| 1. |
- Ma, Tao, et al.
(author)
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Genomic insights into salt adaptation in a desert poplar
- 2013
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 4, s. 2797-
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Journal article (peer-reviewed)abstract
- Despite the high economic and ecological importance of forests, our knowledge of the genomic evolution of trees under salt stress remains very limited. Here we report the genome sequence of the desert poplar, Populus euphratica, which exhibits high tolerance to salt stress. Its genome is very similar and collinear to that of the closely related mesophytic congener, P. trichocarpa. However, we find that several gene families likely to be involved in tolerance to salt stress contain significantly more gene copies within the P. euphratica lineage. Furthermore, genes showing evidence of positive selection are significantly enriched in functional categories related to salt stress. Some of these genes, and others within the same categories, are significantly upregulated under salt stress relative to their expression in another salt-sensitive poplar. Our results provide an important background for understanding tree adaptation to salt stress and facilitating the genetic improvement of cultivated poplars for saline soils.
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| 2. |
- Chen, Zeyuan, et al.
(author)
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Survival in the Tropics despite isolation, inbreeding and asexual reproduction : insights from the genome of the world's southernmost poplar (Populus ilicifolia)
- 2020
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In: The Plant Journal. - : Wiley. - 0960-7412 .- 1365-313X. ; 103:1, s. 430-442
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Journal article (peer-reviewed)abstract
- Species are becoming extinct at unprecedented rates as a consequence of human activity. Hence it is important to understand the evolutionary dynamics of species with already small population sizes. Populus ilicifolia is a vulnerable poplar species that is isolated from other poplar species and is uniquely adapted to the Tropics. It has a very limited size, reproduces partly clonally and is therefore an excellent case study for conservation genomics. We present here the first annotated draft genome of P. ilicifolia, characterize genome-wide patterns of polymorphisms and compare those to other poplar species with larger natural ranges. P. ilicifolia experienced a more prolonged and severe decline of effective population size (Ne) and signs of genetic erosion than any other poplar species with which it was compared. At present, the species has the lowest genome-wide genetic diversity, the highest abundance of long runs of homozygosity, high inbreeding levels as well as a high overall accumulation of deleterious variants. However, more effective purging of severely deleterious variants and adaptation to the Tropics may have contributed to its survival. Hence, in spite of its limited genetic variation, it is certainly worth pursuing the conservation efforts of this unique species.
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| 3. |
- Kang, Xiangpeng, et al.
(author)
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Isatis tinctoria L. combined with co-stimulatory molecules blockade prolongs survival of cardiac allografts in alloantigen-primed mice
- 2010
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In: Transplant Immunology. - : Elsevier BV. - 1878-5492 .- 0966-3274. ; 23:1-2, s. 34-39
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Journal article (peer-reviewed)abstract
- Memory T cells present a unique challenge in transplantation. Although memory T cells express robust immune responses to invading pathogens. they may be resistant to the effects of immunosuppressive therapies used to prolong graft survival. In previous studies, we found that compound K. the synthesized analogue of highly unsaturated fatty acids from Isatis tinctoria L., reduced acute cardiac allograft rejection in mice (Wang et al., 2009 [1]). Here, we further investigated the effect of compound K on cardiac allograft rejection in alloantigen-primed mice. We found that compound K significantly inhibited CD4(+) and CD8(+) memory T cells proliferation in a mixed lymphocyte reaction (MLR). In vivo, compound K combined with anti-CD154 and anti-LFA-1 monoclonal antibodies (mAbs) significantly extended the survival time of heart grafts in alloantigen-primed mice with no obvious toxic side effects. Furthermore, our data suggests that compound K works by reducing the expression of both IL-2 and IFN-gamma within the graft rather than enhancing expression of regulatory T cells (Tregs). Compound K can also inhibit the alloresponses of memory T cells, while increasing the proportion of CD4(+) memory T cells in the spleen of the recipients and significantly reducing the level of alloantibodies in the serum. Our study highlights the unique immune effects of compound K that may be further explored for clinical use in extending the survival of transplant grafts. (C) 2010 Elsevier B.V. All rights reserved.
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| 4. |
- Sai, Hanna, et al.
(author)
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Observations of the very young Type Ia Supernova 2019np with early-excess emission
- 2022
-
In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 514:3, s. 3541-3558
-
Journal article (peer-reviewed)abstract
- Early-time radiative signals from Type Ia supernovae (SNe Ia) can provide important constraints on the explosion mechanism and the progenitor system. We present observations and analysis of SN 2019np, a nearby SN Ia discovered within 1–2 days after the explosion. Follow-up observations were conducted in optical, ultraviolet, and near-infrared bands, covering the phases from ∼−16.7 d to ∼+ 367.8 d relative to its B-band peak luminosity. The photometric and spectral evolutions of SN 2019np resemble the average behaviour of normal SNe Ia. The absolute B-band peak magnitude and the post-peak decline rate are Mmax(B) = −19.52 ± 0.47 mag and Δm15(B) = 1.04 ± 0.04 mag, respectively. No Hydrogen line has been detected in the nebular-phase spectra of SN 2019np. Assuming that the 56Ni powering the light curve is centrally located, we find that the bolometric light curve of SN 2019np shows a flux excess up to 5.0 per cent in the early phase compared to the radiative diffusion model. Such an extra radiation perhaps suggests the presence of an additional energy source beyond the radioactive decay of central nickel. Comparing the observed colour evolution with that predicted by different models, such as interactions of SN ejecta with circumstellar matter (CSM)/companion star, a double-detonation explosion from a sub-Chandrasekhar mass white dwarf (WD) and surface 56Ni mixing, we propose that the nickel mixing is more favoured for SN 2019np.
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| 5. |
- Wang, Feng, et al.
