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In the general population with COVID-19, the male sex is an established risk factor for mortality, in part due to a more robust immune response to COVID-19 in women. Because patients on kidney function replacement therapy (KFRT) have an impaired immune response, especially kidney transplant recipients due to their use of immunosuppressants, we examined whether the male sex is still a risk factor for mortality among patients on KFRT with COVID-19. From the European Renal Association COVID-19 Database (ERACODA), we examined patients on KFRT with COVID-19 who presented between February 1st, 2020, and April 30th, 2021. 1204 kidney transplant recipients (male 62.0%, mean age 56.4 years) and 3206 dialysis patients (male 61.8%, mean age 67.7 years) were examined. Three-month mortality in kidney transplant recipients was 16.9% in males and 18.6% in females (p = 0.31) and in dialysis patients 27.1% in males and 21.9% in females (p = 0.001). The adjusted HR for the risk of 3-month mortality in males (vs females) was 0.89 (95% CI 65, 1.23, p = 0.49) in kidney transplant recipients and 1.33 (95% CI 1.13, 1.56, p = 0.001) in dialysis patients (pinteraction = 0.02). In a fully adjusted model, the aHR for the risk of 3-month mortality in kidney transplant recipients (vs. dialysis patients) was 1.39 (95% CI 1.02, 1.89, p = 0.04) in males and 2.04 (95% CI 1.40, 2.97, p < 0.001) in females (pinteraction = 0.02). In patients on KFRT with COVID-19, the male sex is not a risk factor for mortality among kidney transplant recipients but remains a risk factor among dialysis patients. The use of immunosuppressants in kidney transplant recipients, among other factors, may have narrowed the difference in the immune response to COVID-19 between men and women, and therefore reduced the sex difference in COVID-19 mortality risk.
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COVID-19 , Trasplante de Riñón , Humanos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Diálisis Renal , Trasplante de Riñón/efectos adversos , Caracteres Sexuales , Factores de Riesgo , Inmunosupresores/uso terapéutico , RiñónRESUMEN
BACKGROUND: Symptoms of anxiety are often unrecognized and untreated in dialysis patients. We investigated the diagnostic accuracy of two widely used screening tools for anxiety in hemodialysis patients. METHODS: For this cross-sectional validation study, chronic hemodialysis patients from eight dialysis centers in the Netherlands were included. The Beck Anxiety Inventory (BAI) and Hospital Anxiety and Depression Scale-Anxiety subscale (HADS-A) were validated by the Mini International Neuropsychiatric Inventory (MINI) diagnostic interview. Receiver operating characteristic curves were used to determine the optimal cut-off values. RESULTS: Of 65 participants, 13 (20%) were diagnosed with one or more anxiety disorders on the MINI, of which 5 were included in the analysis. ROC curves showed a good diagnostic accuracy of the BAI and HADS-A. The optimal cut-off value for the BAI was ≥13 (sensitivity 100%, specificity 85%) and for the HADS-A was ≥10 (sensitivity 80%, specificity 100%). CONCLUSIONS: Based on our limited data, both the BAI and the HADS-A seem to be valid screening instruments for anxiety in hemodialysis patients that can be used in routine dialysis care. The HADS-A consists of fewer items and showed fewer false-positive results than the BAI, which might make it more useful in clinical practice.
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OBJECTIVE: To investigate the impact of the coronavirus pandemic on mental health in hemodialysis patients, we assessed depression, anxiety and quality of life with valid mental health measures before and after the start of the pandemic. METHODS: Data were used from 121 hemodialysis patients from the ongoing prospective multicenter DIVERS-II study. COVID-19 related stress was measured with the Perceived Stress Scale - 10, depression with the Beck Depression Inventory - second edition (BDI-II)), anxiety with the Beck Anxiety Inventory (BAI) and quality of life with the Short Form - 12 (SF-12). Scores during the first and second COVID-19 wave in the Netherlands were compared to data prior to the pandemic with linear mixed models. RESULTS: No significant differences were found in BDI-II, BAI and SF-12 scores between before and during the pandemic. During the first wave, 33% of participants reported COVID-19 related stress and in the second wave 37%. These patients had higher stress levels (mean difference (MD) 4.7 (95%CI 1.5; 8.0), p = 0.005) and BDI-II scores (MD 4.9 (95%CI 0.7; 9.0), p = 0.021) and lower SF-12 mental component summary scores (MD -5.3 (95%CI -9.0, -1.6), p = 0.006) than patients who did not experienced COVID-19 stress. These differences were already present before the pandemic. CONCLUSION: The COVID-19 pandemic does not seem to influence mental health in hemodialysis patients. However, a substantial subgroup of patients with pre-existent mental health problems may be more susceptible to experience COVID-19 related stress.
