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AKHUND, ISRAR AHMED, IRSHAD ALI ALVI, GHULAM RASOOL BHURGRI, Muhammad Ali Qureshi y Haji Khan Khoharo. "CIRCULATING LEUKOCYTES". Professional Medical Journal 17, n.º 03 (10 de septiembre de 2010): 455–58. http://dx.doi.org/10.29309/tpmj/2010.17.03.2804.
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Objective: Evaluating circulating leukocytes in acute mental stress & relation with coronary artery disease. Design: Descriptive study Setting: Muhammad Medical College Mirpurkhas, Duration: from March 2007 to August 2007. Methods: Two hundred young healthy adults were studied for stress experiment. Venous blood samples were drawn before and after stress for estimation of leukocyte counts. Values were presented as mean ±standard error of mean (SEM). Results: The difference in Pre and during stress results of variables were TLC = - 4630.85 ± 140.65, N % = -11.8 ± 0.36, L% = 4.03 ± 0.14, M %= 5.48 ± 0.37, E % = 1.18 ± 0.07, B % = 1.11 ± 0.022. Highly significant p-values (≤ 0.001) were found among various parameters, in both groups of subjects. Conclusion: An increase in the number of circulating leukocytes was an important unexpected observation that was noted. We suggest that the real life stress induced leukocytes changes may warrant further investigation about its relation with the coronary artery disease (CAD).
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Kirchhofer, Daniel, Markus A. Riederer y Hans R. Baumgartner. "Specific Accumulation of Circulating Monocytes and Polymorphonuclear Leukocytes on Platelet Thrombi in a Vascular Injury Model". Blood 89, n.º 4 (15 de febrero de 1997): 1270–78. http://dx.doi.org/10.1182/blood.v89.4.1270.
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AbstractThe adhesion of leukocytes to platelets deposited at the site of vascular injury may represent an important mechanism by which leukocytes contribute to hemostasis and thrombosis. In this study, we examined whether, in comparison with their distribution in circulating blood, certain leukocyte types are enriched at sites of platelet deposition. We used an experimental vascular injury model, in which human fibrillar collagen was exposed to anticoagulated human whole blood flowing through parallel-plate chambers (venous shear rate, 65/s). The platelet-adherent leukocytes were detached by EDTA treatment and analyzed by flow cytometry using cell-type–specific antibodies. The predominant leukocytes found in platelet thrombi were polymorphonuclear leukocytes, accounting for 76% of bound leukocytes (62% in circulating blood), whereas T and B lymphocytes did not significantly accumulate on thrombi, comprising a fraction of less than 5% (32% in circulating blood). Monocytes constituted 16% of platelet thrombus-bound leukocytes, which represents an almost fourfold enrichment as compared with their proportion in circulating blood. Almost identical results were obtained when we analyzed leukocytes adhering to platelet monolayers, which were formed by blocking glycoprotein IIb-IIIa, thus preventing platelet aggregation on top of the collagen-adherent platelets. Furthermore, leukocyte adhesion to platelet monolayers was completely inhibited by an anti-P-selectin antibody (50% inhibitory concentration, 0.3 μg/mL), whereas it reached a plateau at about 70% inhibition on platelet thrombi. This difference could be explained by a possible function of glycoprotein IIb-IIIa in leukocyte immobilization to thrombi or by the high local concentration of P-selectin in the growing thrombi. The results suggest that, because of their known abilities to promote coagulation and thrombolysis, the monocytes and polymorphonuclear leukocytes accumulating on forming platelet thrombi could play an important role in modulating thrombotic and hemostatic processes.
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Donahue, Robert E., Laura Tuschong, Thomas R. Bauer, Yu Ying Yau, Susan F. Leitman y Dennis D. Hickstein. "Leukocyte integrin activation mediates transient neutropenia after G-CSF administration". Blood 118, n.º 15 (13 de octubre de 2011): 4209–14. http://dx.doi.org/10.1182/blood-2011-06-360461.
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Abstract After administration of granulocyte colony-stimulating factor (G-CSF), there is a marked, albeit transient, drop in circulating neutrophils. To determine the role of leukocyte integrins in this disappearance, a dog having canine leukocyte adhesion deficiency (CLAD) or CLAD dogs who had undergone gene correction either by matched littermate allogeneic transplant or autologous gene therapy were evaluated. Shortly after G-CSF administration, a dramatic, yet transient, neutropenia was observed in the control littermates. This neutropenia was not as marked in the CLAD dogs. In all instances, it was CD18+ neutrophils that preferentially egressed from the circulation. The association of CD18 with this rapid loss suggested leukocyte integrin activation after G-CSF administration. To determine the activation status of the integrin, a monoclonal antibody recognizing the activated α-subunit cation binding domain (mAb24) was used to evaluate human leukocytes after G-CSF administration. Mirroring the dramatic decrease in circulating neutrophil numbers, there was a dramatic and specific increase in the activation of the α-subunit after G-CSF expression on polymorphonuclear leukocytes. This activation, like the drop in neutrophil count, was transient. These results demonstrate that the leukocyte integrin on circulating neutrophils is transiently activated after G-CSF administration and mediates the transient neutropenia observed after G-CSF administration.
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Wang, Yongzhi, Jonas Roller, Jan E. Slotta, Su Zhang, Lingtao Luo, Milladur Rahman, Ingvar Syk, Michael D. Menger y Henrik Thorlacius. "Distinct patterns of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation". American Journal of Physiology-Lung Cellular and Molecular Physiology 304, n.º 4 (15 de febrero de 2013): L298—L305. http://dx.doi.org/10.1152/ajplung.00246.2012.
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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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Tjwa, Marc, Lola Bellido-Martin, Yuan Lin, Esther Lutgens, Stéphane Plaisance, Françoise Bono, Nathalie Delesque-Touchard et al. "Gas6 promotes inflammation by enhancing interactions between endothelial cells, platelets, and leukocytes". Blood 111, n.º 8 (15 de abril de 2008): 4096–105. http://dx.doi.org/10.1182/blood-2007-05-089565.
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AbstractThe role of Gas6 in endothelial cell (EC) function remains incompletely characterized. Here we report that Gas6 amplifies EC activation in response to inflammatory stimuli in vitro. In vivo, Gas6 promotes and accelerates the sequestration of circulating platelets and leukocytes on activated endothelium as well as the formation and endothelial sequestration of circulating platelet-leukocyte conjugates. In addition, Gas6 promotes leukocyte extravasation, inflammation, and thrombosis in mouse models of inflammation (endotoxinemia, vasculitis, heart transplantation). Thus, Gas6 amplifies EC activation, thereby playing a key role in enhancing the interactions between ECs, platelets, and leukocytes during inflammation.
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Teraoka, S., M. Sugawara, Y. Kitano, T. Hoshino, M. Takahashi, Y. Minagawa, S. Naganuma et al. "Microscopic Observation of Leukocyte Kinesis in the Vascular Bed during Hemodialysis Using the Rabbit Ear Chamber Technique". International Journal of Artificial Organs 12, n.º 4 (abril de 1989): 229–33. http://dx.doi.org/10.1177/039139888901200405.
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Leukocyte kinesis in the capillary vascular bed during hemodialysis (HD) was investigated to elucidate the mechanism of transient leukopenia. Leukocyte movement was observed microscopically during HD using the rabbit ear chamber (REC) technique, which permits visualization of the movement of blood corpuscles in capillaries. Blood was drawn from the femoral artery and returned into the auricular and/or carotid artery so that the blood passing through the hollow fiber artificial kidney (HFAK) flowed into capillaries in the REC. Leukocyte counts of blood samples taken from the afferent and efferent limbs of the HD circuit, the right jugular vein and the right atrium were determined consecutively during HD. The difference in the leukocyte count was observed between the afferent and efferent limbs for the first 15 minutes and thereafter between the efferent limb and the jugular vein. The “transpulmonary” difference in the leukocyte count was not noticed throughout HD. Between 15 and 90 minutes after the start of HD, scarcely any circulating leukocytes were found in capillaries in the REC and some leukocytes were attached to the endothelial surface. Thereafter circulating leukocytes were seen again and detachment of leukocytes from the endothelial surface was observed. No leukocyte aggregation or embolization of aggregating leukocytes was noticed. This evidence suggests that leukopenia may be attributed to the transient shift of leukocytes to the marginal pool of the vessel lumen and this process may not be specific for the pulmonary vasculature, but may occur in the first capillary bed into which the blood passing through the HFAK flows. The attachment of leukocytes to the surface membrane of the HFAK may contribute to the transient leukopenia especially during the initial period of the HD.
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Pistiki, Aikaterini, Anuradha Ramoji, Oleg Ryabchykov, Daniel Thomas-Rüddel, Adrian T. Press, Oliwia Makarewicz, Evangelos J. Giamarellos-Bourboulis et al. "Biochemical Analysis of Leukocytes after In Vitro and In Vivo Activation with Bacterial and Fungal Pathogens Using Raman Spectroscopy". International Journal of Molecular Sciences 22, n.º 19 (28 de septiembre de 2021): 10481. http://dx.doi.org/10.3390/ijms221910481.
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Biochemical information from activated leukocytes provide valuable diagnostic information. In this study, Raman spectroscopy was applied as a label-free analytical technique to characterize the activation pattern of leukocyte subpopulations in an in vitro infection model. Neutrophils, monocytes, and lymphocytes were isolated from healthy volunteers and stimulated with heat-inactivated clinical isolates of Candida albicans, Staphylococcus aureus, and Klebsiella pneumoniae. Binary classification models could identify the presence of infection for monocytes and lymphocytes, classify the type of infection as bacterial or fungal for neutrophils, monocytes, and lymphocytes and distinguish the cause of infection as Gram-negative or Gram-positive bacteria in the monocyte subpopulation. Changes in single-cell Raman spectra, upon leukocyte stimulation, can be explained with biochemical changes due to the leukocyte’s specific reaction to each type of pathogen. Raman spectra of leukocytes from the in vitro infection model were compared with spectra from leukocytes of patients with infection (DRKS-ID: DRKS00006265) with the same pathogen groups, and a good agreement was revealed. Our study elucidates the potential of Raman spectroscopy-based single-cell analysis for the differentiation of circulating leukocyte subtypes and identification of the infection by probing the molecular phenotype of those cells.
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Li, Nailin, Anne Soop, Alf Sollevi y Paul Hjemdahl. "Multi-Cellular Activation In Vivo by Endotoxin in Humans – Limited Protection by Adenosine Infusion". Thrombosis and Haemostasis 84, n.º 09 (2000): 381–87. http://dx.doi.org/10.1055/s-0037-1614032.