(author)
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Anti-CD44 Monoclonal Antibody Inhibits Heart Transplant Rejection Mediated by Alloantigen-primed CD4(+) Memory T Cells in Nude Mice
- 2010
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In: Immunological Investigations. - : Informa UK Limited. - 0882-0139 .- 1532-4311. ; 39:8, s. 807-819
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Journal article (peer-reviewed)abstract
- Donor-reactive CD4(+) memory T cells threaten the survival of transplanted organs. In this study, we used anti-CD44 monoclonal antibody (mAb) to inhibit adoptively transferred B6-reactive CD4(+) memory T cells (BALB/c origin) and to induce tolerance of B6 hearts in nude mice. The median survival time (MST) of the grafts was 6 days in the isotype group, and more than 100 days in the group treated with 8 doses of anti-CD44 at four-day intervals. Histological analysis revealed that the mean rejection level was Grade 3 in the isotype group, and Grade 0 or 1 in the multi-dose anti-CD44 treatment group. Compared with the isotype group, the multiply treated anti-CD44 group had significantly decreased IL-2 and IFN-gamma expressions, while IL-10 and TGF-beta were increased in the serum and the graft. Foxp3 in the graft was also increased. These data demonstrate that alloreactive CD4(+) memory T cells mediate the destruction of allografts, and the adhesion molecule CD44 plays an important role in this course. Anti-CD44 mAb may promote the reduction of CD4(+) memory T cells and the production of regulatory T cells (Tregs). Furthermore, Tregs are maintained at a certain level while suppressing cellular immunity and inducing the grafts long-term survival in transplant recipients.
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| 6. |
- Changhui, Yu, et al.
(author)
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Platelet-Derived CCL5 Regulates CXC Chemokine Formation and Neutrophil Recruitment in Acute Experimental Colitis.
- 2016
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In: Journal of Cellular Physiology. - : Wiley. - 1097-4652 .- 0021-9541. ; 231:2, s. 370-376
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Journal article (peer-reviewed)abstract
- Accumulating data suggest that platelets not only regulate thrombosis and haemostasis but also inflammatory processes. Platelets contain numerous potent pro-inflammatory compounds, including the chemokines CCL5 and CXCL4 although their role in acute colitis remains elusive. The aim of this study was to examine the role of platelets and platelet-derived chemokines in acute colitis. Acute colitis was induced in female Balb/c mice by administration of 5% dextran sodium sulphate (DSS) for five days. Animals received a platelet-depleting, anti-CCL5, anti-CXCL4 or a control antibody prior to DSS challenge. Colonic tissue was collected for quantification of myeloperoxidase (MPO) activity, CXCL5, CXCL2, interleukin-6 (IL-6) and CCL5 levels as well as morphological analyses. Platelet depletion reduced tissue damage and clinical disease activity index in DSS-exposed animals. Platelet depletion not only reduced levels of CXCL2 and CXCL5 but also levels of CCL5 in the inflamed colon. Immunoneutralization of CCL5 but not CXCL4 reduced tissue damage, CXC chemokine expression and neutrophil recruitment in DSS-treated animals. These findings show that platelets play a key role in acute colitis by regulating CXC chemokine generation, neutrophil infiltration and tissue damage in the colon. Moreover, our results suggest that platelet-derived CCL5 is an important link between platelet activation and neutrophil recruitment in acute colitis. This article is protected by copyright. All rights reserved.
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| 7. |
- Ding, Zhiyi, et al.
(author)
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Actin-related protein 2/3 complex regulates neutrophil extracellular trap expulsion and lung damage in abdominal sepsis
- 2022
-
In: American Journal of Physiology - Lung Cellular and Molecular Physiology. - 1040-0605. ; 322:5, s. 662-672
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Journal article (peer-reviewed)abstract
- Neutrophil extracellular trap (NET) formation is a key feature in sepsis. The aim of the present study was to examine the role of the actin cytoskeleton in regulating the expulsion of NETs. Actin-related protein 2/3 (Arp 2/3) complex is an important regulator of F-actin polymerization. Coincubation with CK666, a specific Arp 2/3 inhibitor, decreased 12-phorbol 13-myristate acetate-induced NET formation in vitro. CK666 not only abolished F-actin polymerization but also caused intracellular retention of NETs. Inhibition of Arp 2/3 reduced NET formation on circulating neutrophils and in the bronchoalveolar space in mice undergoing cecal ligation and puncture (CLP). Notably, treatment with CK666 attenuated CLP-induced neutrophil recruitment, edema formation, and tissue damage in the lungs. Moreover, Arp 2/3 inhibition decreased levels of C-X-C motif chemokine ligand 1 (CXCL-1) and interleukin-6 in the lung and plasma of septic animals. Taken together, this study shows that expulsion of NETs is regulated by the actin cytoskeleton and that inhibition of Arp 2/3-dependent F-actin polymerization not only decreases NET formation but also protects against pathological inflammation and tissue damage in septic lung injury. Thus, we suggest that targeting NET release is a novel and useful way to ameliorate lung damage in abdominal sepsis.
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| 8. |
- Dinh, Thanh Theresa, et al.
(author)
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An NKX-COUP-TFII morphogenetic code directs mucosal endothelial addressin expression
- 2022
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
-
Journal article (peer-reviewed)abstract
- Immunoglobulin family and carbohydrate vascular addressins encoded by Madcam1 and St6gal1 control lymphocyte homing into intestinal tissues, regulating immunity and inflammation. The addressins are developmentally programmed to decorate endothelial cells lining gut post-capillary and high endothelial venules (HEV), providing a prototypical example of organ- and segment-specific endothelial specialization. We identify conserved NKX-COUP-TFII composite elements (NCCE) in regulatory regions of Madcam1 and St6gal1 that bind intestinal homeodomain protein NKX2-3 cooperatively with venous nuclear receptor COUP-TFII to activate transcription. The Madcam1 element also integrates repressive signals from arterial/capillary Notch effectors. Pan-endothelial COUP-TFII overexpression induces ectopic addressin expression in NKX2-3+ capillaries, while NKX2-3 deficiency abrogates expression by HEV. Phylogenetically conserved NCCE are enriched in genes involved in neuron migration and morphogenesis of the heart, kidney, pancreas and other organs. Our results define an NKX-COUP-TFII morphogenetic code that targets expression of mucosal vascular addressins.
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| 9. |
- Du, Feifei, et al.