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COVID-19 , Ansiedad/epidemiología , Ansiedad/psicología , COVID-19/epidemiología , Depresión/epidemiología , Depresión/psicología , Humanos , Pandemias , Estudios Prospectivos , Calidad de Vida , Diálisis Renal , SARS-CoV-2RESUMEN
BACKGROUND: Kidney transplant patients are at high risk for coronavirus disease 2019 (COVID-19)-related mortality. However, limited data are available on longer-term clinical, functional, and mental health outcomes in patients who survive COVID-19. METHODS: We analyzed data from adult kidney transplant patients in the European Renal Association COVID-19 Database who presented with COVID-19 between February 1, 2020, and January 31, 2021. RESULTS: We included 912 patients with a mean age of 56.7 (±13.7) y. 26.4% were not hospitalized, 57.5% were hospitalized without need for intensive care unit (ICU) admission, and 16.1% were hospitalized and admitted to the ICU. At 3 mo follow-up survival was 82.3% overall, and 98.8%, 84.2%, and 49.0%, respectively, in each group. At 3 mo follow-up biopsy-proven acute rejection, need for renal replacement therapy, and graft failure occurred in the overall group in 0.8%, 2.6%, and 1.8% respectively, and in 2.1%, 10.6%, and 10.6% of ICU-admitted patients, respectively. Of the surviving patients, 83.3% and 94.4% reached their pre-COVID-19 physician-reported functional and mental health status, respectively, within 3 mo. Of patients who had not yet reached their prior functional and mental health status, their treating physicians expected that 79.6% and 80.0%, respectively, still would do so within the coming year. ICU admission was independently associated with a low likelihood to reach prior functional and mental health status. CONCLUSIONS: In kidney transplant recipients alive at 3-mo follow-up, clinical, physician-reported functional, and mental health recovery was good for both nonhospitalized and hospitalized patients. Recovery was, however, less favorable for patients who had been admitted to the ICU.
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COVID-19 , Trasplante de Riñón , Adulto , Humanos , Unidades de Cuidados Intensivos , Trasplante de Riñón/efectos adversos , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Estudios Retrospectivos , SARS-CoV-2 , Receptores de TrasplantesRESUMEN
OBJECTIVE: To investigate the effectiveness of a guided internet-based self-help intervention for hemodialysis patients with depressive symptoms. METHOD: Chronic hemodialysis patients from nine Dutch hospitals with a depression score on the Beck Depression Inventory - second edition (BDI-II) of ≥10, were cluster-randomized into a five modules guided internet-based self-help problem solving therapy intervention or a parallel care-as-usual control group. Clusters were based on hemodialysis shift. The primary outcome depression was measured with the BDI-II. Analysis was performed with linear mixed models. RESULTS: A total of 190 hemodialysis patients were cluster-randomized to the intervention (n = 89) or control group (n = 101). Post-intervention measurement was completed by 127 patients (67%) and more than half of the patients (54%) completed the intervention. No significant differences were found on the BDI-II score between the groups (mean difference - 0.1, 95%CI -3.0; 2.7, p = 0.94). Per protocol sensitivity analysis showed comparable results. No significant differences in secondary outcomes were observed between groups. CONCLUSIONS: Guided internet-based self-help problem solving therapy for hemodialysis patients with depressive symptoms does not seem to be effective in reducing these symptoms as compared to usual care. Future research should examine how to best design content and accessibility of an intervention for depressive symptoms in hemodialysis patients. TRIAL REGISTRATION: Dutch Trial Register: Trial NL6648 (NTR6834) (prospectively registered 13th November 2017).
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Terapia Cognitivo-Conductual , Intervención basada en la Internet , Terapia Cognitivo-Conductual/métodos , Depresión/terapia , Humanos , Internet , Diálisis Renal , Resultado del TratamientoRESUMEN
INTRODUCTION: Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia and sepsis. Activated protein C (APC) has been implicated as an important anticoagulant and anti-inflammatory mediator. We here sought to determine the role of the anticoagulant and cytoprotective functions of endogenous APC during pneumonia and sepsis caused by S. pneumoniae. MATERIALS & METHODS: Mice were treated intraperitoneally with monoclonal antibody (mAb) 1609 (which inhibits both anticoagulant and cytoprotective effects of APC), mAb 1591 (which inhibits only the anticoagulant effects of APC) or a control antibody mAb prior to infection with viable S. pneumoniae via the airways (to induce pneumonia) or via the tail vein (to induce primary sepsis). Mice were analyzed at 24 or 48 hours after infection. RESULTS: mAb 1609, but not mAb 1591, enhanced the procoagulant response to pneumococcal pneumonia and sepsis, as indicated by elevated levels of thrombin-antithrombin complexes and D-dimer in plasma and lungs. mAb 1609 only modestly affected the fibrinolytic response (elevated plasma and lung levels of the fibrinolysis inhibitor plasminogen activator inhibitor type I during sepsis) and cytokine release (elevated plasma interleukin-6 concentrations during pneumonia). CONCLUSION: The cytoprotective effects of endogenous APC reduce activation of coagulation during murine pneumococcal pneumonia and sepsis.