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SummaryThe influence of adenosine infusion (40 µg/kg/min for 4 h) on inflammatory and hemostatic parameters was investigated in healthy males without (n = 10) or with (n = 11) intravenous endotoxin injection (4 ng/kg). Without endotoxin, adenosine elevated circulating leukocytes and circulating platelet-leukocyte aggregates. Endotoxin activated platelets and leukocytes in vivo. Platelet activation was seen as slightly increased platelet P-selectin expression, decreased platelet counts, and elevated plasma soluble P-selectin (from 39.6 ± 3.4 to 68.9 ± 6.6 ng/ml; P <0.01). Leukocyte activation was evidenced by increased CD11b expression (from MFI of 0.54 ± 0.02 to 2.21 ± 0.17; P <0.01) and plasma elastase levels (from 25.3 ± 2.5 to 169.3 ± 22.5 ng/ml; P <0.01). Endotoxin also enhanced platelet and leukocyte responsiveness to in vitro stimulation. Endotoxin induced von Willebrand factor secretion (from 92 ± 8 units to 265 ± 19 units at 4 h; P <0.001) and enhanced thrombin generation in vivo. Endotoxin induced leukocytosis and thus increased circulating platelet-leukocyte, mainly platelet-neutrophil, aggregates. Adenosine caused slight attenuation of platelet reactivity to agonist stimulation, enhanced the endotoxin-induced leukocytosis, and detained more platelet-leukocyte aggregates in circulation, but did not attenuate endotoxin-induced neutrophil elastase secretion, von Willebrand factor secretion, or thrombin generation. Thus, endotoxemia induces multi-cellular activation in vivo. Adenosine inhibits leukocyte adhesion and extravasation, and mildly attenuates platelet responsiveness and soluble P-selectin release. Adenosine has the potential of becoming a therapeutic antiinflammatory drug, but an optimal treatment strategy needs to be developed.
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Almeida, Camila Bononi, Maria Emilia Favero, Fernanda Gonçalves Pereira-Cunha, Irene Lorand-Metze, Sara T. Olalla Saad, Fernando Ferreira Costa y Nicola Conran. "Alterations in cell maturity and serum survival factors may modulate neutrophil numbers in sickle cell disease". Experimental Biology and Medicine 236, n.º 11 (noviembre de 2011): 1239–46. http://dx.doi.org/10.1258/ebm.2011.011130.
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Leukocytes are known to exacerbate inflammatory and vaso-occlusive processes in sickle cell disease (SCD). The aim of this study was to determine whether alterations in neutrophil maturity and/or cell-death modulating factors in the circulation contribute to the increased leukocyte counts and leukocyte survival observed in SCD. The maturity of circulating neutrophils from healthy control individuals (CON), SCD and SCD patients on hydroxyurea therapy (SCDHU) was determined immunophenotypically. Serum factors affecting neutrophil apoptosis (determined by annexin V-binding) were analyzed by culturing control neutrophils (CON neutrophils) with pooled serum from CON, SCD and SCDHU individuals. Immunophenotypic characterization of neutrophils suggested a slight, but significant, increase in the circulation of immature neutrophils in SCD. While SCD neutrophils cultured in the presence of CON serum presented delayed apoptosis, unexpectedly, the culture of CON neutrophils with SCD serum significantly augmented apoptosis and caspase-9 activity. Inhibition of the activity of serum interleukin-8, a neutrophil-apoptosis-inhibiting cytokine, significantly increased SCD serum-induced CON neutrophil apoptosis, indicating that SCD serum may have both apoptotic and antiapoptotic properties. The decreased maturity of SCD neutrophils observed is suggestive of an accelerated immigration of leukocytes from the bone marrow to the circulating pool that may contribute to an increase in cell survival, subject to modulation by a complex balance of both anti- and proapoptotic factors contained in the circulation of SCD individuals.
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Gào, Xīn, Yan Zhang, Xiangwei Li, Lina Jansen, Elizabeth Alwers, Melanie Bewerunge-Hudler, Matthias Schick, Jenny Chang-Claude, Michael Hoffmeister y Hermann Brenner. "DNA Methylation-Based Estimates of Circulating Leukocyte Composition for Predicting Colorectal Cancer Survival: A Prospective Cohort Study". Cancers 13, n.º 12 (12 de junio de 2021): 2948. http://dx.doi.org/10.3390/cancers13122948.
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Leukocytes are involved in the progression of colorectal cancer (CRC). The proportion of six major leukocyte subtypes can be estimated using epigenome-wide DNA methylation (DNAm) data from stored blood samples. Whether the composition of circulating leukocytes can be used as a prognostic factor is unclear. DNAm-based leukocyte proportions were obtained from a prospective cohort of 2206 CRC patients. Multivariate Cox regression models and survival curves were applied to assess associations between leukocyte composition and survival outcomes. A higher proportion of lymphocytes, including CD4+ T cells, CD8+ T cells, B cells, and NK cells, was associated with better survival, while a higher proportion of neutrophils was associated with poorer survival. CD4+ T cells outperformed other leukocytes in estimating the patients’ prognosis. Comparing the highest quantile to the lowest quantile of CD4+ T cells, hazard ratios (95% confidence intervals) of all-cause and CRC-specific mortality were 0.59 (0.48, 0.72) and 0.59 (0.45, 0.77), respectively. Furthermore, the association of CD4+ T cells and prognosis was stronger among patients with early or intermediate CRC or patients with colon cancer. In conclusion, the composition of circulating leukocytes estimated from DNAm, particularly the proportions of CD4+ T cells, could be used as promising independent predictors of CRC survival.
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Stenmark, Kurt R., Neil J. Davie, John T. Reeves y Maria G. Frid. "Hypoxia, leukocytes, and the pulmonary circulation". Journal of Applied Physiology 98, n.º 2 (febrero de 2005): 715–21. http://dx.doi.org/10.1152/japplphysiol.00840.2004.
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Data are rapidly accumulating in support of the idea that circulating monocytes and/or mononuclear fibrocytes are recruited to the pulmonary circulation of chronically hypoxic animals and that these cells play an important role in the pulmonary hypertensive process. Hypoxic induction of monocyte chemoattractant protein-1, stromal cell-derived factor-1, vascular endothelial growth factor-A, endothelin-1, and tumor growth factor-β1in pulmonary vessel wall cells, either directly or indirectly via signals from hypoxic lung epithelial cells, may be a critical first step in the recruitment of circulating leukocytes to the pulmonary circulation. In addition, hypoxic stress appears to induce release of increased numbers of monocytic progenitor cells from the bone marrow, and these cells may have upregulated expression of receptors for the chemokines produced by the lung circulation, which thus facilitates their specific recruitment to the pulmonary site. Once present, macrophages/fibrocytes may exert paracrine effects on resident pulmonary vessel wall cells stimulating proliferation, phenotypic modulation, and migration of resident fibroblasts and smooth muscle cells. They may also contribute directly to the remodeling process through increased production of collagen and/or differentiation into myofibroblasts. In addition, they could play a critical role in initiating and/or supporting neovascularization of the pulmonary artery vasa vasorum. The expanded vasa network may then act as a conduit for further delivery of circulating mononuclear cells to the pulmonary arterial wall, creating a feedforward loop of pathological remodeling. Future studies will need to determine the mechanisms that selectively induce leukocyte/fibrocyte recruitment to the lung circulation under hypoxic conditions, their direct role in the remodeling process via production of extracellular matrix and/or differentiation into myofibroblasts, their impact on the phenotype of resident smooth muscle cells and adventitial fibroblasts, and their role in the neovascularization observed in hypoxic pulmonary hypertension.
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Lee, TH, E. Donegan, S. Slichter y MP Busch. "Transient increase in circulating donor leukocytes after allogeneic transfusions in immunocompetent recipients compatible with donor cell proliferation". Blood 85, n.º 5 (1 de marzo de 1995): 1207–14. http://dx.doi.org/10.1182/blood.v85.5.1207.bloodjournal8551207.
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Donor leukocytes in therapeutic blood components are implicated in transfusion-related complications ranging from alloimmunization to graft-versus-host disease (GVHD) to viral transmission and reactivation. To further characterize the kinetics of donor leukocyte clearance after allogeneic transfusion, we developed allele-specific polymerase chain reaction (PCR) assays directed at a single-copy Y chromosome gene and HLA class II alleles. These assays enable sensitive detection and quantitation of donor leukocytes at concentrations ranging from one cell to greater than 1,000 cells per 125 microL of recipient blood. When applied to serial samples from five consecutive orthopedic surgery patients who met study criteria, we observed 99.9% clearance of donor leukocytes over the initial 2 days posttransfusion, followed by a transient, 1-log increase in circulating donor leukocytes on days 3 to 5. This phenomenon was reproduced in a canine transfusion model, where the transient donor leukocyte expansion phase was prevented by gamma irradiation of donor blood, and was not observed after transfusions into alloimmunized dogs. We hypothesize that this transient increase in circulating allogeneic donor cells represents one arm of an in vivo mixed lymphocyte reaction, with activated donor T lymphocytes proliferating in an abortive GVHD reaction to HLA- incompatible recipient cells. Further investigation of this phenomenon should provide insight into the mechanisms involved in donor-recipient leukocyte interactions posttransfusion and the relationship of these interactions to leukocyte-induced complications.
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R.Vandendries, Erik, Barbara Furie y Bruce Furie. "Role of P-selectin and PSGL-1 in coagulation and thrombosis". Thrombosis and Haemostasis 92, n.º 09 (2004): 459–66. http://dx.doi.org/10.1160/th04-05-0306.
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SummaryP-selectin and PSGL-1 are cell adhesion molecules, regulating the initial interactions between leukocytes and the blood vessel wall as well as between activated platelets and leukocytes. P-selectin is expressed on activated endothelial cells and platelets, while its major ligand PSGL-1 is expressed on leukocytes. Multiple studies have shown that these adhesion molecules are required for the normal recruitment of leukocytes during an inflammatory reaction. More recently, these adhesion molecules have been implicated in recruitment of leukocytes and leukocyte microparticles to thrombi. The P-selectinand PSGL-1-dependent delivery of circulating microparticles to thrombi appears to be important for normal tissue factor accumulation and fibrin generation in thrombi.
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Pitchford, Simon C., Stefania Momi, Silvia Giannini, Lucio Casali, Domenico Spina, Clive P. Page y Paolo Gresele. "Platelet P-selectin is required for pulmonary eosinophil and lymphocyte recruitment in a murine model of allergic inflammation". Blood 105, n.º 5 (1 de marzo de 2005): 2074–81. http://dx.doi.org/10.1182/blood-2004-06-2282.
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AbstractPlatelets are necessary for lung leukocyte recruitment in a murine model of allergic inflammation, and platelet–leukocyte aggregates are formed in circulating blood of patients with asthma after allergen exposure. However, it is unknown how platelets induce pulmonary leukocyte recruitment in asthma. Here, we have investigated the importance of platelet adhesion molecule expression on pulmonary eosinophil and lymphocyte recruitment and on leukocyte CD11b and very late antigen (VLA)–4 expression in mice. Pulmonary leukocyte recruitment in platelet-depleted mice (sensitized and exposed to ovalbumin) transfused with fixed, unstimulated platelets (FUSPs) was abolished, whereas transfusion with platelets stimulated and fixed (FSPs), expressing P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1), restored eosinophil and lymphocyte recruitment. Transfusion with platelets from P-selectin–deficient mice, or with FSPs stimulated in the presence of a blocking anti–P-selectin antibody, were unable to restore pulmonary leukocyte recruitment. Flow cytometric analysis revealed increased expression of CD11b and VLA-4 on leukocytes attached to platelets after allergen exposure, and CD11b expression on leukocytes was suppressed in thrombocytopenic mice but was restored with the transfusion of FSPs, but not FUSPs, a phenomenon concurrent with the formation of platelet–leukocyte complexes. P-selectin expression on the surfaces of platelets is a major requirement for pulmonary eosinophil and lymphocyte recruitment, allowing circulating platelets to bind to and stimulate leukocytes for endothelial attachment.