(author)
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E3 Ubiquitin Ligase Midline 1 Regulates Endothelial Cell ICAM-1 Expression and Neutrophil Adhesion in Abdominal Sepsis
- 2023
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In: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 24:1
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Journal article (peer-reviewed)abstract
- Septic lung damage is associated with endothelial cell and neutrophil activation. This study examines the role of the E3 ubiquitin ligase midline 1 (Mid1) in abdominal sepsis. Mid1 expression was increased in endothelial cells derived from post-capillary venules in septic mice and TNF-α challenge increased Mid1 levels in endothelial cells in vitro. The siRNA-mediated knockdown of Mid1 decreased TNF-α-induced upregulation of ICAM-1 and neutrophil adhesion to endothelial cells. Moreover, Mid1 silencing reduced leukocyte adhesion in post-capillary venules in septic lungs in vivo. The silencing of Mid1 not only decreased Mid1 expression but also attenuated expression of ICAM-1 in lungs from septic mice. Lastly, TNF-α stimulation decreased PP2Ac levels in endothelial cells in vitro, which was reversed in endothelial cells pretreated with siRNA directed against Mid1. Thus, our novel data show that Mid1 is an important regulator of ICAM-1 expression and neutrophil adhesion in vitro and septic lung injury in vivo. A possible target of Mid1 is PP2Ac in endothelial cells. Targeting the Mid1-PP2Ac axis may be a useful way to reduce pathological lung inflammation in abdominal sepsis.
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| 10. |
- Du, Feifei, et al.
(author)
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Microvascular Mechanisms of Polyphosphate-Induced Neutrophil-Endothelial Cell Interactions in vivo
- 2019
-
In: European Surgical Research. - : S. Karger AG. - 0014-312X .- 1421-9921. ; 60:1-2, s. 53-62
-
Journal article (peer-reviewed)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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| 11. |
- Fiore, Achille, et al.
(author)
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Detailed spectrophotometric analysis of the superluminous and fast evolving SN 2019neq
- 2024
-
In: Monthly notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 527:3, s. 6473-6494
-
Journal article (peer-reviewed)abstract
- SN 2019neq was a very fast evolving superluminous supernova. At a redshift z = 0.1059, its peak absolute magnitude was −21.5 ± 0.2 mag in g band. In this work, we present data and analysis from an extensive spectrophotometric follow-up campaign using multiple observational facilities. Thanks to a nebular spectrum of SN 2019neq, we investigated some of the properties of the host galaxy at the location of SN 2019neq and found that its metallicity and specific star formation rate are in a good agreement with those usually measured for SLSNe-I hosts. We then discuss the plausibility of the magnetar and the circumstellar interaction scenarios to explain the observed light curves, and interpret a nebular spectrum of SN 2019neq using published SUMO radiative-transfer models. The results of our analysis suggest that the spin-down radiation of a millisecond magnetar with a magnetic field B ≃ 6×1014 G could boost the luminosity of SN 2019neq.
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| 12. |
- Karlsson, Iulia, et al.
(author)
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Pathogenic Escherichia coli and lipopolysaccharide enhance the expression of IL-8, CXCL5, and CXCL10 in canine endometrial stromal cells
- 2015
-
In: Theriogenology. - : Elsevier BV. - 0093-691X .- 1879-3231. ; 84, s. 34-42
-
Journal article (peer-reviewed)abstract
- Chemokines play a central role in cellular communication in response to bacterial infection. However, the knowledge of the chemokine responses to bacterial infections in dogs remains limited. Uterine bacterial infection (pyometra) is one of the most common bacterial diseases in dogs and causes sepsis in most of the cases. We have shown previously that dogs with pyometra have higher messenger RNA (mRNA) levels of chemokines in uterus. To assess whether the stromal part of the endometrium expresses chemokines in response to bacterial infection, we cultured endometrial stromal cells isolated from healthy dogs and exposed them to either live pathogenic Escherichia coli, isolated from the uterus of a dog with pyometra, or lipopolysaccharide. Changes in the mRNA expression of ELR+ CXC chemokines, IL-8, CXCL5, CXCL7, and ELR- CXC chemokine, CXCL10, were measured after 24 hours using quantitative real-time polymerase chain reaction. Levels of IL-8, CXCL5, and CXCL10 were upregulated in endometrial stromal cells exposed to E coli and lipopolysaccharide, whereas the level of CXCL7 was decreased or unaffected. In addition, levels of IL-8 and CXCL5, but not CXCL7 or CXCL10, were significantly higher in dogs with pyometra than those in healthy dogs. Our findings show that pathogenic uterine-derived E coli induces a CXC chemokine response both in cultured endometrial stromal cells within 24 hours and in pyometra-affected uteri from dogs. Stromal cells could therefore play an important role in early neutrophil and T cell recruitment to the site of inflammation during gram-negative bacterial infection of the uterus. Further studies are needed to clarify the role of chemokines in host response to bacterial infection in dogs and the possibility of using chemokines as diagnostic parameters for bacterial infection in this species. (C) 2015 Elsevier Inc. All rights reserved.
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| 13. |
- Luo, Lingtao, et al.
(author)
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Pro-inflammatory role of neutrophil extracellular traps in abdominal sepsis.
- 2014
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In: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 307:7, s. 586-596
-
Journal article (peer-reviewed)abstract
- Excessive neutrophil activation is a major component in septic lung injury. Neutrophil-derived DNA may form extracellular traps in response to bacterial invasions. The aim of the present study was to investigate the potential role of neutrophil extracellular traps (NETs) in septic lung injury. Male C57BL/6 mice were treated with rhDNAse (5 mg/kg) after cecal ligation and puncture (CLP). Extracellular DNA was stained by Sytox green and NET formation was quantified by confocal microscopy and cell-free DNA in plasma, peritoneal cavity and lung. Blood, peritoneal fluid and lung tissue were harvested for analysis of neutrophil infiltration, NET levels, tissue injury as well as CXC chemokine and cytokine formation. We observed that CLP caused increased formation of NETs in the plasma, peritoneal cavity and lung. Administration of rhDNAse not only eliminated NET formation in the plasma, peritoneal cavity and bronchoalveolar space but also reduced lung edema and tissue damage 24 h after CLP induction. Moreover, treatment with rhDNAse decreased CLP-induced formation of CXC chemokines, IL-6 and HMGB1 in the plasma as well as CXC chemokines and IL-6 in the lung. In vitro, we found that neutrophil-derived NETs had the capacity to stimulate secretion of CXCL2, TNF-α and HMGB1 from alveolar macrophages. Taken together, our findings show that NETs regulate pulmonary infiltration of neutrophils and tissue injury via formation of pro-inflammatory compounds in abdominal sepsis. Thus, we conclude that NETs exert a pro-inflammatory role in septic lung injury.
