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1.
J Oral Biosci ; 65(1): 111-118, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36640838

RESUMEN

OBJECTIVES: Glycocalyx lines the vascular intraluminal space that regulates fluid movement between the intra- and extra-vascular compartments. The depletion of glycocalyx (GCX) is associated with leukocyte accumulation, possibly causing the endothelial cells to become hyperpermeable in various organs, including oral tissues. Whether neutrophils or macrophages are responsible for developing interstitial edema remains controversial. We explored the pathophysiological mechanism of interstitial edema by examining the role of reactive neutrophils and macrophages and their interactions with GCX. METHODS: An anti-MHC class I antibody was administered intravenously to male BALB/c mice to induce pulmonary edema. Pulmonary edema was evaluated by measuring the lung wet-to-dry weight ratio. Changes in the GCX were evaluated by electron microscopy and measurements of the serum level of soluble syndecan-1. Heparin sulfate was administered to examine its protective effect on the GCX. The macrophages were depleted using clodronate to examine their role in developing edema. RESULTS: The GCX degradation induced by the anti-MHC class I antibody was accompanied by increased serum syndecan-1 and heparan sulfate levels. Macrophage depletion inhibited the development of pulmonary edema, and the administration of supplemental heparin suppressed the edema. CONCLUSIONS: We demonstrated that the degradation of the GCX induced by the anti-MHC class I antibody was suppressed by macrophage depletion. These results suggest that macrophages may play a key role in interstitial edema. Heparin inhibited both the degradation of the GCX and interstitial edema. This study's results may be extrapolated to develop an interventional strategy for inhibiting interstitial edema in various organs.


Asunto(s)
Células Endoteliales , Edema Pulmonar , Ratones , Animales , Masculino , Células Endoteliales/metabolismo , Sindecano-1/metabolismo , Sindecano-1/farmacología , Glicocálix/metabolismo , Edema Pulmonar/metabolismo , Heparina/metabolismo , Heparina/farmacología
2.
Nutrients ; 14(20)2022 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-36297099

RESUMEN

(1) Background: The disease-modifying mechanisms of high-dose intravenous vitamin C (HDIVC) in sepsis induced acute respiratory distress syndrome (ARDS) is unclear. (2) Methods: We performed a post hoc study of plasma biomarkers from subjects enrolled in the randomized placebo-controlled trial CITRIS-ALI. We explored the effects of HDIVC on cell-free DNA (cfDNA) and syndecan-1, surrogates for neutrophil extracellular trap (NET) formation and degradation of the endothelial glycocalyx, respectively. (3) Results: In 167 study subjects, baseline cfDNA levels in HDIVC (84 subjects) and placebo (83 subjects) were 2.18 ng/µL (SD 4.20 ng/µL) and 2.65 ng/µL (SD 3.87 ng/µL), respectively, p = 0.45. At 48-h, the cfDNA reduction was 1.02 ng/µL greater in HDIVC than placebo, p = 0.05. Mean baseline syndecan-1 levels in HDIVC and placebo were 9.49 ng/mL (SD 5.57 ng/mL) and 10.83 ng/mL (SD 5.95 ng/mL), respectively, p = 0.14. At 48 h, placebo subjects exhibited a 1.53 ng/mL (95% CI, 0.96 to 2.11) increase in syndecan-1 vs. 0.75 ng/mL (95% CI, 0.21 to 1.29, p = 0.05), in HDIVC subjects. (4) Conclusions: HDIVC infusion attenuated cell-free DNA and syndecan-1, biomarkers associated with sepsis-induced ARDS. Improvement of these biomarkers suggests amelioration of NETosis and shedding of the vascular endothelial glycocalyx, respectively.


Asunto(s)
Ácidos Nucleicos Libres de Células , Trampas Extracelulares , Síndrome de Dificultad Respiratoria , Sepsis , Humanos , Glicocálix , Sindecano-1/metabolismo , Sindecano-1/farmacología , Ácido Ascórbico/uso terapéutico , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/etiología , Vitaminas/uso terapéutico , Biomarcadores
3.
J Surg Res ; 251: 287-295, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32199337

RESUMEN

BACKGROUND: The endothelial glycocalyx (EG) is involved in critical regulatory mechanisms that maintain endothelial vascular integrity. We hypothesized that prolonged cardiopulmonary bypass (CPB) may be associated with EG degradation. We performed an analysis of soluble syndecan-1 levels in relation to duration of CPB, as well as factors associated with cell stress and damage, such as mitochondrial DNA (mtDNA) and inflammation. METHODS: Blood samples from subjects undergoing cardiac surgery with CPB (n = 54) were obtained before and during surgery, 4-8 h and 24 h after completion of CPB, and on postoperative day 4. Flow cytometry was used to determine subpopulations of white blood cells. Plasma levels of mtDNA were determined using quantitative polymerase chain reaction and plasma content of shed syndecan-1 was measured. To determine whether syndecan-1 was signaling white blood cells, the effect of recombinant syndecan-1 on mobilization of neutrophils from bone marrow was tested in mice. RESULTS: CPB is associated with increased mtDNA during surgery, increased syndecan-1 blood levels at 4-8 h, and increased white blood cell count at 4-8 h and 24 h. Correlation analysis revealed significant positive associations between time on CPB and syndecan-1 (rs = 0.488, P < 0.001) and level of syndecan-1 and neutrophil count (rs = 0.351, P = 0.038) at 4-8 h. Intravenous administration of recombinant syndecan-1 in mice resulted in a 2.5-fold increase in the number of circulating neutrophils, concurrent with decreased bone marrow neutrophil number. CONCLUSIONS: Longer duration of CPB is associated with increased plasma levels of soluble syndecan-1, a signal for EG degradation, which can induce neutrophil egress from the bone marrow. Development of therapy targeting EG shedding may be beneficial in patients with prolonged CPB.