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Cheng, Chao, Xiao-Bo Liu, Dong-Ling Xu y Juan Zhang. "Increased ROCK1 not ROCK2 in circulating leukocytes in rats with myocardial ischemia/reperfusion". Perfusion 35, n.º 8 (20 de abril de 2020): 819–25. http://dx.doi.org/10.1177/0267659120915140.
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Background: Rho-associated protein kinase (ROCK) plays a vital role in the pathogenesis of many cardiovascular diseases. Previous studies have demonstrated that ROCK is overactivated and involved in myocardial ischemia/reperfusion in vivo. But the role of ROCK in circulating leukocytes during myocardial ischemia/reperfusion is not well studied. Material and methods: This study was performed to evaluate ROCK activity in circulating leukocytes in rats with myocardial ischemia/reperfusion injury. Myocardial ischemia/reperfusion Wistar rats were subjected to 30-min ischemia followed by 180-min reperfusion. ROCK activity in circulating leukocytes was examined by the phosphorylation state of myosin phosphatase targeting subunit 1, a substrate of ROCK. Results: ROCK activity significantly increased in leukocytes in rat ischemia/reperfusion models compared to the sham group. ROCK1 not ROCK2 level in circulating leukocytes was significantly elevated in ischemia/reperfusion. Administration of the selective inhibitor of ROCK, fasudil, significantly reduced myocardial infarct size, myocyte apoptosis, and inflammatory cytokine, including interleukin 6 and tumor necrosis factor α. Furthermore, fasudil upregulated ischemia/reperfusion-induced reduction of nitric oxide production. Conclusion: Increased ROCK1 not ROCK2 in circulating leukocytes plays a role in the pathogenesis of myocardial ischemia/reperfusion injury. Inhibition of ROCK1 in circulating leukocytes has an important role in fasudil-induced cardioprotective effects. ROCK1 in circulating leukocytes might be a new biomarker in myocardial ischemia/reperfusion injury.
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Zhao, Yue, Min Liu, Xue Ying Chan, Sue Yee Tan, Sharrada Subramaniam, Yong Fan, Eva Loh, Kenneth Tou En Chang, Thiam Chye Tan y Qingfeng Chen. "Uncovering the mystery of opposite circadian rhythms between mouse and human leukocytes in humanized mice". Blood 130, n.º 18 (2 de noviembre de 2017): 1995–2005. http://dx.doi.org/10.1182/blood-2017-04-778779.
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Key Points Human circulating leukocytes in humanized mice reproduce similar circadian oscillations as seen in humans. A novel molecular clock network exhibiting opposite effects on regulating human and mouse leukocyte circadian rhythm is discovered.
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Davis, Andrew K. y John C. Maerz. "Effects of Exogenous Corticosterone on Circulating Leukocytes of a Salamander (Ambystoma talpoideum) with Unusually Abundant Eosinophils". International Journal of Zoology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/735937.
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When animals become stressed, their levels of glucocorticoid hormones increase, causing white blood cells to move from tissues to circulation or vice versa. The primary alteration is an increase in the abundance of circulating neutrophils and a decrease in lymphocytes in circulation. A lesser-known effect is a decrease in the number of circulating eosinophils. Salamanders in the genusAmbystomahave unusually high numbers of circulating eosinophils, and as such, any effect of stress hormones on circulating leukocytes (especially eosinophils) of these species should be especially pronounced. We conducted an experiment to determine the effect of corticosterone administration on leukocyte counts (from blood smears) ofA. talpoideumsalamanders. Salamanders were captured and sampled as reference animals(n=11), given a sham injection(n=8), or injected with 0.1cc of a 100 μg/mL corticosterone solution(n=28). After 24 hours, relative neutrophil counts were higher and relative lymphocyte counts lower, in the corticosterone group than the sham and control groups. Absolute counts showed that this effect was driven by a reduction in lymphocytes, since neutrophil counts were statistically similar across treatments. Importantly, relative and absolute numbers of eosinophils decreased in the sham and corticosterone groups, confirming the sensitivity of this cell to stress in amphibians.
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Mancuso, F., R. J. Flower y M. Perretti. "Leukocyte transmigration, but not rolling or adhesion, is selectively inhibited by dexamethasone in the hamster post-capillary venule. Involvement of endogenous lipocortin 1." Journal of Immunology 155, n.º 1 (1 de julio de 1995): 377–86. http://dx.doi.org/10.4049/jimmunol.155.1.377.
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Abstract This study investigates the effect of dexamethasone on leukocyte extravasation in the post-capillary venules of the hamster cheek pouch, using an intravital microscopy technique, and seeks to clarify the potential involvement of the steroid-inducible protein lipocortin 1. Topical application of FMLP (10 nmol), or substance P (10 nmol), to the superfused cheek pouch induced at the level of the post-capillary venules the three characteristic phenomena of leukocyte rolling, adhesion, and transmigration. Pretreatment of hamsters with an anti-inflammatory dose of dexamethasone (1 mg/kg) increased lipocortin 1 levels in circulating leukocytes as assessed by flow cytometry, but did not modify either leukocyte rolling or the number of adherent cells; however approximately 65% of the adherent leukocytes subsequently detached and returned to the blood stream, whereas those that entered into the diapedesis process exhibited a long latency (approximately three- to fourfold longer than in control animals) before transmigration. In hamsters passively immunized with a polyclonal anti-lipocortin 1 serum, leukocyte diapedesis started at similar times in both control and dexamethasone-treated animals, whereas a significant prolongation was observed in those animals treated with a non-immune sheep serum. These observations indicate that 1) lipocortin 1 is elevated in circulating leukocytes following dexamethasone treatment; 2) the step of leukocyte extravasation affected by dexamethasone in the actual transmigration process, and 3) this specific effect upon leukocyte diapedesis is mediated by endogenous lipocortin 1.
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Scotland, Ramona S., Melanie J. Stables, Shimona Madalli, Peter Watson y Derek W. Gilroy. "Sex differences in resident immune cell phenotype underlie more efficient acute inflammatory responses in female mice". Blood 118, n.º 22 (24 de noviembre de 2011): 5918–27. http://dx.doi.org/10.1182/blood-2011-03-340281.
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Abstract Females are protected against mortality arising from severe sepsis; however, the precise mechanisms that confer this survival advantage in females over males are unclear. Resident leukocytes in resting tissues have a significant influence on circulating cytokine levels and recruitment of blood leukocytes during acute inflammatory responses. Whether the phenotype of resident leukocytes is distinct in females is unknown. In the present study, we show that the numbers of leukocytes occupying the naive peritoneal and pleural cavities is higher in female than in male mice and rats, comprising more T and B lymphocytes and macrophages. The altered immune cell composition of the female peritoneum is controlled by elevated tissue chemokine expression. Female resident macrophages also exhibit greater TLR expression and enhanced phagocytosis and NADPH oxidase–mediated bacterial killing. However, macrophage-derived cytokine production is diminished by proportionally more resident immunomodulatory CD4+ T lymphocytes. Ovarian hormones regulate macrophage phenotype, function, and numbers, but have no significant impact on T-lymphocyte populations in females. We have identified a fundamental sex difference in phenotype of resident leukocytes. We propose that the distinct resident leukocyte population in females allows aggressive recognition and elimination of diverse infectious stimuli without recruitment of circulating neutrophils or excessive cytokine production.
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Shibamiya, Aya, Noriyuki Tabuchi, Jihwa Chung, Makoto Sunamori y Takatoshi Koyama. "Formation of tissue factor-bearing leukocytes during and after cardiopulmonary bypass". Thrombosis and Haemostasis 92, n.º 07 (2004): 124–31. http://dx.doi.org/10.1160/th03-12-0787.
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SummaryDuring cardiopulmonary bypass (CPB), the extrinsic coagulation system initiated by tissue factor (TF) is a major procoagulant stimulus. TF is present in surgical wounds and could be expressed on activated monocytes. However, recent studies have suggested that collagen stimulation rapidly induces TF by leukocyte-platelet complex formation. Therefore, the appearance of TF-bearing leukocytes and their effect on promoting coagulation were investigated in 5 patients undergoing coronary bypass surgery. Neutrophils and monocytes positive for CD41a and TF increased abruptly in circulating blood during CPB. Their increase was most prominent in blood pooled in the pericardial cavity. Monocytes, but not neutrophils positive for TF showed a second peak one day after operation, which accords with the increase in TF mRNA levels in leukocytes. Similarly, an increase in leukocytes positive for TF accords with the activated factor X generation assay using isolated leukocytes, and with an increase in thrombin-antithrombin complex in circulating blood. The second increase in TF-positive monocytes seems to be responsible for these coagulation parameters that remained high one day after operation. After 10 min of blood incubation stimulated by collagen in vitro, simulating activation in the pericardial cavity, significant increases in neutrophils and monocytes positive for TF and platelet were observed. Our present study suggested the involvement of two distinct mechanisms for the appearance of TF-bearing leukocytes responsible for promoting coagulation: the quick appearance being partly explained by the formation of leukocyte-platelet complex that occurs mainly in the pericardial cavity, and the slow appearance via transcriptional activation in monocytes.
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Cole, S., L. C. Hawkley, J. M. Arevalo y J. T. Cacioppo. "1. Molecular dissection of the circulating leukocyte pool: Which leukocytes get lonely?" Brain, Behavior, and Immunity 25 (agosto de 2011): S179. http://dx.doi.org/10.1016/j.bbi.2011.07.004.
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Kakurina, Gelena V., Marina N. Stakheeva, Islombek A. Bakhronov, Elena E. Sereda, Olga V. Cheremisina, Evgeny L. Choynzonov y Irina V. Kondakova. "Circulating Actin-Binding Proteins in Laryngeal Cancer: Its Relationship with Circulating Tumor Cells and Cells of the Immune System". Acta Naturae 13, n.º 4 (15 de diciembre de 2021): 64–68. http://dx.doi.org/10.32607/actanaturae.11413.