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| 14. |
- Puegge, Johanna, et al.
(author)
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Adhesive Mechanisms of Histone-Induced Neutrophil-Endothelium Interactions in the Muscle Microcirculation.
- 2015
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In: European Surgical Research. - : S. Karger AG. - 0014-312X .- 1421-9921. ; 56:1-2, s. 19-31
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Journal article (peer-reviewed)abstract
- Extracellular histones released during cell damage have the capacity to cause tissue injury associated with increased leukocyte accumulation. However, the molecular mechanisms regulating histone-induced leukocyte recruitment remain elusive. The objective of this study was to examine the role of adhesion molecules in histone-dependent leukocyte accumulation by use of intravital microscopy of the mouse cremaster microcirculation.
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| 15. |
- Rahman, Milladur, et al.
(author)
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Ticagrelor reduces neutrophil recruitment and lung damage in abdominal sepsis.
- 2014
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In: Platelets. - : Informa UK Limited. - 1369-1635 .- 0953-7104. ; 25:4, s. 257-263
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Journal article (peer-reviewed)abstract
- Abstract Platelets play an important role in abdominal sepsis and P2Y12 receptor antagonists have been reported to exert anti-inflammatory effects. Herein, we assessed the impact of platelet inhibition with the P2Y12 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis. Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were treated with ticagrelor (100 mg/kg) or vehicle prior to CLP induction. Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified. Flow cytometry was used to determine expression of platelet-neutrophil aggregates, neutrophil activation and CD40L expression on platelets. CLP-induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50% in ticagrelor-treated animals. Moreover, ticagrelor abolished CLP-provoked lung edema and decreased lung damage score by 41%. Notably, ticagrelor completely inhibited formation of platelet-neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals. In addition, ticagrelor reduced platelet shedding of CD40L in septic mice. Our data indicate that ticagrelor can reduce CLP-induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists, such as ticagrelor, in the management of patients with abdominal sepsis.
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| 16. |
- Wang, Yongzhi, et al.
(author)
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Distinct patterns of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation
- 2013
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In: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 304:4, s. 298-305
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Journal article (peer-reviewed)abstract
- Wang Y, Roller J, Slotta JE, Zhang S, Luo L, Rahman M, Syk I, Menger MD, Thorlacius H. Distinct patterns of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation. Am J Physiol Lung Cell Mol Physiol 304: L298-L305, 2013. First published December 28, 2012; doi:10.1152/ajplung.00246.2012.The mechanisms of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation remain elusive. Male C57BL/6 mice received lipopolysaccharide (LPS) intrapulmonary (intratracheally, it) or systemically (intravenously, iv) for 1-18 h. Leukocyte responses in lung were analyzed by use of intravital fluorescence microscopy. Plasma and lung levels of CXC chemokines as well as Mac-1 and F-actin expression in leukocytes and bronchoalveolar leukocytes were quantified. Venular leukocyte rolling was markedly increased in response to local LPS but only marginally after systemic LPS. Leukocyte adhesion in venules was enhanced in both groups although adhesion was higher in mice receiving LPS intratracheally compared with LPS intravenously. Systemic LPS caused more leukocytes trapping in capillaries compared with local LPS. The ratio of adherent leukocytes in venules compared with capillaries was higher in response to local LPS, suggesting that leukocytes were more prone to accumulate in venules in local inflammation and in capillaries in systemic inflammation. Systemic LPS triggered higher F-actin formation and Mac-1 expression in leukocytes compared with local LPS. Local and systemic LPS caused similar increases in CXC chemokines in the lung whereas intravenous endotoxin provoked higher levels of CXC chemokines in the circulation. Interestingly, intratracheal LPS increased recruitment of leukocytes in the alveolar space whereas intravenous LPS was ineffective in promoting leukocyte accumulation in the bronchoalveolar space. In conclusion, our data demonstrate that pulmonary microvascular recruitment of leukocytes differs in local and systemic inflammation, which might be related to premature activation and stiffening of circulating leukocytes in endotoxemia.
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| 17. |
- Wang, Yongzhi, et al.
(author)
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DYNAMIC CHANGES IN THROMBIN GENERATION IN ABDOMINAL SEPSIS IN MICE.
- 2014
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In: Shock. - 1540-0514. ; 42:4, s. 343-349
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Journal article (peer-reviewed)abstract
- ABSTRACT-Systemic inflammatory response syndrome and severe infections are associated with major derangements in the coagulation system. The purpose of this study was to examine the dynamic alterations in thrombin generation in abdominal sepsis. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in C57/Bl6 mice. CLP caused a systemic inflammatory response with neutrophil recruitment and tissue damage in the lung as well as thrombocytopenia and leukocytopenia. Thrombin generation, coagulation factors, lung histology and myeloperoxidase (MPO) activity was determined 1h, 3h, 6h and 24h after induction of CLP. It was found that thrombin generation was increased 1h after CLP and that thrombin generation started to decrease at 3h and was markedly reduced 6h and 24h after CLP induction. Platelet poor plasma from healthy mice could completely reverse the inhibitory effect of CLP on thrombin generation, suggesting that sepsis caused a decrease in the levels of plasma factors regulating thrombin generation in septic animals. Indeed, it was found that CLP markedly decreased plasma levels of prothrombin, factor V and factor X at 6h and 24h. Moreover, we observed that CLP increased plasma levels of activated protein C at 6h, which returned to baseline levels 24h after CLP induction. Finally, pretreatment with imipenem/cilastatin attenuated the CLP-evoked decrease in thrombin generation and consumption of prothrombin 24h after CLP induction. Our novel findings suggest that thrombin generation is initially increased and later decreased in abdominal sepsis. Sepsis-induced reduction in thrombin generation is correlated to changes in the plasma levels of coagulation factors and activated protein C. These findings help explain the dynamic changes in global hemostasis in abdominal sepsis.