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Anticoagulantes/metabolismo , Crioprotectores/metabolismo , Neumonía Neumocócica/metabolismo , Proteína C/metabolismo , Sepsis/metabolismo , Animales , Coagulación Sanguínea , Activación Enzimática , Masculino , Ratones , Ratones Endogámicos C57BL , Neumonía Neumocócica/sangre , Neumonía Neumocócica/complicaciones , Neumonía Neumocócica/diagnóstico , Sepsis/sangre , Sepsis/complicaciones , Sepsis/diagnóstico , Streptococcus pneumoniae/aislamiento & purificaciónRESUMEN
OBJECTIVES: Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia. In patients, thrombocytopenia is correlated with an adverse outcome of pneumonia. Platelets can modulate the host response to infection in several ways, that is, by facilitating clot formation, production of antimicrobial proteins, and interaction with neutrophils. We studied the effect of thrombocytopenia during murine pneumococcal pneumonia. DESIGN: Animal study. SETTING: University research laboratory. SUBJECTS: Mice. INTERVENTIONS: Pneumonia was induced by intranasal inoculation of S. pneumoniae. Platelets were depleted by anti-mouse thrombocyte serum; controls received nonimmunogenic serum. In separate studies, mice were treated with the platelet P2Y12 receptor inhibitor clopidogrel or placebo. MEASUREMENTS AND MAIN RESULTS: Thrombocytopenic mice (platelet counts < 1% of uninfected controls) showed a reduced survival during pneumococcal pneumonia (27% vs 75% among controls; p = 0.003), which was associated with higher bacterial loads in lungs, spleen, and blood. Thrombocytopenic mice showed enhanced coagulation activation (thrombin-antithrombin complexes) in plasma. Proinflammatory cytokine levels were higher in plasma but not in lungs of thrombocytopenic mice. Although clopidogrel treatment strongly prolonged the bleeding time, it did not impact on bacterial loads during pneumococcal pneumonia. CONCLUSIONS: Platelets play a protective role during pneumococcal pneumonia independent of their aggregation.
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Neumonía Neumocócica/inmunología , Streptococcus pneumoniae , Trombocitopenia/inmunología , Animales , Antitrombina III/metabolismo , Clopidogrel , Citocinas/metabolismo , Modelos Animales de Enfermedad , Ratones , Péptido Hidrolasas/metabolismo , Neumonía Neumocócica/epidemiología , Neumonía Neumocócica/patología , Antagonistas del Receptor Purinérgico P2Y/farmacología , Trombocitopenia/epidemiología , Trombocitopenia/patología , Ticlopidina/análogos & derivados , Ticlopidina/farmacologíaRESUMEN
Pneumococcal pneumonia is a frequent cause of gram-positive sepsis and has a high mortality. The endothelial protein C receptor (EPCR) has been implicated in both the activation of protein C (PC) and the anti-inflammatory actions of activated (A)PC. The aim of this study was to determine the role of the EPCR in murine pneumococcal pneumonia and sepsis. Wild-type (WT), EPCR knockout (KO) and Tie2-EPCR mice, which overexpress EPCR on the endothelium, were infected intranasally (pneumonia) or intravenously (sepsis) with viable Streptococcus pneumoniae and euthanised at 24 or 48 hours after initiation of the infection for analyses. Pneumonia did not alter constitutive EPCR expression on pulmonary endothelium but was associated with an influx of EPCR positive neutrophils into lung tissue. In pneumococcal pneumonia EPCR KO mice demonstrated diminished bacterial growth in the lungs and dissemination to spleen and liver, reduced neutrophil recruitment to the lungs and a mitigated inflammatory response. Moreover, EPCR KO mice displayed enhanced activation of coagulation in the early phase of disease. Correspondingly, in pneumococcal sepsis EPCR KO mice showed reduced bacterial growth in lung and liver and attenuated cytokine release. Conversely, EPCR-overexpressing mice displayed higher bacterial outgrowth in lung, blood, spleen and liver in pneumococcal sepsis. In conclusion, EPCR impairs antibacterial defense in both pneumococcal pneumonia and sepsis, which is associated with an enhanced pro-inflammatory response.