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We previously exposed the role of actin-binding proteins (ABPs) in cancer development and progression. In this paper, we studied the relationship between circulating ABPs and the number of ABP-expressing leukocytes and circulating tumor cells (CTCs) in patients with highly aggressive laryngeal squamous cell carcinoma (LSCC). The levels of cofilin (CFL1), profilin (PFN1), ezrin (EZR), fascin (FSCN1), and adenylate cyclase-associated protein 1 (CAP1) were determined using enzyme immunoassay. The ABP expression by the cellular pools was analyzed by flow cytometry. The highest levels of FSCN1 and EZR were found in the blood serum of LSCC patients. There was a difference in ABP expression between the pools of leukocytes and CTCs. Leukocytes were mainly represented by CAP1+ and FSCN1+ pools, and CTCs contained CAP1+, FSCN1+, and EZR+ cells. The serum FSCN1 level correlated with the number of FSCN1-containing and CFL1-containing leukocytes. Thus, the level of circulating EZR is likely related to its expression in CTCs. The levels of CFL1 and PFN1 are likely to be supported by the expression of these proteins by leukocytes. Both CTCs and leukocytes can be a source of FSCN1 and CAP1 in blood serum. The results suggest that serum proteins can be produced by various cells, thus indicating both cancer development and the response of the immune system to this process.
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Suwa, Tatsushi, James C. Hogg, Kevin B. Quinlan y Stephan F. van Eeden. "The effect of interleukin-6 on L-selectin levels on polymorphonuclear leukocytes". American Journal of Physiology-Heart and Circulatory Physiology 283, n.º 3 (1 de septiembre de 2002): H879—H884. http://dx.doi.org/10.1152/ajpheart.00185.2002.
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Interleukin-6 (IL-6) shortens the transit time of polymorphonuclear leukocytes (PMN) through the marrow and accelerates their release into the circulation. In contrast to other inflammatory stimuli, this response is associated with a decrease in L-selectin levels on circulating PMN. The present study was designed to determine the effect of IL-6 on L-selectin levels of PMN in rabbits. Recombinant human IL-6 (2 μg/kg) caused a decrease in L-selectin levels on circulating PMN 3 to 12 h after treatment ( P < 0.05). L-selectin levels decreased on PMN already in the circulation for up to 4 h ( P < 0.05), on PMN released from the marrow posttreatment for up to 12 h ( P < 0.01) and on PMN in the marrow for up to 6 h ( P < 0.05) after IL-6 treatment. We conclude that IL-6 decreases L-selectin levels on circulating PMN by demarginating PMN with low levels of L-selectin and by releasing PMN from the marrow with low levels of L-selectin. We postulate that this prolonged downregulation of L-selectin on circulating PMN could influence their recruitment into inflammatory sites.
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Laidlaw, Tanya M., Molly S. Kidder, Neil Bhattacharyya, Wei Xing, Shiliang Shen, Ginger L. Milne, Mariana C. Castells, Heng Chhay y Joshua A. Boyce. "Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes". Blood 119, n.º 16 (19 de abril de 2012): 3790–98. http://dx.doi.org/10.1182/blood-2011-10-384826.
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Abstract Cysteinyl leukotriene (cysLT) overproduction is a hallmark of aspirin-exacerbated respiratory disease (AERD), but its mechanism is poorly understood. Because adherent platelets can convert the leukocyte-derived precursor leukotriene (LT)A4 to LTC4, the parent cysLT, through the terminal enzyme LTC4 synthase, we investigated the contribution of platelet-dependent transcellular cysLT production in AERD. Nasal polyps from subjects with AERD contained many extravascular platelets that colocalized with leukocytes, and the percentages of circulating neutrophils, eosinophils, and monocytes with adherent platelets were markedly higher in the blood of subjects with AERD than in aspirin-tolerant controls. Platelet-adherent subsets of leukocytes had higher expression of several adhesion markers than did platelet nonadherent subsets. Adherent platelets contributed more than half of the total LTC4 synthase activity of peripheral blood granulocytes, and they accounted for the higher level of LTC4 generation by activated granulocytes from subjects with AERD compared with aspirin-tolerant controls. Urinary LTE4 levels, a measure of systemic cysLT production, correlated strongly with percentages of circulating platelet-adherent granulocytes. Because platelet adherence to leukocytes allows for both firm adhesion to endothelial cells and augmented transcellular conversion of leukotrienes, a disturbance in platelet-leukocyte interactions may be partly responsible for the respiratory tissue inflammation and the overproduction of cysLTs that characterize AERD.
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Kollmar, R., M. Herrmann, T. Stöckl, U. Weinzierl, S. Schwab, J. Kornhuber y R. Kalb. "Significant decreases of circulating endothelial cells but no changes of endothelial progenitor cells or mesenchymal stem cells during antidepressant treatment". European Psychiatry 26, S2 (marzo de 2011): 1187. http://dx.doi.org/10.1016/s0924-9338(11)72892-9.
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ObjectiveWe examined leukocyte numbers, circulating endothelial progenitor cells (CD34+, CD133+), circulating mesenychmal stem cells (CD105+) and circulating endothelial cells (CD146+) at the beginning, after 4 weeks and at the end of an inpatient antidepressant treatment.Methods24 insufficiently pretreated inpatients with major depression were included. At admission, after four weeks and at demission blood samples were obtained, and cell numbers were counted by flow cytometric analysis (FACS). At each examination the severity of the depression was evaluated with the Beck Depression Inventory (BDI). We were especially interested in the changes of cell numbers during the antidepressant treatment. The data were statistically analyzed using SPSS 14.0.ResultsThe mean BDI score fell from 34 ± 7 at the beginning to 26.5 ± 6.6 after four weeks and 13.5 ± 5.7 at demission. The longer the overall duration of the depressive illness, the higher the number of leukocytes at admission (P < 0.0001). The lower the depression score at demission, the lower the final number of leukocytes (P < 0.001). During the antidepressant treatment the BDI depression score improved significantly (P < 0.0001). The number of CD146+ cells showed a significant decrease (P < 0.006). We did not find any significant changes of circulating CD34+, CD105+, or CD133+ cells during the antidepressant treatment.ConclusionsThe leukocyte results suggest an activation of the immune system in major depression and a deactivation due to antidepressant treatment.
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Wang, Wei, Nathalie Burg, Spandana Vootukuri y Barry S. Coller. "Systemic Activation of Platelet-Derived TGF-β1 Leads to Increased Smad2/3 Phosphorylation in Circulating Leukocytes and Platelet-Leukocyte Aggregates in a Mouse Model of Aortic Valve Stenosis". Blood 124, n.º 21 (6 de diciembre de 2014): 2756. http://dx.doi.org/10.1182/blood.v124.21.2756.2756.
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Abstract Shear stress (SS) can activate platelets, leading to exposure of surface P-selectin and development of platelet-leukocyte aggregates (PLAs). Increased numbers of PLAs has been reported in the circulation of patients with aortic valve stenosis (AS), who have high SS across the stenotic valves, and aortic valve replacement decreases the SS and number of PLAs. Activated platelets release their granule contents, which includes transforming growth factor-β1 (TGF-β1). Our lab has reported that SS can activate latent TGF-β1 released from platelets both in vitro and in in vivo mouse models of AS. Since current assays are not sensitive enough to detect activated TGF-β1 in plasma, we searched for evidence of active TGF-β1 in a mouse model of AS by assessing the level of phosphorylated Smad2/3, a downstream mediator of the classical TGF-β1 signaling pathway, in both circulating leukocytes free of platelets and PLAs. We studied Ldlr-/-Apob100/100/Mttpfl/fl/Mx1Cre+/+ mice (Reversa), which spontaneously develop AS when fed a western diet (WD) (n=13), and compared them to the same mice fed a chow diet (n=13), who do not develop AS, and wild type (WT) mice (n=13). We identified leukocytes with an antibody to CD45 (clone 30-F11), platelets with an antibody to CD41 (clone MWReg30), PLAs by double staining, and p-Smad2/3 with an antibody to p-Smad2 (pS465/pS467)/Smad3 (pS423/pS425) (clone O72-670). Leukocytes and PLAs were analyzed by both a flow cytometer and an instrument that combines digital fluorescence microscopy with flow cytometry (ImageStream-X). Reversa mice on WD for 3 months developed AS with increased SS across the valves and increased plasma total TGF-β1 levels in circulation as we previously reported (Wang et al., ATVB, 2014). Reversa mice on WD also had a significantly increased percentage of PLAs compared to the other two groups (both p<0.05; Table), suggesting platelet activation under high SS. The intensity of p-Smad2/3 staining in leukocytes free of platelets of Reversa mice on a WD was greater than the intensity in the other two groups (both p<0.01). In all 3 groups, p-Smad2/3 in PLAs was higher than in leukocytes free of platelets (all p<0.001), but Reversa mice on a WD had the highest p-Smad2/3 levels in their PLAs (p<0.05 for both. Fluorescent microscopy showed that p-Smad2/3 was located primarily in the leukocytes of the PLAs (Figure 1). There was no correlation between p-Smad2/3 staining of PLAs and the number of platelets per leukocyte (p=0.78 for WT group, p=0.52 for Reversa chow diet, and p=0.15 for Reversa WD). In summary: (1) PLAs have more leukocyte p-Smad2/3 than leukocytes that are free of platelets, regardless of genotype/diet. (2) Leukocytes free of platelets in Reversa mice on a WD have more p-Smad2/3 than those in the other two groups. (3) Reversa mice on WD have both more PLAs and more leukocyte p-Smad2/3 in their PLAs. We conclude that the increased leukocyte p-Smad2/3 in Reversa mice on WD reflects increased TGF-β1 signaling through both: 1) direct platelet-leukocyte interactions and 2) release of TGF-β1 from platelets into plasma and its subsequent activation by high SS. TableGroupPLA (% of total leukocytes)p-Smad2/3 Mean Fluorescence Intensity (AU)Leukocytes free of plateletsPLAsWT16.9 ± 1.9173.9 ± 15.49204.7 ± 17.9 #Reversa (chow diet)16.4 ± 2.1172.3 ± 15.24200.8 ± 15.9 #Reversa (WD)26.1 ± 3.1*^237.5 ± 17.42*^268.9 ± 17.1 *^# * p<0.05 Reversa (WD) vs. WT; ^ p<0.05 Reversa (WD) vs. Reversa (chow diet); # p<0.001 PLA vs. leukocytes free of platelets. AU: arbitrary unit; WD: western diet Figure 1: Figure 1:. representative images of PLAs in each group from ImageStream-X. Disclosures No relevant conflicts of interest to declare.
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Ley, K., J. B. Baker, M. I. Cybulsky, M. A. Gimbrone y F. W. Luscinskas. "Intravenous interleukin-8 inhibits granulocyte emigration from rabbit mesenteric venules without altering L-selectin expression or leukocyte rolling." Journal of Immunology 151, n.º 11 (1 de diciembre de 1993): 6347–57. http://dx.doi.org/10.4049/jimmunol.151.11.6347.