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| 18. |
- Wang, Yongzhi
(author)
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Innate immune cell response in sepsis
- 2015
-
Doctoral thesis (other academic/artistic)abstract
- Leukocyte recruitment is known to be a key feature at sites of inflammation and important in the combat against infectious agents. However, the mechanisms of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation remain elusive. Abdominal sepsis is associated with significant changes in systemic inflammation and coagulation. We hypothesized that leukocytes might exhibit different spatial patterns of accumulation in the pulmonary microvasculature in local versus systemic inflammation induced by injection lipopolysaccharide (LPS) intratracheally (i.t.) or intravenously (i.v.), monocytes and platelets might be important regulators of thrombin generation in abdominal sepsis induced by cecal ligation and puncture (CLP). We observed that systemic LPS caused more leukocytes trapping in capillaries compared to local LPS. The ratio of adherent leukocytes in venules compared to capillaries was higher in response to local LPS, suggesting that leukocytes were more prone to accumulate in venules in local inflammation and in capillaries in systemic inflammation. Alveolar accumulation of leukocytes was more efficient in local compared to systemic inflammation. Rho-kinase signaling appears to regulate both adhesive and mechanical aspects of endotoxin-induced leukocyte infiltration in the lung. In study II, It was found that dynamic changes in the coagulation system characterized by a hypercoagulable phase followed by a hypocoagulable phase in response to a septic insult. In addition, we found peripheral blood monocytes regulate sepsis-induced thrombin generation and consumption of coagulation factors. Moreover, monocytes are critical for formation of pro-inflammatory compounds and neutrophil accumulation in the lung in abdominal sepsis. We also found platelets regulate thrombin generation in abdominal sepsis and platelet-derived microparticles (PMPs) have the capacity to trigger thrombin formation and that this effect could be due to PS-mediated activation of the coagulation system. Moreover, our data demonstrated that Rac1 signaling is critical for the formation of PMPs and thrombin generation in sepsis. Taken together, these findings increase our understanding of the important role of neutrophils, monocytes and platelets in the pathophysiology of sepsis and data of this thesis may help to develop potential therapies in management of patients with sepsis.
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| 19. |
- Wang, Yongzhi, et al.
(author)
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Monocytes regulate systemic coagulation and inflammation in abdominal sepsis.
- 2015
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In: American Journal of Physiology: Heart and Circulatory Physiology. - : American Physiological Society. - 1522-1539 .- 0363-6135. ; 308:5, s. 540-547
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Journal article (peer-reviewed)abstract
- Abdominal sepsis is associated with significant changes in systemic inflammation and coagulation. The purpose of this study was to examine the role of peripheral blood monocytes for systemic coagulation, including thrombin generation and consumption of coagulation factors. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Plasma and lung levels of interleukin-6 (IL-6), CXC chemokines (CXCL1, CXCL2 and CXCL5) as well as pulmonary activity of myeloperoxidase (MPO), thrombin generation and coagulation factors were determined 6h after CLP induction. Administration of clodronate liposomes decreased circulating levels of monocytes by 96%. Time to peak thrombin formation was increased and peak and total thrombin generation was decreased in plasma from CLP animals. Monocyte depletion decreased time to peak formation of thrombin and increased peak and total generation of thrombin in septic animals. In addition, monocyte depletion decreased the CLP-induced increase in the levels of thrombin-antithrombin complexes in plasma. Depletion of monocytes increased plasma levels of prothrombin, factor V, factor X, protein C and in septic mice. Moreover, depletion of monocytes decreased CLP-induced levels of IL-6 and CXC chemokines in plasma and lung by more than 59% and 20%, respectively. CLP-induced MPO activity in the lung was attenuated by 44% in animals depleted of monocytes. Taken together, our findings show for the first time that peripheral blood monocytes regulates systemic coagulation and improve our understanding of the pathophysiology of sepsis and encourage further attempts to target innate immune cell functions in abdominal sepsis.
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| 20. |
- Wang, Yongzhi, et al.
(author)
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Neutrophil extracellular trap-microparticle complexes enhance thrombin generation via the intrinsic pathway of coagulation in mice
- 2018
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
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Journal article (peer-reviewed)abstract
- Abdominal sepsis is associated with dysfunctional hemostasis. Thrombin generation (TG) is a rate-limiting step in systemic coagulation. Neutrophils can expell neutrophil extracellular traps (NETs) and/or microparticles (MPs) although their role in pathological coagulation remains elusive. Cecal ligation and puncture (CLP)-induced TG in vivo was reflected by a reduced capacity of plasma from septic animals to generate thrombin. Depletion of neutrophils increased TG in plasma from CLP mice. Sepsis was associated with increased histone 3 citrullination in neutrophils and plasma levels of cell-free DNA and DNA-histone complexes and administration of DNAse not only eliminated NET formation but also elevated TG in sepsis. Isolated NETs increased TG and co-incubation with DNAse abolished NET-induced formation of thrombin. TG triggered by NETs was inhibited by blocking factor XII and abolished in factor XII-deficient plasma but intact in factor VII-deficient plasma. Activation of neutrophils simultaneously generated large amount of neutrophil-derived MPs, which were found to bind to NETs via histone-phosphatidylserine interactions. These findings show for the first time that NETs and MPs physically interact, and that NETs might constitute a functional assembly platform for MPs. We conclude that NET-MP complexes induce TG via the intrinsic pathway of coagulation and that neutrophil-derived MPs play a key role in NET-dependent coagulation.
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| 21. |
- Wang, Yongzhi, et al.
(author)
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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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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 176:17, s. 3350-3363
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Journal article (peer-reviewed)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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| 22. |
- Wang, Yongzhi, et al.
