS, histone 3 citrullination, and NETs in isolated bone marrow neutrophils. Our findings demonstrate that c-Abl kinase regulates NET formation in the inflamed pancreas. In addition, inhibition of c-Abl kinase reduced pancreatic tissue inflammation, and damage in AP. Thus, targeting c-Abl kinase might be a useful way to protect the pancreas in severe AP.
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| 4. |
- Madhi, Raed, et al.
(författare)
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Targeting peptidylarginine deiminase reduces neutrophil extracellular trap formation and tissue injury in severe acute pancreatitis
- 2019
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Ingår i: Journal of Cellular Physiology. - : Wiley. - 0021-9541 .- 1097-4652. ; 234:7, s. 11850-11860
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Tidskriftsartikel (refereegranskat)abstract
- Recent evidence suggests that neutrophil extracellular traps (NETs) play an important role in the development of acute pancreatitis (AP). Herein, we examined the role of peptidylarginine deiminase (PAD), which has been shown to regulate NET formation, in severe AP. AP was induced by retrograde of taurocholate infusion into pancreatic duct in C57BL/6 mice. PAD was pharmacologically inhibited using Cl-amidine, a pan-PAD inhibitor. Pancreata were collected, and histones, citrullinated histone 3, chemokines, myeloperoxidase, and NETs were quantified. Chemokines, matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6), and DNA-histone complexes were determined in plasma samples. Infusion of taurocholate induced formation of NETs in pancreatic tissues of mice. Pretreatment with Cl-amidine markedly reduced the NET formation in the inflamed pancreas. Moreover, inhibition of PAD decreased the levels of blood amylase as well as edema, acinar cell necrosis, hemorrhage, and neutrophil infiltration in the pancreas of animals with AP. Administration of Cl-amidine attenuated the myeloperoxidase levels in the pancreas and lung of mice exposed to taurocholate. In addition, Cl-amidine decreased pancreatic levels of CXC chemokines, plasma levels of IL-6, and MMP-9 in mice with severe AP. This study shows that Cl-amidine is a potent inhibitor of NET formation in severe AP. Also, our results suggest that PAD regulates pathological inflammation and tissue damage in the inflamed pancreas. Thus, targeting PAD might be a useful strategy to treat patients with severe AP.
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| 5. |
- Rönnow, Carl Fredrik, et al.
(författare)
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Forceps Biopsies Are Not Reliable in the Workup of Large Colorectal Lesions Referred for Endoscopic Resection : Should They Be Abandoned?
- 2019
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Ingår i: Diseases of the Colon and Rectum. - 0012-3706. ; 62:9, s. 1063-1070
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Biopsies are routinely obtained in the workup of large colorectal polyps before endoscopic resection. OBJECTIVE: This study aimed to examine how reliable biopsies are in terms of reflecting the true histopathology of large colorectal polyps, in the clinical routine. DESIGN: This is a retrospective study. SETTINGS: Data from patients undergoing polypectomy of large colorectal polyps at the endoscopy unit, Skåne University Hospital Malmö, between January 2014 and December 2016 were scrutinized. PATIENTS: A total of 485 colorectal lesions were biopsied within 1 year before complete endoscopic removal. Biopsy-obtained specimens were compared with completely resected specimens in terms of concordance and discordance and if the final result was upgraded or downgraded. MAIN OUTCOME MEASURES: The primary outcome measured was the concordance between biopsy-obtained specimens and completely resected specimens. RESULTS: Median lesion size was 3 cm (range 1-11). In 189 cases (39%), biopsies did not provide a correct dysplastic grade compared with final pathology after complete resection. One hundred forty-three cases (29%) and 46 cases (9%) were upgraded and downgraded. The percentage of cases with discordant biopsy results was 40% in cases with 1 biopsy taken and 38% in cases where multiple biopsies had been sampled. Time from biopsy to complete resection did not influence the erroneous outcome of biopsies. Notably, the percentage of discordant biopsy results was 37% and 35% in lesions measuring 1 to 2 cm and 2 to 4 cm. However, this percentage increased to 48% in colorectal lesions larger than 4 cm. LIMITATIONS: This study was designed to reflect the clinical routine, the number of biopsies obtained and forceps technique were hence not standardized, which constitutes a limitation. CONCLUSIONS: This study demonstrates that cancer-negative forceps biopsies of large colorectal polyps, referred for endoscopic resection, are not reliable. Considering that endoscopic resection of lesions containing superficial cancer is plausible, the clinical value of forceps biopsies in lesions suitable for endoscopic resection is questionable. See Video Abstract at http://links.lww.com/DCR/A984. LAS BIOPSIAS CON FÓRCEPS NO SON CONFIABLES EN EL ESTUDIO DE LAS LESIONES COLORRECTALES GRANDES REFERIDAS PARA RESECCIÓN ENDOSCÓPICA: ¿DEBERÍAN ABANDONARSE?: Las biopsias se obtienen de forma rutinaria en el estudio de pólipos colorrectales grandes previo a resección endoscópica. OBJETIVO: Analizar que tan confiables son las biopsias en cuanto a reflejar la verdadera histopatología de los pólipos colorrectales grandes, en la rutina clínica. DISEÑO:: Este es un estudio retrospectivo. AJUSTES: Los datos de pacientes sometidos a polipectomía de pólipos colorrectales grandes en la unidad de endoscopia, en Skåne University Hospital Malmö, entre enero de 2014 y diciembre de 2016 fueron examinados. PACIENTES: Un total de 485 lesiones colorrectales se biopsiaron dentro de un año antes de la resección endoscópica completa. Las muestras obtenidas mediante biopsia se compararon con las muestras completas resecadas en términos de concordancia y discordancia, y si el resultado final ascendió o disminuyó de categoría. PRINCIPALES MEDIDAS DE RESULTADO: Concordancia entre muestras obtenidas mediante biopsia y muestras completamente resecadas. RESULTADOS: La mediana de tamaño de lesiones fue de 3 cm (rango 1-11). En 189 casos (39%) las biopsias no proporcionaron un grado de displasia correcto en comparación con la patología final después de la resección completa. 