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Abstract Injection (i.v.) of the granulocyte chemoattractant/activator IL-8 has been shown to reduce neutrophil recruitment into dermal inflammatory sites in vivo. To further investigate the mechanism of this phenomenon, we examined the effect of i.v. [Ser-IL-8]72 (12-20 micrograms/kg) on leukocyte rolling and chemoattractant-induced emigration in mesenteric venules of New Zealand White rabbits and on expression of L-selectin (mAb LAM1-3) and CD18 (mAb 60.3) on circulating rabbit granulocytes. Within 1 min of IL-8 i.v., granulocytes virtually disappeared from carotid blood samples for approximately 5 min. Concomitantly, the flux of rolling leukocytes in mesenteric venules fell from 83 +/- 21 to 2 +/- 1 leukocytes/min. Both rolling leukocyte flux and systemic granulocyte count returned to or exceeded control values within less than 30 min. The chemoattractant/activator FMLP (0.15 microgram/kg i.v.) produced similar results. A second i.v. injection of IL-8 or FMLP, 90 min after the first challenge, had equipotent effects. Local extravascular application of IL-8 via micropipette close to a venule induced adhesion and emigration of 63 +/- 21 leukocytes per site before, but only 26 +/- 9 leukocytes per site 50 to 75 min after i.v. IL-8, when systemic granulocyte count and rolling leukocyte flux had reached or exceeded control values. This was not due to agonist-specific desensitization, because a similar reduction of leukocyte emigration was seen after FMLP i.v. Rabbit granulocytes circulating in vivo uniformly expressed near-control levels of L-selectin at all times between 3 and 360 min after IL-8 i.v. CD18 expression transiently increased after IL-8 i.v. and returned to base line by 90 min. These findings show that IL-8 i.v. reduces granulocyte recruitment to inflammatory sites by inhibiting function(s) necessary for transmigration that are independent of L-selectin and subsequent to rolling.
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Ray, M. R., S. Mukherjee, S. Roychoudhury, P. Bhattacharya, M. Banerjee, S. Siddique, S. Chakraborty y T. Lahiri. "Platelet activation, upregulation of CD11b/CD18 expression on leukocytes and increase in circulating leukocyte-platelet aggregates in Indian women chronically exposed to biomass smoke". Human & Experimental Toxicology 25, n.º 11 (noviembre de 2006): 627–35. http://dx.doi.org/10.1177/0960327106074603.
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The majority of households in rural India still rely on unprocessed solid biomass for domestic energy. The aim of this study was to investigate whether chronic exposure to biomass smoke causes activation of leukocytes and the formation of leukocyte-platelet aggregates. We conducted flow cytometric analysis of β2 Mac-1 integrin (CD11b/CD18) expression on polymorphonuclear leukocytes (PMN) and monocytes, and P-selectin (CD62P) expression on the platelets of 165 women from eastern India, who cook solely with wood, dung and agricultural wastes, and 155 age- and socio-economic condition-matched control subjects, who used relatively cleaner fuel, liquefied petroleum gas (LPG). Leukocyte-platelet aggregates were defined as CD11b-positive PMN and monocytes co-expressing platelet-specific markers CD41 or CD62P. A significant increase in leukocyte-platelet aggregates was found in women who used biomass as cooking fuel. In addition, they showed increased surface expression of CD11b/CD18 in circulating PMN and monocytes and CD62P expression on platelets. The mean fluorescence intensity (MFI) of CD11b on the surface of circulating monocytes and PMN of biomass users increased by 50 and 68%, respectively. Similarly, a 62 and 48% increase in MFI was observed in CD18 expression on the surface of these cells in biomass users. The results show that chronic biomass smoke exposure activates circulating platelets, PMN and monocytes, and increases the number of leukocyte-platelet aggregates, which are considered a risk factor for thrombosis.
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García-García, Andrés, Claudia Korn, María García-Fernández, Olivia Domingues, Javier Villadiego, Daniel Martín-Pérez, Joan Isern et al. "Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes". Blood 133, n.º 3 (17 de enero de 2019): 224–36. http://dx.doi.org/10.1182/blood-2018-08-867648.
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AbstractHematopoietic stem and progenitor cells (HSPCs) and leukocytes circulate between the bone marrow (BM) and peripheral blood following circadian oscillations. Autonomic sympathetic noradrenergic signals have been shown to regulate HSPC and leukocyte trafficking, but the role of the cholinergic branch has remained unexplored. We have investigated the role of the cholinergic nervous system in the regulation of day/night traffic of HSPCs and leukocytes in mice. We show here that the autonomic cholinergic nervous system (including parasympathetic and sympathetic) dually regulates daily migration of HSPCs and leukocytes. At night, central parasympathetic cholinergic signals dampen sympathetic noradrenergic tone and decrease BM egress of HSPCs and leukocytes. However, during the daytime, derepressed sympathetic noradrenergic activity causes predominant BM egress of HSPCs and leukocytes via β3–adrenergic receptor. This egress is locally supported by light-triggered sympathetic cholinergic activity, which inhibits BM vascular cell adhesion and homing. In summary, central (parasympathetic) and local (sympathetic) cholinergic signals regulate day/night oscillations of circulating HSPCs and leukocytes. This study shows how both branches of the autonomic nervous system cooperate to orchestrate daily traffic of HSPCs and leukocytes.
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Kubes, P., G. Ibbotson, J. Russell, J. L. Wallace y D. N. Granger. "Role of platelet-activating factor in ischemia/reperfusion-induced leukocyte adherence". American Journal of Physiology-Gastrointestinal and Liver Physiology 259, n.º 2 (1 de agosto de 1990): G300—G305. http://dx.doi.org/10.1152/ajpgi.1990.259.2.g300.
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The objective of this study was to determine whether platelet-activating factor (PAF) mediates the leukocyte-endothelial cell interactions elicited by ischemia/reperfusion. The rates of adherence and extravasation of leukocytes were monitored in cat mesenteric venules subjected to 60 min of ischemia (blood flow reduced to 20% of control) followed by 60 min of reperfusion. Leukocyte rolling velocity, red blood cell velocity, and vessel diameter were also measured. The experiments were performed in control (untreated) animals and in animals pretreated with one of two PAF receptor antagonists, i.e., BN 52021 or WEB 2086. The responses of venular blood flow, wall shear rate, and vessel diameter did not differ between the three groups. In the control group, 1 h of ischemia was associated with significant adherence and extravasation of leukocytes, with reperfusion greatly enhancing these responses. The rates of leukocyte adherence and extravasation during reperfusion were greatly attenuated by both PAF antagonists. Furthermore, the proportion of adherent leukocytes that ultimately extravasate during reperfusion was markedly reduced by WEB 2086. These results suggest that PAF plays an important role in mediating the adhesive interaction between circulating leukocytes and microvascular endothelium induced by ischemia/reperfusion and that the phospholipid promotes the leukocyte extravasation associated with ischemia/reperfusion.
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Balnis, Joseph, Alejandro P. Adam, Amit Chopra, Hau C. Chieng, Lisa A. Drake, Nina Martino, Ramon Bossardi Ramos et al. "Unique inflammatory profile is associated with higher SARS-CoV-2 acute respiratory distress syndrome (ARDS) mortality". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 320, n.º 3 (1 de marzo de 2021): R250—R257. http://dx.doi.org/10.1152/ajpregu.00324.2020.
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The COVID19 pandemic has caused more than a million of deaths worldwide, primarily due to complications from COVID19-associated acute respiratory distress syndrome (ARDS). Controversy surrounds the circulating cytokine/chemokine profile of COVID19-associated ARDS, with some groups suggesting that it is similar to patients without COVID19 ARDS and others observing substantial differences. Moreover, although a hyperinflammatory phenotype associates with higher mortality in non-COVID19 ARDS, there is little information on the inflammatory landscape’s association with mortality in patients with COVID19 ARDS. Even though the circulating leukocytes’ transcriptomic signature has been associated with distinct phenotypes and outcomes in critical illness including ARDS, it is unclear whether the mortality-associated inflammatory mediators from patients with COVID19 are transcriptionally regulated in the leukocyte compartment. Here, we conducted a prospective cohort study of 41 mechanically ventilated patients with COVID19 infection using highly calibrated methods to define the levels of plasma cytokines/chemokines and their gene expressions in circulating leukocytes. Plasma IL1RA and IL8 were found positively associated with mortality, whereas RANTES and EGF negatively associated with that outcome. However, the leukocyte gene expression of these proteins had no statistically significant correlation with mortality. These data suggest a unique inflammatory signature associated with severe COVID19.
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Alberti, Michael, Jessy Deshane, Larisa Pereboeva, Yuko Tsuruta, Ed Abraham, David Chaplin, Stanton Gerson, David Curiel y Justin Roth. "A recombinant adenovirus for targeted gene therapy of pulmonary inflammation (155.23)". Journal of Immunology 186, n.º 1_Supplement (1 de abril de 2011): 155.23. http://dx.doi.org/10.4049/jimmunol.186.supp.155.23.
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Abstract Inflammation is a pathological component of many debilitating lung diseases. Thus, therapeutics that suppress the inflammatory response should also minimize inflammation-induced airway destruction. In this regard, Adenovirus type 5 (Ad5) vectors have a long history as therapeutic agents, due to their in vivo stability and amenability to genetic manipulation. Since circulating leukocytes infiltrate and mediate damage to the sites of pathology, we proposed to modulate Ad5 tropism to the dense leukocyte pool in the lung microvasculature for localized therapeutic intervention of inflammation. However, leukocytes do not express the coxsackie and adenovirus receptor (CAR) and are thus resistant to Ad5 infection. Therefore, we utilized phage display to identify a myeloid-binding peptide (MBP) and then genetically incorporated this sequence into an Ad5 fiber lacking the native CAR-binding domain (knob). Non-replicative Ad reporter vectors containing these MBP-fibers (Ad.MBP) maintained myeloid-binding specificity, and upon intravenous delivery the altered tropism enhanced lung gene transfer by five orders of magnitude over that obtained with unmodified Ad5. Disparity between cell types bound and those transduced suggest Ad.MBP is first sequestered by circulating leukocytes and subsequently “handed-off” to transduce pulmonary endothelium. These studies highlight the importance of pulmonary leukocytes as a target for therapeutic delivery in inflammatory lung disease.
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Zaldivar, F., R. G. McMurray, D. Nemet, P. Galassetti, P. J. Mills y D. M. Cooper. "Body fat and circulating leukocytes in children". International Journal of Obesity 30, n.º 6 (17 de enero de 2006): 906–11. http://dx.doi.org/10.1038/sj.ijo.0803227.
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Mathison, Ronald, Richard Woodman y Joseph S. Davison. "Regulation of leukocyte adhesion to heart by the tripeptides feG and feG(NH2)". Canadian Journal of Physiology and Pharmacology 79, n.º 9 (1 de septiembre de 2001): 785–92. http://dx.doi.org/10.1139/y01-055.