(author)
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Platelet-derived microparticles regulates thrombin generation via phophatidylserine in abdominal sepsis
- 2018
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In: Journal of Cellular Physiology. - : Wiley. - 1097-4652 .- 0021-9541. ; 233:2, s. 1051-1060
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Journal article (peer-reviewed)abstract
- Sepsis is associated with dysfunctional coagulation. Recent data suggest that platelets play a role in sepsis by promoting neutrophil accumulation. Herein, we show that cecal ligation and puncture (CLP) triggered systemic inflammation, which is characterized by formation of IL-6 and CXC chemokines as well as neutrophil accumulation in the lung. Platelet depletion decreased neutrophil accumulation, IL-6, and CXC chemokines formation in septic lungs. Depletion of platelets increased peak thrombin formation and total thrombin generation (TG) in plasma from septic animals. CLP elevated circulating levels of platelet-derived microparticles (PMPs). In vitro generated PMPs were a potent inducer of TG. Interestingly, in vitro wild-type recombinant annexin V abolished PMP-induced thrombin formation whereas a mutant annexin V protein, which does not bind to phosphatidylserine (PS), had no effect. Administration of wild-type, but not mutant annexin V, significantly inhibited thrombin formation in septic animals. Moreover, CLP-induced formation of thrombin-antithrombin complexes were reduced in platelet-depleted mice and in animals pretreated with annexin V. PMP-induced TG attenuated in FXII- and FVII-deficient plasma. These findings suggest that sepsis-induced TG is dependent on platelets. Moreover, PMPs formed in sepsis are a potent inducer of TG via PS exposure, and activation of both the intrinsic and extrinsic pathway of coagulation. In conclusion, these observations suggest that PMPs and PS play an important role in dysfunctional coagulation in abdominal sepsis.
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| 23. |
- Wang, Yongzhi, et al.
(author)
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Rac1 regulates bacterial toxin-induced thrombin generation.
- 2016
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In: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830.
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Journal article (peer-reviewed)abstract
- Systemic inflammatory response syndrome is associated with severe coagulopathy. The purpose of this study was to examine thrombin generation in systemic inflammation triggered by the endotoxin lipopolysaccharide (LPS) and the exotoxin streptococcal M1 protein.
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| 24. |
- Wang, Yongzhi, et al.
(author)
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Rac1 regulates sepsis-induced formation of platelet-derived microparticles and thrombin generation
- 2017
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In: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X. ; 487:4, s. 887-891
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Journal article (peer-reviewed)abstract
- Dysfunctional coagulation aggravates clinical outcome in patients with sepsis. The aim of this study was to define the role of Rac-1 in the formation of platelet-derived microparticles (PMPs) and thrombin generation (TG) in abdominal sepsis. Male C57BL/6 mice underwent cecal ligation and puncture (CLP). Scanning electron microscopy and flow cytometry were used to quantify PMPs. TG was determined by use of a fluorimetric assay. It was found that CLP increased Rac1 activity in platelets, which was abolished by administration of the Rac1 inhibitor NSC23766. Sepsis-induced TG in vivo was reflected by reduced capacity of plasma from septic animals to generate thrombin ex vivo. Administration of NSC23766 increased peak and total TG in plasma from CLP mice indicating that Rac-1 regulates sepsis-induced formation of thrombin. The number of circulating PMPs was markedly elevated in animals with abdominal sepsis. Treatment with NSC23766 significantly decreased formation of PMPs in septic mice. Platelet activation in vitro caused release of numerous MPs. Notably, NSC23766 abolished PMP formation in activated platelets in vitro. These findings suggest that Rac-1 regulates PMP formation and TG in sepsis and that inhibition of Rac1 activity could be a useful target to inhibit dysfunctional coagulation in abdominal sepsis.
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| 25. |
- Wang, Yongzhi, et al.
(author)
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Sepsis-induced leukocyte adhesion in the pulmonary microvasculature in vivo is mediated by CD11a andCD11b.
- 2013
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In: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 702:1-3, s. 135-141
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Journal article (peer-reviewed)abstract
- Leukocyte accumulation is a rate-limiting step in inflammatory lung injury. The aim of this study was to define the role of CD11a/CD18 and CD11b/CD18 in sepsis-induced leukocyte rolling and adhesion in lung arterioles, capillaries and venules in male C57BL/6 mice using intravital fluorescence microscopy. Cecal ligation and puncture (CLP) markedly increased leukocyte rolling in arterioles and venules but not in capillaries in the lung. Immunoneutralization of CD11a, but not CD11b, decreased CLP-provoked leukocyte rolling in lung arterioles. Inhibition of CD11a or CD11b abolished CLP-induced arteriolar and venular leukocyte adhesion. Immunoneutralization of CD11a and CD11b reduced sepsis-induced leukocyte sequestration in pulmonary capillaries. Moreover, blocking CD11a or CD11b function improved microvascular blood flow in the lung of CLP animals. Considered together, our novel findings show that CD11a and CD11b mediate leukocyte adhesion in both arterioles and venules as well as trapping in capillaries in the lung. In addition, our data demonstrate that CD11a but not CD11b supports leukocyte rolling in pulmonary arterioles. Thus, these findings elucidate the molecular mechanisms behind leukocyte-endothelium interactions in the lung during systemic inflammation.
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| 26. |
- Wang, Yongzhi, et al.
(author)
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Thrombin generation in abdominal sepsis is Rho-kinase-dependent.
- 2015
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In: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 460:3, s. 691-696
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Journal article (peer-reviewed)abstract
- Sepsis causes severe derangements of the coagulation system. However, the signaling mechanisms regulating sepsis-induced thrombin generation remain elusive. Herein, we hypothesized that Rho-kinase might be an important regulator of thrombin generation in abdominal sepsis. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in C57Bl/6 mice. Thrombin generation, coagulation factors, lung histology and myeloperoxidase (MPO) activity were determined 6 h and 24 h after induction of CLP. Induction of CLP triggered a systemic inflammatory response characterized by neutrophil accumulation and tissue injury in the lung as well as thrombocytopenia and leukocytopenia. Administration of Y-27632, a Rho-kinase inhibitor, attenuated these markers of systemic inflammation in CLP animals. Moreover, peak thrombin formation was decreased by 77% and 81% in plasma from mice 6 h and 24 h after induction of CLP. Total thrombin generation was reduced by 64% and 67% 6 h and 24 h after CLP induction, respectively. Notably, administration of Y-27632 increased peak formation by 99% and total thrombin generation by 66% in plasma from septic animals. In addition, CLP markedly decreased plasma levels of prothrombin, factor V and factor X at 6 h and 24 h. Interestingly, Rho-kinase inhibition significantly enhanced levels of prothrombin, factor V and factor X in plasma from septic mice. In addition, inhibition of Rho-kinase decreased CLP-induced elevations of CXCL2 by 36%and interleukin-6 by 38%. These novel findings suggest that sepsis-induced thrombin generation is regulated by Rho-kinase. Moreover, inhibition of Rho-kinase reverses sepsis-evoked consumption of coagulation factors. Thus, our results show that targeting Rho-kinase signaling might protect against coagulation dysfunction in abdominal sepsis.