143 casos (29%) y 46 casos (9%) ascendieron y descendieron de categoría, respectivamente. El porcentaje de casos con resultados de biopsia discordantes fue del 40% en los casos con una sola biopsia tomada y del 38% en los casos en los que se tomaron múltiples biopsias. El tiempo desde la biopsia hasta la resección completa no influyó en el resultado erróneo de las biopsias. Notablemente, el porcentaje de resultados de biopsia discordantes fue de 37% y 35% en lesiones que midieron 1-2 cm y 2-4 cm, respectivamente. Sin embargo, este porcentaje aumentó a 48% en lesiones colorrectales mayores de 4 cm. LIMITACIONES: Este estudio se diseñó para reflejar la rutina clínica, el número de biopsias obtenidas y la técnica de fórceps no fueron estandarizadas, lo que constituye una limitación. CONCLUSIONES: Este estudio demuestra que las biopsias con fórceps negativas a cáncer, de pólipos colorrectales grandes referidas para resección endoscópica, no son confiables. Teniendo en cuenta que la resección endoscópica de lesiones que contienen cáncer superficial es posible, el valor clínico de las biopsias con fórceps en lesiones aptas para la resección endoscópica es cuestionable. Vea el Resumen en video en http://links.lww.com/DCR/A984.
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| 6. |
- Thorlacius, Henrik, et al.
(författare)
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European experience of colorectal endoscopic submucosal dissection : a systematic review of clinical efficacy and safety
- 2019
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Ingår i: Acta Oncologica. - 0284-186X. ; 58:sup1, s. 10-14
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Forskningsöversikt (refereegranskat)abstract
- Background: Endoscopic submucosal dissection (ESD) is an advanced method allowing en bloc resection of large and complex lesions in colon and rectum. Herein, the European experience of colorectal ESD was systematically reviewed in the medical literature to determine the clinical efficacy and safety of colorectal ESD in Europe. Material and methods: A systematic search of PubMed for full-text studies including more than 20 cases of colorectal ESD emanating from European centres was performed. Data were independently extracted by two authors using predefined data fields, including efficacy and safety. Results: We included 15 studies containing a total of 1404 colorectal ESD cases (41% in the colon) performed between 2007 and 2018. Lesion size was 40 mm (range 24–59 mm) and procedure time was 102 min (range 48–176 min). En bloc resection rate was 83% (range 67–93%) and R0 resection rate was 70% (range 35–91%). Perforation rate was 7% (range 0–19%) and bleeding rate was 5% (range 0–12%). The percentage of ESD cases undergoing emergency surgery was 2% (range 0–6%). Additional elective surgery was performed in 3% of all cases due to histopathological findings showing deep submucosal invasion or more advanced cancer. The recurrence rate was 4% (range 0–12%) after a median follow-up time of 12 months (range 3–24 months). Conclusions: This review shows that ESD is effective and safe for treating large and complex colorectal lesions in Europe although there is room for improvement. Thus, it is important to develop standardized and high-quality educational programs in colorectal ESD in Europe.
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| 7. |
- Wang, Yongzhi, et al.
(författare)
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Neutrophil extracellular trap-microparticle complexes trigger neutrophil recruitment via high-mobility group protein 1 (HMGB1)-toll-like receptors(TLR2)/TLR4 signalling
- 2019
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 176:17, s. 3350-3363
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: Recent data suggest that neutrophil extracellular traps (NETs) form aggregates with microparticles (MPs) upon activation of neutrophils although the functional role of NET-MP complexes remain elusive. The objective of this study was to examine the role of NET-MP aggregates in leukocyte recruitment in vivo. Experimental Approach: PMA stimulation of murine bone marrow neutrophils generated NET-MP complexes and pretreatment with caspase and calpain inhibitors resulted in the formation of NETs depleted of MPs. Leukocyte–endothelium interactions were studied by using intravital microscopy of the mouse cremaster microcirculation. Key Results: Intrascrotal injection of NET-MP aggregates dose-dependently increased leukocyte recruitment. In contrast, leukocyte responses were markedly reduced after administration of NETs depleted of MPs. Neutrophil depletion abolished intravascular and extravascular leukocytes in response to challenge with NET-MP complexes. Electron microscopy revealed that NET-associated MPs express HMGB1. Notably, immunoneutralization of HMGB1 markedly decreased NET-MP complex-induced neutrophil accumulation. Moreover, inhibition of TLR2 and TLR4 significantly reduced neutrophil recruitment in response to NET-MP aggregates. Conclusions and Implications: These data show that NET-MP complexes are potent inducers of neutrophil recruitment, which is dependent on HMGB1 expressed on MPs and mediated via TLR2 and TLR4. Blocking MP binding to NETs or downstream inhibition of the HMGB1-TLR2/TLR4 axis might provide useful targets to attenuating NET-dependent tissue damage in acute inflammation.
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