Asunto(s)
Puente Cardiopulmonar/efectos adversos , Endotelio/ultraestructura , Glicocálix/fisiología , Tempo Operativo , Anciano , Animales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/patología , Puente Cardiopulmonar/métodos , ADN Mitocondrial/sangre , Femenino , Humanos , Interleucina-6/sangre , Recuento de Leucocitos , Masculino , Ratones , Persona de Mediana Edad , Neutrófilos/patología , Proteínas Recombinantes/farmacología , Sindecano-1/sangre , Sindecano-1/farmacología
4.
Cell Death Dis ; 9(11): 1119, 2018 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-30389911

RESUMEN

Syndecans, a family of cell surface heparan sulfate proteoglycans, regulate cell differentiation via binding of their heparan sulfate chains to growth factors and cytokines and play a role in tumor growth and progression, wound repair, and intestinal mucosal damage. However, the functional and mechanistic roles of syndecans in osteoclast differentiation and bone metabolism are yet unclear. Here, we demonstrated that post-translationally glycosylated ectodomains of syndecan-1 to 4 obtained from mammalian cells efficiently suppressed osteoclast differentiation compared to those obtained from Escherichia coli with no systems for glycosylation. A concomitant decrease in the expression of osteoclast markers such as nuclear factor of activated T cells 1 (NFATc1), c-Fos, and ATP6V0D2 was observed. In addition, heparan sulfate and selectively N-desulfated heparin derivatives with 2-O- and 6-O-sulfate groups and no anticoagulant activity in blood inhibited osteoclast differentiation. The inhibitory effects of syndecan ectodomains, heparan sulfate, and N-desulfated heparin derivatives on osteoclast differentiation were attributed to their direct binding to the macrophage-colony stimulating factor (M-CSF), resulting in the blocking of M-CSF-mediated downstream signals such as extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), p38, and Akt. Furthermore, mice injected with syndecan ectodomains, heparan sulfate, and N-desulfated heparin derivatives into periosteal regions of calvaria showed reduction in the formation of tartrate-resistant acid phosphatase (TRAP)-positive mature osteoclasts on the calvarial bone surface, thereby exhibiting decreased bone resorption. Together, these results revealed a novel role of heparan sulfate chains of syndecan ectodomains in the regulation of osteoclast differentiation.


Asunto(s)
Factor Estimulante de Colonias de Macrófagos/metabolismo , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Procesamiento Proteico-Postraduccional , Sindecano-1/farmacología , Sindecano-4/farmacología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fémur/citología , Fémur/metabolismo , Glicosilación , Heparina/análogos & derivados , Heparina/química , Heparina/farmacología , Humanos , Factor Estimulante de Colonias de Macrófagos/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Osteoclastos/citología , Osteoclastos/metabolismo , Osteogénesis/genética , Unión Proteica , Dominios Proteicos , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Sindecano-1/genética , Sindecano-1/metabolismo , Sindecano-4/genética , Sindecano-4/metabolismo , ATPasas de Translocación de Protón Vacuolares/genética , ATPasas de Translocación de Protón Vacuolares/metabolismo
5.
Am J Respir Crit Care Med ; 194(3): 333-44, 2016 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-26959387

RESUMEN

RATIONALE: Syndecan-1 is a cell surface heparan sulfate proteoglycan primarily expressed in the lung epithelium. Because the influenza virus is tropic to the airway epithelium, we investigated the role of syndecan-1 in influenza infection. OBJECTIVES: To determine the mechanism by which syndecan-1 regulates the lung mucosal response to influenza infection. METHODS: Wild-type (WT) and Sdc1(-/-) mice were infected with a H1N1 virus (PR8) as an experimental model of influenza infection. Human and murine airway epithelial cell cultures were also infected with PR8 to study the mechanism by which syndecan-1 regulates the inflammatory response. MEASUREMENT AND MAIN RESULTS: We found worsened outcomes and lung injury in Sdc1(-/-) mice compared with WT mice after influenza infection. Our data demonstrated that syndecan-1 suppresses bronchial epithelial apoptosis during influenza infection to limit widespread lung inflammation. Furthermore, we determined that syndecan-1 attenuated apoptosis by crosstalking with c-Met to potentiate its cytoprotective signals in airway epithelial cells during influenza infection. CONCLUSIONS: Our work shows that cell-associated syndecan-1 has an important role in regulating lung injury. Our findings demonstrate a novel mechanism in which cell membrane-associated syndecan-1 regulates the innate immune response to influenza infection by facilitating cytoprotective signals through c-Met signaling to limit bronchial epithelial apoptosis, thereby attenuating lung injury and inflammation.