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| 27. |
- Xia, Junjie, et al.
(author)
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Suppressing memory T cell activation induces islet allograft tolerance in alloantigen-primed mice
- 2010
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In: Transplant International. - : Frontiers Media SA. - 1432-2277 .- 0934-0874. ; 23:11, s. 1154-1163
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Journal article (peer-reviewed)abstract
- P>Memory T cells are known to play a key role in prevention of allograft tolerance in alloantigen-primed mice. Here, we used an adoptively transferred memory T cell model and an alloantigen-primed model to evaluate the abilities of different combinations of monoclonal antibodies (mAb) to block key signaling pathways involved in activation of effector and memory T cells. In the adoptively transferred model, the use of anti-CD134L mAb effectively prevented activation of CD4+ memory T cells and significantly prolonged islet survival, similar to the action of anti-CD122 mAb to CD8+ memory T cells. In the alloantigen-primed model, use of anti-CD134L and anti-CD122 mAbs in addition to co-stimulatory blockade with anti-CD154 and anti-LFA-1 prolonged secondary allograft survival and significantly reduced the proportion of memory T cells; meanwhile, this combination therapy increased the proportion of regulatory T cells (Tregs) in the spleen, inhibited lymphocyte infiltration in the graft, and suppressed alloresponse of recipient splenic T cells. However, we also detected high levels of alloantibodies in the serum which caused high levels of damage to the allogeneic spleen cells. Our results suggest that combination of four mAbs can significantly suppress the function of memory T cells and prolong allograft survival in alloantigen primed animals.
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| 28. |
- Xie, Baiyi, et al.
(author)
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Combined Costimulation Blockade Inhibits Accelerated Rejection Mediated by Alloantigen-primed Memory T Cells in Mice
- 2009
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In: Immunological Investigations. - : Informa UK Limited. - 0882-0139 .- 1532-4311. ; 38:7, s. 639-651
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Journal article (peer-reviewed)abstract
- Donor-reactive memory T cells threaten the survival of transplanted organs via multiple pathways. This study was undertaken to induce tolerance of cardiac allografts in mice, in which alloreactive memory T cells were adoptively transferred, by combined costimulatory blockade of both effector and memory T cells. We found that the median survival time (MST) of the grafts was 5.17 days in the untreated group, 10.33 days in the CTLA4Ig- and antiCD40L- treated (2-combined) group, and more than 100 days in the CTLA4Ig-, anti-CD40L-, anti-LFA-1-, and anti-OX40L-treated (4-combined) group. Histological analysis revealed that the mean rejection level was Grade 4 in the untreated group, Grade 3 in the 2-combined treatment group, and Grade 0 in the 4-combined treatment group. CD44(high) T cells were detected only in the untreated group. The in vitro proliferation of lymphocytes of both untreated and 2-combined group was higher than that of the 4-combined treatment group (p < 0.01). Compared with the untreated group, the expression levels of IL-2, IFN-gamma, and Foxp3 were lower in the 2-combined treatment group; the expression levels of these genes were the lowest in the 4-combined treatment group. IL-10 expression was significantly higher in the 4-combined treatment group than in the other groups. These results demonstrate the inhibition efficacy of combined costimulation blockade in accelerated-rejection models and the possible mechanisms underlying the suppression of cellular immunity in mice receiving grafts as well as in inducing the activation of IL-10-producing Tr1 cells in grafts.
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| 29. |
- Ye, Yingying, et al.
(author)
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A critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic beta-cells
- 2022
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- Glucose-induced insulin secretion depends on beta-cell electrical activity. Inhibition of ATP-regulated potassium (K-ATP) channels is a key event in this process. However, K-ATP channel closure alone is not sufficient to induce beta-cell electrical activity; activation of a depolarizing membrane current is also required. Here we examine the role of the mechanosensor ion channel PIEZO1 in this process. Yoda1, a specific PIEZO1 agonist, activates a small membrane current and thereby triggers beta-cell electrical activity with resultant stimulation of Ca2+-influx and insulin secretion. Conversely, the PIEZO1 antagonist GsMTx4 reduces glucose-induced Ca2+-signaling, electrical activity and insulin secretion. Yet, PIEZO1 expression is elevated in islets from human donors with type-2 diabetes (T2D) and a rodent T2D model (db/db mouse), in which insulin secretion is reduced. This paradox is resolved by our finding that PIEZO1 translocates from the plasmalemma into the nucleus (where it cannot influence the membrane potential of the beta-cell) under experimental conditions emulating T2D (high glucose culture). beta-cell-specific Piezo1-knockout mice show impaired glucose tolerance in vivo and reduced glucose-induced insulin secretion, beta-cell electrical activity and Ca2+ elevation in vitro. These results implicate mechanotransduction and activation of PIEZO1, via intracellular accumulation of glucose metabolites, as an important physiological regulator of insulin secretion. Insulin secretion depends on action potential firing in pancreatic islet beta-cells, but the underlying mechanism is unclear. Here, the authors show that activation of the mechanosensor ion channel PIEZO1 plays a central role in beta-cell electrical activity and insulin release.
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| 30. |
- Zhang, Su, et al.
(author)
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NFAT regulates neutrophil recruitment, systemic inflammation and T-cell dysfunction in abdominal sepsis.
- 2014
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In: Infection and Immunity. - 1098-5522. ; 82:8, s. 3275-3288
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Journal article (peer-reviewed)abstract
- The signaling mechanisms regulating neutrophil recruitment, systemic inflammation and T-cell dysfunction in polymicrobial sepsis are not clear. This study explored the potential involvement of the calcium/calcineurin-dependent transcription factor, nuclear factor of activated T-cells (NFAT) in abdominal sepsis. Cecal ligation and puncture (CLP) triggered NFAT-dependent transcriptional activity in the lung, spleen, liver and aorta in NFAT-luciferase reporter mice. Treatment with the NFAT inhibitor A-285222 prior to CLP completely prevented sepsis-induced NFAT activation in all these organs. Inhibition of NFAT activity reduced sepsis-induced formation of CXCL1, CXCL2 and CXCL5 chemokines and edema as well as neutrophil infiltration in the lung. Notably, NFAT inhibition efficiently reduced the CLP-evoked increases in HMBG1, IL-6 and CXCL5 levels in plasma. Moreover, administration of A-285222 restored sepsis-induced T-cell dysfunction, as evidenced by markedly decreased apoptosis and restored proliferative capacity of CD4 T-cells. Along these lines, treatment with A-285222 restored IFN-γ and IL-4 levels in the spleen, which were markedly reduced in septic mice. CLP-induced formation of regulatory T-cells (CD4(+)CD25(+)Foxp3(+)) in the spleen was also abolished in A-285222-treated animals. Altogether, these novel findings suggest that NFAT is a powerful regulator of pathological inflammation and T-cell immune dysfunction in abdominal sepsis. Thus, our data suggest that NFAT signaling might be a useful target to protect against respiratory failure and immunosuppression in patients with sepsis.