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The role of the D-isomeric form of the salivary gland tripeptide FEG (feG) and its carboxyl-amidated derivative, feG(NH2), in regulating leukocyte adherence to nonfixed atrial slices from Sprague-Dawley rats was examined under static conditions. Optimal binding of the leukocytes was seen if the leukocytes were treated with platelet activating factor (PAF; 10-9M). The increased adherence of PAF-treated peripheral blood leukocytes was totally inhibited by both feG and feG(NH2) (10-9M), as well as by antibodies against CD18 and CD49d. In contrast, the binding of peritoneal leukocytes was blocked only by CD49d antibody. Circulating leukocytes obtained from lipopolysaccharide (LPS) treated (2 mg/kg ip) rats did not bind to atrial slices obtained from normal hearts, but readily bound to atrial slices obtained from LPS-treated rats. This leukocyte binding was inhibited by in vivo feG treatment (100 µg/kg ip, 24 h before harvest) or by treating the isolated cells with feG (10-9M). The amidated peptide feG(NH2) reduced neutrophil accumulation in the atrium elicited by ip injection of LPS, whereas feG was ineffective. The reduction in neutrophil infiltration into the myocardium by feG(NH2) and the prevention of leukocyte interaction with myocytes seen with both feG and feG(NH2) probably results in hindered leukocyte migration in the inflamed heart, resulting in less tissue damage. The inhibition by these tripeptides on neutrophil adhesion to myocytes suggests that salivary glands hormones regulate the severity of cardiac inflammation.Key words: endotoxemia, inflammation, salivary glands, leukocytes, heart, adhesion.
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Kusterer, Klaus, Jörg Bojunga, Michael Enghofer, Edmund Heidenthal, Klaus H. Usadel, Hubert Kolb y Stephan Martin. "Soluble ICAM-1 reduces leukocyte adhesion to vascular endothelium in ischemia-reperfusion injury in mice". American Journal of Physiology-Gastrointestinal and Liver Physiology 275, n.º 2 (1 de agosto de 1998): G377—G380. http://dx.doi.org/10.1152/ajpgi.1998.275.2.g377.
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Ischemia-reperfusion injury is a pathogenic factor in the course of many clinical disorders, such as myocardial infarction, stroke, organ transplantation, burns, and circulatory shock. The extent of ischemia-reperfusion injury is dependent on the number of infiltrating leukocytes. With in vivo microscopy, we evaluated the effect of the recombinant form of soluble murine intercellular adhesion molecule-1 (ICAM-1) on ischemia-reperfusion injury in an animal model. A mesenteric vein was occluded with a clamp for 45 min. During a reperfusion period of 30 min, the number of leukocytes rolling along the endothelium and the number of adherent leukocytes were measured with and without pretreatment with recombinant ICAM-1. The number of leukocytes rolling along the endothelial surface increased more than twofold during postischemic perfusion ( P < 0.05). Recombinant ICAM-1 had no effect on leukocyte rolling. In the control group, firm adherence of leukocytes was increased 10-fold. Recombinant ICAM-1 dose dependently reduced firm adhesion to the endothelium in response to prior ischemia. After 30 min, reperfusion pretreatment with recombinant ICAM-1 inhibited leukocyte adherence from 512 ± 123 to 166 ± 34 leukocytes/mm2( P < 0.01). We demonstrate here for the first time that soluble recombinant ICAM-1 is able to reduce leukocyte adherence to mesenteric venules in postischemic reperfusion injury dose dependently. Because soluble ICAM-1 is naturally circulating in human serum, the therapeutic use of soluble recombinant forms of ICAM-1 may represent a physiological way to protect against ischemiareperfusion injury.
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Kuebler, W. M., G. E. Kuhnle, J. Groh y A. E. Goetz. "Leukocyte kinetics in pulmonary microcirculation: intravital fluorescence microscopic study". Journal of Applied Physiology 76, n.º 1 (1 de enero de 1994): 65–71. http://dx.doi.org/10.1152/jappl.1994.76.1.65.
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To determine the site of sequestration of leukocytes in the lung, we investigated the kinetics of fluorescently labeled erythrocytes and leukocytes in pulmonary arterioles, venules, and alveolar capillaries in vivo by using fluorescence videomicroscopy. The subpleural pulmonary microcirculation of the ventilated rabbit lung was visualized via a transparent window implanted into the right thoracic wall. Fluorescein isothiocyanate-labeled erythrocytes were administered intravenously, whereas leukocytes were labeled in vivo by intravenous injection of rhodamine 6G. Rolling and adherence of leukocytes on the surface of the vessel walls were observed in arterioles as well as in venules. The median velocity of nonadherent leukocytes was significantly higher in arterioles than in venules (84 +/- 12 vs. 15 +/- 3% of erythrocyte velocity, respectively). In alveolar capillaries the majority of leukocytes were retained at distinct sites for periods of 0.1 to > 5 s (median 0.61 s). The relative velocity of leukocytes moving in capillaries was comparable to that determined in arterioles (80 +/- 9% of erythrocyte velocity). These measurements indicate that leukocyte sequestration in the lung is governed by the retention of leukocytes in capillaries and by the interaction of leukocytes with microvascular endothelium of arterioles and venules. We propose that the kinetics of these phenomena determine the equilibrium between circulating and sequestered leukocytes.
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Bárány, Tamás, Andrea Simon, Gergő Szabó, Rita Benkő, Zsuzsanna Mezei, Levente Molnár, Dávid Becker, Béla Merkely, Endre Zima y Eszter M. Horváth. "Oxidative Stress-Related Parthanatos of Circulating Mononuclear Leukocytes in Heart Failure". Oxidative Medicine and Cellular Longevity 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/1249614.
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Background. The present study aims to examine the oxidative stress-related activation of poly(ADP-ribose) polymerase (PARP), a cause of parthanatos in circulating mononuclear leukocytes of patients with chronic heart failure (CHF), that was rarely investigated in the human setting yet. Methods. Patients with CHF (n=20) and age- and body mass index-matched volunteers (n=15) with a normal heart function were enrolled. C-reactive protein, N-terminal probrain-type natriuretic peptide (pro-BNP), plasma total peroxide level (PRX), plasma total antioxidant capacity (TAC), oxidative stress index (OSI), leukocyte lipid peroxidation (4-hydroxynonenal; HNE), protein tyrosine nitration (NT), poly(ADP-ribosyl)ation (PARylation), and apoptosis-inducing factor (AIF) translocation were measured in blood samples of fasting subjects. Results. Plasma PRX, leukocyte HNE, NT, PARylation, and AIF translocation were significantly higher in the heart failure group. Pro-BNP levels in all study subjects showed a significant positive correlation to PRX, OSI, leukocyte HNE, NT, PARylation, and AIF translocation. Ejection fraction negatively correlated with the same parameters. Among HF patients, a positive correlation of pro-BNP with PRX, OSI, and PARylation was still present. Conclusions. Markers of oxidative-nitrative stress, PARP activation, and AIF translocation in blood components showed correlation to reduced cardiac function and the clinical appearance of CHF. These results may reinforce the consideration of PARP inhibition as a potential therapeutic target in CHF.
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Tuschong, Laura, Catherine E. Dejesus, Meredith Adams, Aylin C. Bonifacino, Dennis D. Hickstein y Robert E. Donahue. "Leukocyte Integrin CD18 Expression Mediates Transient Neutropenia Following G-CSF Administration." Blood 114, n.º 22 (20 de noviembre de 2009): 3587. http://dx.doi.org/10.1182/blood.v114.22.3587.3587.
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Abstract Abstract 3587 Poster Board III-524 The mechanism whereby neutrophils traffic from the circulation in response to G-CSF has remained unclear despite the observation of ourselves and others that there is a dramatic, yet transient, loss of circulating neutrophils shortly following the administration of G-CSF in humans, non-human primates, and mice (Gordon BC, et al. Exp Hematol. 35:872-8, 2007). To determine the role of the CD18 leukocyte integrin on neutrophils in the egress of neutrophils from the circulation, we used dogs with canine leukocyte adhesion deficiency (CLAD), a genetic disease in which a mutation in CD18 prevents CD18 surface expression. We selected CLAD dogs who had 5-10% CD18+ neutrophils following either matched littermate allogeneic transplant or autologous gene therapy for CLAD. Three CLAD dogs meeting these criteria were evaluated. Three carrier dogs served as controls. G-CSF was administered at 10μg/kg SQ to all six animals. Peripheral blood samples (EDTA) were taken immediately prior to G-CSF administration, and at 15, 30, 60, 120, 240 minutes, and 24 hours following G-CSF administration. Total white blood cell counts, neutrophil counts, and the number and percentage of CD18+ peripheral blood leukocytes were assessed. As anticipated, the control dogs had a 60% decrease in circulating neutrophils 30 minutes following G-CSF administration: the mean +/− standard of deviation (SD) absolute neutrophil baseline count decreased from 6806+/−1072/μL to 2727+/−767/μL. In five control animals the neutrophil nadir occurred at 30 minutes post-G-CSF, and in one control dogs it occurred 15 minutes following G-CSF administration. Experimental CLAD dogs had only a 35% decline in neutrophil numbers at 30 minutes, from a mean baseline of 6777+/− 672/μL to 4433+/−265/μL. In these dogs the neutrophil count returned to pre-G-CSF levels by 60 minutes post-G-CSF. By 24 hours after G-CSF, the neutrophil level was increased 3-fold from baseline. Immunophenotyping using an anti-CD18 and a canine specific anti-neutrophil PE conjugated antibody indicated that only the CD18+ neutrophils disappeared from the circulation following G-CSF administration. At baseline the transplanted CLAD dogs had a mean of 15.2+/−3.9% CD18+ peripheral blood leukocytes, of these 50.7+/−7.1% were CD18+ neutrophils. Thirty minutes following G-CSF administration the mean+/−SD percentage of CD18+ leukocytes declined to 13.7+/−3.7% with 33.4+/−5.8% being neutrophils. There was also a slight decline in CD14+CD18+ monocytes from 6.2 +/− 1.5% to 4.0 +/− 1.2%, which was not observed in the controls. There was no change in CD18- leukocyte numbers. The percentage of CD18+ neutrophils returned to baseline by 60 minutes and remained there at subsequent time points. These results demonstrate that the CD18 leukocyte integrin on circulating neutrophils mediates the transient neutropenia associated with G-CSF administration. Disclosures: No relevant conflicts of interest to declare.
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Boivin, G., M. R. Quirk, B. A. Kringstad, M. Germain y M. C. Jordan. "Early effects of ganciclovir therapy on the quantity of cytomegalovirus DNA in leukocytes of immunocompromised patients." Antimicrobial Agents and Chemotherapy 41, n.º 4 (abril de 1997): 860–62. http://dx.doi.org/10.1128/aac.41.4.860.
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The cytomegalovirus (CMV) DNA load in leukocytes was measured in 26 immunocompromised patients with CMV disease before and after 10 days of intravenous ganciclovir therapy. Before therapy, the circulating DNA burden of bone marrow transplant recipients was significantly lower than that of other transplant or AIDS patients. Ganciclovir induction therapy significantly decreased the viral DNA load in the leukocyte populations of most patients.
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Orth, Teresa A., Julie A. Allen, John G. Wood y Norberto C. Gonzalez. "Exercise training prevents the inflammatory response to hypoxia in cremaster venules". Journal of Applied Physiology 98, n.º 6 (junio de 2005): 2113–18. http://dx.doi.org/10.1152/japplphysiol.00694.2004.