Asunto(s)
Apoptosis/inmunología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Lesión Pulmonar/prevención & control , Infecciones por Orthomyxoviridae/inmunología , Proteínas Proto-Oncogénicas c-met/inmunología , Transducción de Señal/inmunología , Sindecano-1/farmacología , Animales , Modelos Animales de Enfermedad , Células Epiteliales/inmunología , Humanos , Inmunidad Innata/inmunología , Pulmón/inmunología , Lesión Pulmonar/inmunología , Ratones , Proteínas Proto-Oncogénicas c-met/genética , Sindecano-1/inmunología
6.
Free Radic Biol Med ; 50(9): 1075-80, 2011 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-21334435

RESUMEN

The extracellular matrix is a complex system that regulates cell function within a tissue. The antioxidant enzyme extracellular superoxide dismutase (EC-SOD) is bound to the matrix, and previous studies show that a lack of EC-SOD results in increased cardiac injury, fibrosis, and loss of cardiac function. This study tests the hypothesis that EC-SOD protects against cardiac fibrosis mechanistically by limiting oxidative stress and oxidant-induced shedding of syndecan-1 in the extracellular matrix. Wild-type and EC-SOD null mice were treated with a single dose of doxorubicin, 15 mg/kg, and evaluated on day 15. Serum and left-ventricle tissue were collected for biochemical assays, including Western blot, mRNA expression, and immunohistochemical staining for syndecan-1. The loss of EC-SOD and doxorubicin-induced oxidative injury led to increases in shed syndecan-1 in the serum, which originates from the endothelium of the vasculature. The shed syndecan-1 ectodomain induces proliferation of primary mouse cardiac fibroblasts. This study suggests that one mechanism by which EC-SOD protects the heart against cardiac fibrosis is the prevention of oxidative shedding of cardiovascular syndecan-1 and its subsequent induction of fibroblast proliferation. This study provides potential new targets for understanding and altering fibrosis progression in the heart.


Asunto(s)
Doxorrubicina/efectos adversos , Matriz Extracelular/enzimología , Fibroblastos/metabolismo , Superóxido Dismutasa/metabolismo , Sindecano-1/metabolismo , Sindecano-1/farmacología , Animales , Antioxidantes/metabolismo , Western Blotting , Técnicas de Cultivo de Célula , Proliferación Celular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/patología , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Fibrosis/prevención & control , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
7.
Antimicrob Agents Chemother ; 54(7): 2753-66, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20439611

RESUMEN

In the absence of a vaccine, there is an urgent need for the development of safe and effective topical microbicides to prevent the sexual transmission of human immunodeficiency virus type 1 (HIV-1). In this study, we proposed to develop a novel class of microbicides using syndecan as the antiviral agent. Specifically, we generated a soluble syndecan-Fc hybrid molecule by fusing the ectodomain of syndecan-1 to the Fc domain of a human IgG. We then tested the syndecan-Fc hybrid molecule for various in vitro microbicidal anti-HIV-1 properties. Remarkably, the syndecan-Fc hybrid molecule possesses multiple attractive microbicidal properties: (i) it blocks HIV-1 infection of primary targets including T cells, macrophages, and dendritic cells (DC); (ii) it exhibits a broad range of antiviral activity against primary HIV-1 isolates, multidrug resistant HIV-1 isolates, HIV-2, and simian immunodeficiency virus (SIV); (iii) it prevents transmigration of HIV-1 through human primary genital epithelial cells; (iv) it prevents HIV-1 transfer from dendritic cells to CD4(+) T cells; (v) it is potent when added 2 h prior to addition of HIV-1 to target cells; (vi) it is potent at a low pH; (vii) it blocks HIV-1 infectivity when diluted in genital fluids; and (viii) it prevents herpes simplex virus infection. The heparan sulfate chains of the syndecan-Fc hybrid molecule are absolutely required for HIV-1 neutralization. Several lines of evidence suggest that the highly conserved Arg298 in the V3 region of gp120 serves as the locus for the syndecan-Fc hybrid molecule neutralization. In conclusion, this study suggests that the syndecan-Fc hybrid molecule represents the prototype of a new generation of microbicidal agents that may have promise for HIV-1 prevention.


Asunto(s)
Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Fragmentos Fc de Inmunoglobulinas/metabolismo , Fragmentos Fc de Inmunoglobulinas/farmacología , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Sindecano-1/metabolismo , Sindecano-1/farmacología , Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/uso terapéutico , Línea Celular , Línea Celular Tumoral , Células Dendríticas/virología , Ensayo de Inmunoadsorción Enzimática , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Concentración de Iones de Hidrógeno , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Macrófagos/virología , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/uso terapéutico , Sindecano-1/genética , Sindecano-1/uso terapéutico , Linfocitos T/virología , Integración Viral/efectos de los fármacos
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