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| 31. |
- Zhang, Songen, et al.
(author)
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p38 Mitogen-activated protein kinase signaling regulates streptococcal M1 protein-induced neutrophil activation and lung injury.
- 2012
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In: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 91, s. 137-145
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Journal article (peer-reviewed)abstract
- M1 serotype of Streptococcus pyogenes can cause STSS and acute lung damage. Herein, the purpose was to define the role of p38 MAPK signaling in M1 protein-induced pulmonary injury. Male C57BL/6 mice were treated with specific p38 MAPK inhibitors (SB 239063 and SKF 86002) prior to M1 protein challenge. Edema, neutrophil infiltration, and CXC chemokines were determined in the lung, 4 h after M1 protein administration. Flow cytometry was used to determine Mac-1 expression. Phosphorylation and activity of p38 MAPK were determined by immunoprecipitation and Western blot. IVM was used to analyze leukocyte-endothelium interactions in the pulmonary microcirculation. M1 protein challenge increased phosphorylation and activity of p38 MAPK in the lung, which was inhibited by SB 239063 and SKF 86002. Inhibition of p38 MAPK activity decreased M1 protein-induced infiltration of neutrophils, edema, and CXC chemokine formation in the lung, as well as Mac-1 up-regulation on neutrophils. IVM showed that p38 MAPK inhibition reduced leukocyte rolling and adhesion in the pulmonary microvasculature of M1 protein-treated mice. Our results indicate that p38 MAPK signaling regulates neutrophil infiltration in acute lung injury induced by streptococcal M1 protein. Moreover, p38 MAPK activity controls CXC chemokine formation in the lung, as well as neutrophil expression of Mac-1 and recruitment in the pulmonary microvasculature. In conclusion, these findings suggest that targeting the p38 MAPK signaling pathway may open new opportunities to protect against lung injury in streptococcal infections.
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| 32. |
- Zhang, Su, et al.
(author)
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Simvastatin protects against T cell immune dysfunction in abdominal sepsis.
- 2012
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In: Shock. - 1540-0514. ; 38:5, s. 524-531
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Journal article (peer-reviewed)abstract
- ABSTRACT: Sepsis-triggered immune paralysis including T-cell dysfunction increases susceptibility to infections. Statins exert beneficial effects in patients with sepsis, although the mechanisms remain elusive. Herein, we hypothesized that simvastatin may attenuate T-cell dysfunction in abdominal sepsis. Male C57BL/6 mice were pretreated with simvastatin (10 mg/kg) before cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation, and regulatory T cells (CD4CD25Foxp3) were quantified by use of flow cytometry. Formation of interferon γ (IFN-γ) and interleukin 4 (IL-4) in the spleen and plasma levels of high-mobility box group 1 (HMBG1) and IL-6 were determined using enzyme-linked immunosorbent assay. Cecal ligation and puncture caused a clear-cut increase in apoptosis and decrease in proliferation in splenic CD4 T cells. It was found that simvastatin markedly reduced apoptosis and improved proliferation in CD4 T cells in septic mice. Moreover, CLP-induced formation of regulatory T cells in the spleen was abolished in simvastatin-treated animals. Cecal ligation and puncture greatly decreased the levels of IFN-γ and IL-4 in the spleen. Simvastatin completely reversed this sepsis-mediated inhibition of IFN-γ and IL-4 formation in the spleen. We observed that CLP increased plasma levels of HMBG1 by 25-fold and IL-6 by 99,595-fold. Notably, treatment with simvastatin abolished this CLP-evoked increase in HMBG1 and IL-6 levels in the plasma, suggesting that simvastatin is a potent inhibitor of systemic inflammation in sepsis. Lastly, it was found that simvastatin reduced CLP-induced bacteremia. In conclusion, these novel findings suggest that simvastatin is a powerful regulator of T-cell immune dysfunction in abdominal sepsis. Thus, these protective effects of simvastatin on T-cell functions help to explain the protective effect of statins in patients with sepsis.
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| 33. |
- Zhang, Songen, et al.
(author)
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Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury
- 2013
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In: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 305:10, s. 756-763
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Journal article (peer-reviewed)abstract
- Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome and acute lung damage. CD162 is an adhesion molecule that has been reported to mediate neutrophil recruitment in acute inflammatory reactions. In this study, the purpose was to investigate the role of CD162 in M1 protein-provoked lung injury. Male C57BL/6 mice were treated with monoclonal antibody directed against CD162 or a control antibody before M1 protein challenge. Edema, neutrophil infiltration, and CXC chemokines were determined in the lung, 4 h after M1 protein administration. Fluorescence intravital microscopy was used to analyze leukocyte-endothelium interactions in the pulmonary microcirculation. Inhibition of CD162 reduced M1 protein-provoked accumulation of neutrophils, edema, and CXC chemokine formation in the lung by >54%. Moreover, immunoneutralization of CD162 abolished leukocyte rolling and firm adhesion in pulmonary venules of M1 protein-treated animals. In addition, inhibition of CD162 decreased M1 protein-induced capillary trapping of leukocytes in the lung microvasculature and improved microvascular perfusion in the lungs of M1 protein-treated animals. Our findings suggest that CD162 plays an important role in M1 protein-induced lung damage by regulating leukocyte rolling in pulmonary venules. Consequently, inhibition of CD162 attenuates M1 protein-evoked leukocyte adhesion and extravasation in the lung. Thus, our results suggest that targeting the CD162 might pave the way for novel opportunities to protect against pulmonary damage in streptococcal infections.
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