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Systemic hypoxia produces microvascular inflammation in several tissues, including skeletal muscle. Exercise training (ET) has been shown to reduce the inflammatory component of several diseases. Alternatively, ET could influence hypoxia-induced inflammation by improving tissue oxygenation or increasing mechanical antiadhesive forces at the leukocyte-endothelial interface. The effect of 5 wk of treadmill ET on hypoxia-induced microvascular inflammation was studied in the cremaster microcirculation of rats using intravital microscopy. In untrained rats, hypoxia (arterial Po2 = 32.3 ± 2.1 Torr) increased leukocyte-endothelial adherence from 2.3 ± 0.4 to 10.2 ± 0.3 leukocytes per 100 μm of venule ( P < 0.05) and was accompanied by extravasation of FITC-labeled albumin after 4 h of hypoxia (extra-/intravascular fluorescence intensity ratio = 0.50 ± 0.07). These responses were attenuated in ET (leukocyte adherence was 1.5 ± 0.4 during normoxia and 1.8 ± 0.7 leukocytes per 100 μm venule after 10 min of hypoxia; extra-/intravascular fluorescence intensity ratio = 0.11 ± 0.02; P < 0.05 vs. untrained) despite similar reductions of arterial (32.4 ± 1.8 Torr) and microvascular Po2 (measured with an oxyphor-quenching method) in both groups. Shear rate decreased during hypoxia to similar extents in ET and untrained rats. In addition, circulating blood leukocyte count was similar in ET and untrained rats. The effects of ET on hypoxia-induced leukocyte-endothelial adherence remained up to 4 wk after discontinuing training. Thus ET attenuated hypoxia-induced inflammation despite similar effects of hypoxia on tissue Po2, venular shear rate, and circulating leukocyte count.
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Wood, John G., Leone F. Mattioli y Norberto C. Gonzalez. "Hypoxia causes leukocyte adherence to mesenteric venules in nonacclimatized, but not in acclimatized, rats". Journal of Applied Physiology 87, n.º 3 (1 de septiembre de 1999): 873–81. http://dx.doi.org/10.1152/jappl.1999.87.3.873.
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Although the effects of ischemia-reperfusion have received considerable attention, few studies have directly evaluated the microcirculatory response to systemic hypoxia. The overall objective of this study was to assess the effect of environmental hypoxia on adhesive interactions of circulating leukocytes with rat mesenteric venules by using intravital microscopy. Experiments were designed to 1) characterize the adhesive interactions of circulating leukocytes to venules during acute hypoxia produced by a reduction in inspired[Formula: see text], 2) evaluate the role of nitric oxide in these adhesive interactions, 3) determine whether the effect of hypoxia on leukocyte adhesive interactions differs between acclimatized and nonacclimatized rats, and 4) assess whether compensatory changes in nitric oxide formation contribute to this difference. The results showed that acute hypoxia promotes leukocyte-endothelial adherence in mesenteric venules of nonacclimatized rats. The mechanism of this response is consistent with depletion of nitric oxide within the microcirculation. In contrast, no leukocyte-endothelial adherence occurred during hypoxia in rats acclimatized to hypobaric hypoxia. The results are consistent with increased nitric oxide formation due to expression of inducible nitric oxide synthase during the acclimatization period. Further studies are needed to establish the cause of nitric oxide depletion during acute hypoxia as well as to define the compensatory responses that attenuate hypoxia-induced leukocyte-endothelial adherence in the microvasculature of acclimatized rats.
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Sutton, D. W. y G. W. Schmid-Schonbein. "Elevation of organ resistance due to leukocyte perfusion". American Journal of Physiology-Heart and Circulatory Physiology 262, n.º 6 (1 de junio de 1992): H1646—H1650. http://dx.doi.org/10.1152/ajpheart.1992.262.6.h1646.
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Leukocytes are larger and considerably less deformable than erythrocytes, thereby causing a disproportionate effect on local blood flow, which despite their low concentration, may be significant at the organ level. To investigate the degree to which circulating leukocytes affect whole organ resistance, a hemodynamically isolated rat gracilis muscle was perfused in situ under well-controlled conditions. Comparison of organ pressure-flow data from vasodilated vasculature using normal physiological cell concentrations and perfusion pressures indicates that leukocytes (60–75% neutrophils) provide approximately 22% of the whole blood resistance despite their relatively small cell volume fraction of approximately 0.1%. On a single cell basis, each leukocyte imposes a resistance elevation equivalent to that of approximately 750 erythrocytes. Furthermore, when leukocytes are activated via pretreatment using N-formyl-methionyl-leucyl-phenylalanine or endotoxin, they show a higher resistance, accounting for 50-60% of the total resistance. These findings indicate that leukocytes play a significant role in normal skeletal muscle organ perfusion and may be a major determinant of organ perfusion during disease states.
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Cheng, Zhangrui, Danielle L. McLaughlin, Mark W. Little, Conrad Ferris, Mazdak Salavati, Klaus L. Ingvartsen, Mark A. Crowe, D. Claire Wathes y the GplusE Consortium. "Proportion of Concentrate in the Diet of Early Lactation Dairy Cows Has Contrasting Effects on Circulating Leukocyte Global Transcriptomic Profiles, Health and Fertility According to Parity". International Journal of Molecular Sciences 24, n.º 1 (20 de diciembre de 2022): 39. http://dx.doi.org/10.3390/ijms24010039.
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The functionality of circulating leukocytes in dairy cows is suppressed after calving, with negative energy balance as a risk factor. Leukocyte transcriptomic profiles were compared separately in 44 multiparous (MP) and 18 primiparous (PP) Holstein–Friesian cows receiving diets differing in concentrate proportion to test whether immune dysfunction could be mitigated by appropriate nutrition. After calving, cows were offered either (1) low concentrate (LC); (2) medium concentrate (MC) or (3) high concentrate (HC) diets with proportions of concentrate to grass silage of 30%:70%, 50%:50% and 70%:30%, respectively. Cow phenotype data collected included circulating metabolites, milk yield and health and fertility records. RNA sequencing of circulating leukocytes at 14 days in milk was performed. The HC diet improved energy balance in both age groups. There were more differentially expressed genes in PP than MP cows (460 vs. 173, HC vs. LC comparison) with few overlaps. The MP cows on the LC diet showed upregulation of the complement and coagulation cascade and innate immune defence mechanisms against pathogens and had a trend of more cases of mastitis and poorer fertility. In contrast, the PP cows on the HC diet showed greater immune responses based on both gene expression and phenotypic data and longer interval of calving to conception. The leukocytes of MP and PP cows therefore responded differentially to the diets between age, nutrient supply and immunity affecting their health and subsequent fertility.
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Bothwell, Alfred, WookJin Chae, Alexandra Teixeira, Pamela Chan, Liming Hao, Carla Rothlin y Diane Krause. "Regulation of chronic lung inflammation to house dust mite allergen by Wnt antagonist (CAM1P.144)". Journal of Immunology 194, n.º 1_Supplement (1 de mayo de 2015): 48.1. http://dx.doi.org/10.4049/jimmunol.194.supp.48.1.
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Abstract Recruitment of leukocytes in response to allergen is an important step in the initiation of airway inflammation. Here we demonstrate that the Wnt antagonist Dkk-1 regulates the formation of leukocyte-platelet aggregates (LPAs) following house dust mite (HDM) allergen challenge. We show that circulating Dkk-1 is elevated after recurrent HDM allergen challenges and the source is activated platelets. The increase of P-selectin glycoprotein ligand-1 (PSGL-1) expression in leukocytes was mediated by Dkk-1 while other cell adhesion molecules such as ICAM-1 or LFA-1 were only marginally affected. The formation of LPAs was markedly reduced in Dkk-1 hypomorphic doubleridge (Dkk-1d/d) mice that had a 90% reduction of circulating Dkk-1. Recurrent allergen challenges in Dkk-1d/d mice showed significantly reduced infiltration of leukocytes including neutrophils in the lung compared to wildtype mice. Importantly, we show that type 2 cytokines (e.g. IL-4, IL-5 and IL-13) from CD4 T cells in mediastinal lymph nodes (med LNs) of Dkk-1d/d mice were substantially reduced compared to wildtype mice following allergen exposure. Consistently, we observed Gata-3 and c-Maf induction in Th2 cells did not occur in med LN CD4 T cells from Dkk-1d/d mice. Therefore, our results demonstrate that the Wnt antagonist from activated platelets regulates the early stage of leukocyte infiltration in the challenged tissue, thereby regulating inflammation and type 2 immune responses.
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Shen, K., K. L. P. Sung, D. E. Whittemore, F. A. DeLano, B. W. Zweifach y G. W. Schmid-Schönbein. "Properties of circulating leukocytes in spontaneously hypertensive rats". Biochemistry and Cell Biology 73, n.º 7-8 (1 de julio de 1995): 491–500. http://dx.doi.org/10.1139/o95-054.
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The factors responsible for predisposition to progressive organ injury and vascular complications in arterial hypertension are uncertain. Recent evidence shows that leukocytes participate in cardiovascular conditions for which hypertension is a risk factor. Therefore, there is a need to define the properties of circulating leukocytes in hypertensives. There are about twice as many circulating leukocytes in spontaneous hypertensive rats (SHRs) compared with their normotensive controls, the Wistar–Kyoto rats (WKYs). The SHR neutrophils are viscoelastic and similar to neutrophils in WKYs but exhibit lower deformability in short-term elastic deformation. Mature SHRs have elevated levels of spontaneous pseudopod formation. Mild stimulation with N-formyl-Met-Leu-Phe or platelet-activating factor (10−8 M) results in a significantly enhanced level of neutrophil pseudopod formation in SHRs but not in WKYs. SHRs exhibit higher levels of spontaneous superoxide formation. Alkaline phosphatase content of individual circulating neutrophils in SHRs is on average lower while plasma levels of alkaline phosphatase in the same samples are elevated in the SHRs. Spontaneous degranulation of SHR neutrophils is also detectable with myeloperoxidase measurements. Such activity of circulating leukocytes poses a significant risk for vascular cytotoxicity in the hypertensive rats.Key words: neutrophil, degranulation, alkaline phosphatase, myeloperoxidase, nitro blue tetrazolium reduction, rheological properties, adhesion.
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Ma, Xiaoqing, Ho Jun Yun, Kenneth Elkin, Yunliang Guo, Yuchuan Ding y Guangwen Li. "MicroRNA-29b Suppresses Inflammation and Protects Blood-Brain Barrier Integrity in Ischemic Stroke". Mediators of Inflammation 2022 (23 de agosto de 2022): 1–11. http://dx.doi.org/10.1155/2022/1755416.
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Objectives. Following cerebral ischemia, microRNA- (miR-) 29b in circulating blood is downregulated. This study investigates the underlying mechanism and implications of miR-29b in leukocyte induction. Methods. miR-29b from stroke patients and rats with middle cerebral artery occlusion (MCAO) were assessed using real-time polymerase chain reaction (PCR). miR-29b agomir was used to increase miR-29b expression in leukocytes via intravenous injection. C1q and tumor necrosis factor (C1QTNF) 6, interleukin- (IL-) 1β, zonula occludens- (ZO-) 1, occludin, and ischemic outcomes were assessed in MCAO rats. Additionally, hCMEC/D3 cells were subjected to oxygen–glucose deprivation (OGD) and cocultured with HL-60 cells. Results. miR-29b levels in neutrophils were found to be significantly lower in stroke patients compared with healthy controls, which may indicate its high diagnostic sensitivity and specificity for stroke. Moreover, miR-29b levels in leukocytes showed a negative correlation with National Institute of Health Stroke Scale (NIHSS) scores and C1QTNF6 levels. In MCAO rats, miR-29b overexpression reduced brain infarct volume and brain edema, decreasing IL-1β levels in leukocytes and in the brain 24 hours poststroke. miR-29b attenuated IL-1β expression via C1QTNF6 inhibition, leading to decreased blood-brain barrier (BBB) disruption and leukocyte infiltration. Moreover, miR-29b overexpression in HL-60 cells downregulated OGD-induced hCMEC/D3 cell apoptosis and increased ZO-1 and occludin levels in vitro. Conclusion. Leukocytic miR-29b attenuates inflammatory response by augmenting BBB integrity through C1QTNF6, suggesting a novel miR-29b-based therapeutic therapy for ischemic stroke.
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Kunisaki, Yuya, Daniel Lucas y Paul S. Frenette. "Circadian Expression of Endothelial Selectins, Regulated by the Sympathetic Nervous System, Controls Peripheral Leukocyte Homeostasis". Blood 112, n.º 11 (16 de noviembre de 2008): 548. http://dx.doi.org/10.1182/blood.v112.11.548.548.
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Abstract We have recently shown that hematopoietic stem cells (HSCs) are released into peripheral blood in a circadian manner, controlled by the sympathetic nervous system (SNS) through the regulation of CXCL12 levels in the bone marrow (BM) (Mendez-Ferrer et. al. Nature2008;452:442). In addition to the oscillations in circulating HSC numbers, we have also observed circadian fluctuations in the numbers of blood leukocytes in mice maintained on a standard 12h light - 12h dark cycle. Systemic leukocyte counts (4129 ± 521/μl (12 pm) vs 2000 ± 233/μl (8 pm); p=0.003) and their subsets, neutrophils (2762 ± 118 vs 732 ± 45/μl; p=0.02) and lymphocytes (5997 ± 151 vs 1867 ± 661/μl; p=0.03), were significantly reduced at night compared to the morning. We hypothesized that peripheral leukocyte counts are regulated by their interactions with endothelial cells in the BM microcirculation. To test this hypothesis we analyzed the constitutive interactions of leukocytes with BM microvessels using intravital microscopy to evaluate whether the trafficking of leukocytes in the BM microvasculature is also subjected to circadian regulation. We found that the absolute number of rolling leukocytes (18.0 ± 0.2 (12 pm) vs 31.1 ± 3.5 (8 pm) x103/mm2;p=0.004) and the rolling flux fraction (RFF, i.e. rolling/systemic leukocyte counts)(6.5 ± 0.6 vs 20.7 ± 3.1 %; p=0.0001) were increased three-fold at night, inversely correlating with the number of circulating leukocytes. Adoptive transfer experiments of fluorescently labeled BM leukocytes also revealed a two-fold increase in the number of recruited adherent leukocytes at night compared to when cells were injected in the morning (0.97 ± 0.17 (12 pm) vs 2.54 ± 0.53 (8 pm)/vessel area (μm2);p=0.007). Flow cytometry analyses revealed that the majority of these recruited cells were Mac-1+/Gr-1+ myeloid cells. This suggests that the capacity of the BM to recruit leukocytes fluctuates over the course of a day. Moreover, adoptively transferred cells formed clusters at specific sites in the BM at night. To investigate the mechanisms, we first subjected mice lacking both endothelial selectins (P-and E-selectins) to the same experimental protocols. Double deficient mice did not exhibit circadian variations in PB (9725 ± 1185/μl (12 pm) vs 8271 ± 1394/μl (8 pm); p=0.50) or BM (RFF 0.28 ± 0.05 vs 0.34 ± 0.05 %; p=0.48), and did not show clusters of adoptively transferred cells in the BM. To investigate the role of the SNS, we sympathectomized mice with 6-hydroxydopamine. Chemical sympathectomy significantly reduced the circadian differences of leukocyte rolling on BM endothelium (RFF 7.8 ± 1.1% (12 pm) vs 14.9 ± 2.8% (8 pm); p=0.01) and leukocyte numbers in PB (2750 ± 322 vs 2225 ± 363/μl; p=0.32). In addition, the number of adherent adoptively transferred cells in the BM did not show significant fluctuation (1.66 ± 0.26 vs 1.54 ± 0.20/vessel area(μm2);p=0.72). These results suggest that the process of homing/cluster formation is dependent on constitutive, oscillatory expression of P- and/or E-selectins and regulated by the SNS.
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Lishko, Valeryi K., Timothy Burke y Tatiana Ugarova. "Antiadhesive effect of fibrinogen: a safeguard for thrombus stability". Blood 109, n.º 4 (18 de julio de 2006): 1541–49. http://dx.doi.org/10.1182/blood-2006-05-022764.
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Abstract The recruitment of phagocytic leukocytes to sites of vessel wall injury plays an important role in thrombus dissolution by proteases elaborated on their adhesion. However, leukocyte adhesion to the fibrin clot can be detrimental at the early stages of wound healing when hemostatic plug integrity is critical for preventing blood loss. Adhesion of circulating leukocytes to the insoluble fibrin(ogen) matrix is mediated by integrins and occurs in the presence of a high concentration of plasma fibrinogen. In this study, the possibility that soluble fibrinogen could protect fibrin from excessive adhesion of leukocytes was examined. Fibrinogen was a potent inhibitor of adhesion of U937 monocytoid cells and neutrophils to fibrin gel and immobilized fibrin(ogen). An investigation of the mechanism by which soluble fibrinogen exerts its influence on leukocyte adhesion indicated that it did not block integrins but rather associated with the fibrin(ogen) substrate. Consequently, leukocytes that engage fibrinogen molecules loosely bound to the surface of fibrin(ogen) matrix are not able to consolidate their grip on the substrate; subsequently, cells detach. This conclusion is based on the evidence obtained in adhesion studies using various cells and performed under static and flow conditions. These findings reveal a new role of fibrinogen in integrin-mediated leukocyte adhesion and suggest that this mechanism may protect the thrombus from premature dissolution.
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Christoffersson, Gustaf, Evelina Vågesjö, Jennifer Vandooren, Majken Lidén, Sara Massena, Rachel B. Reinert, Marcela Brissova, Alvin C. Powers, Ghislain Opdenakker y Mia Phillipson. "VEGF-A recruits a proangiogenic MMP-9–delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue". Blood 120, n.º 23 (29 de noviembre de 2012): 4653–62. http://dx.doi.org/10.1182/blood-2012-04-421040.
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Abstract Recruitment and retention of leukocytes at a site of blood vessel growth are crucial for proper angiogenesis and subsequent tissue perfusion. Although critical for many aspects of regenerative medicine, the mechanisms of leukocyte recruitment to and actions at sites of angiogenesis are not fully understood. In this study, we investigated the signals attracting leukocytes to avascular transplanted pancreatic islets and leukocyte actions at the engraftment site. Expression of the angiogenic stimulus VEGF-A by mouse pancreatic islets was elevated shortly after syngeneic transplantation to muscle. High levels of leukocytes, predominantly CD11b+/Gr-1+/CXCR4hi neutrophils, were observed at the site of engraftment, whereas VEGF-A–deficient islets recruited only half of the amount of leukocytes when transplanted. Acute VEGF-A exposure of muscle increased leukocyte extravasation but not the levels of SDF-1α. VEGF-A–recruited neutrophils expressed 10 times higher amounts of MMP-9 than neutrophils recruited to an inflammatory stimulus. Revascularization of islets transplanted to MMP-9–deficient mice was impaired because blood vessels initially failed to penetrate grafts, and after 2 weeks vascularity was still disturbed. This study demonstrates that VEGF-A recruits a proangiogenic circulating subset of CD11b+/Gr-1+ neutrophils that are CXCR4hi and deliver large amounts of the effector protein MMP-9, required for islet revascularization and functional integration after transplantation.
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Pavlov, O. V., S. V. Chepanov, A. V. Selutin y S. A. Selkov. "Platelet-leukocyte interactions: immunoregulatory role and pathophysiological relevance". Medical Immunology (Russia) 24, n.º 5 (31 de octubre de 2022): 871–88. http://dx.doi.org/10.15789/1563-0625-pli-2511.
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Blood platelets are the central players in thrombosis and blood coagulation. Moreover, they also exhibit immunoregulatory properties and bridge hemostasis and immunity. Morphological and functional characteristics of the platelets ensure continuous surveillance for the vascular system, recognition of different hazards, development of appropriate response and recruitment of immune cells. Indirect platelet-leukocyte interactions are mediated by immunoregulatory molecules that are released, along with coagulation and thrombosis factors in the course of platelet activation and degranulation. Chemokines, cytokines, growth factors, some of which are synthesized de novo, are released from activated platelets and modulate cellular functions, thus modulating both innate and adaptive immune response. Activated platelets enter contacts with immune cells to form heterotypic aggregates, i.e., platelet-leukocyte complexes that reside in blood circulation along with other blood cells. The aggregate formation and stabilization is mediated by interaction between the molecules expressed on the surface of platelets and leukocytes, in particular, P-selectin (CD62P) and PSGL-1 (CD162). Platelet-monocyte and platelet-neutrophil complexes are most abundant, with platelet-monocyte aggregates being most stable. Moreover, the platelet-derived microvesicles also interact with leukocytes to form heterotypic aggregates, thus, probably, modulating the immune cell functions via transfer of non-coding RNA molecules. Formation of platelet-leukocyte complexes results into mutual activation of platelets and leukocytes. Platelets and platelet-derived microvesicles stimulate phagocytic activity, cytokine secretion, and generation of reactive oxygen species in monocytes and neutrophils, inducing formation of neutrophilic extracellular traps and procoagulant phenotype in monocytes. The blood platelets regulate monocyte differentiation, promote adhesion, as well as transmigration of lymphocytes and NK cells. At the sites of inflammation, platelets enhance extravasation and infiltration of leukocytes into the damaged tissue. Impaired interactions of platelets with endothelial layer and immune cells may underlie pathogenic conditions. Increased level of circulating plateletleukocyte complexes is observed in various disorders including cardiovascular diseases, acute ischemic stroke, respiratory disorders, renal pathologies, liver diseases, diabetes, reproductive disorders, bacterial and viral infections. Further studies of platelet-leukocyte interactions are warranted to unveil pathogenic mechanisms and to develop new therapeutic approaches.