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Endotelio/metabolismo , Pulmón/patología , Neutrófilos/metabolismo , Neumonía Neumocócica/inmunología , Receptores de Superficie Celular/metabolismo , Sepsis/inmunología , Streptococcus pneumoniae/inmunología , Animales , Carga Bacteriana/genética , Movimiento Celular/genética , Células Cultivadas , Modelos Animales de Enfermedad , Receptor de Proteína C Endotelial , Endotelio/inmunología , Endotelio/microbiología , Femenino , Humanos , Inmunidad Innata/genética , Inflamación/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Ratones Transgénicos , Neutrófilos/inmunología , Neutrófilos/microbiología , Neumonía Neumocócica/microbiología , Receptores de Superficie Celular/genética , Streptococcus pneumoniae/crecimiento & desarrolloRESUMEN
BACKGROUND: The endothelial protein C receptor (EPCR) enhances anticoagulation by accelerating activation of protein C to activated protein C (APC) and mediates anti-inflammatory effects by facilitating APC-mediated signaling via protease activated receptor-1. We studied the role of EPCR in the host response during pneumonia-derived sepsis instigated by Burkholderia (B.) pseudomallei, the causative agent of melioidosis, a common form of community-acquired Gram-negative (pneumo)sepsis in South-East Asia. METHODOLOGY/PRINCIPAL FINDINGS: Soluble EPCR was measured in plasma of patients with septic culture-proven melioidosis and healthy controls. Experimental melioidosis was induced by intranasal inoculation of B. pseudomallei in wild-type (WT) mice and mice with either EPCR-overexpression (Tie2-EPCR) or EPCR-deficiency (EPCR(-/-)). Mice were sacrificed after 24, 48 or 72 hours. Organs and plasma were harvested to measure colony forming units, cellular influxes, cytokine levels and coagulation parameters. Plasma EPCR-levels were higher in melioidosis patients than in healthy controls and associated with an increased mortality. Tie2-EPCR mice demonstrated enhanced bacterial growth and dissemination to distant organs during experimental melioidosis, accompanied by increased lung damage, neutrophil influx and cytokine production, and attenuated coagulation activation. EPCR(-/-) mice had an unremarkable response to B. pseudomallei infection as compared to WT mice, except for a difference in coagulation activation in plasma. CONCLUSION/SIGNIFICANCE: Increased EPCR-levels correlate with accelerated mortality in patients with melioidosis. In mice, transgenic overexpression of EPCR aggravates outcome during Gram-negative pneumonia-derived sepsis caused by B. pseudomallei, while endogenous EPCR does not impact on the host response. These results add to a better understanding of the regulation of coagulation during severe (pneumo)sepsis.
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Antígenos CD/sangre , Melioidosis/patología , Neumonía Bacteriana/complicaciones , Receptores de Superficie Celular/sangre , Sepsis/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Asia , Asia Sudoriental , Modelos Animales de Enfermedad , Receptor de Proteína C Endotelial , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Análisis de Supervivencia , Adulto JovenRESUMEN
The protein C (PC) system is an important regulator of both coagulation and inflammation. Activated PC (APC), together with its receptor the endothelial protein C receptor (EPCR), has anticoagulant and anti-inflammatory properties. During tuberculosis (TB), a devastating chronic pulmonary disease caused by Mycobacterium (M.) tuberculosis, both a local inflammatory reaction characterised by the recruitment of mainly mononuclear cells and the formation of pulmonary granulomas as well as activation of coagulation occurs as part of the host immune response. We investigated the role of EPCR and APC in a mouse model of TBusing mice overexpressing EPCR (Tie2-EPCR), mice deficient for EPCR (EPCR-/-), mice treated with APC-inhibiting antibodies and mice overexpressing APC (APChigh) and compared them with wild-type (WT) mice. Blood and organs were harvested to quantify bacterial loads, cellular influxes, cytokines, histopathology and coagulation parameters. Additionally observation studies were performed. Lung EPCR expression was upregulated during experimental TB. No significant differences in bacterial growth were seen between WT and Tie2-EPCR mice. However, Tie2-EPCR mice had decreased pulmonary coagulation activation, displayed an increased influx of macrophages 2 and 6 weeks after infection, but no increase in other proinflammatory markers. On the other hand, in EPCR-/--mice coagulation activation was decreased 6 weeks post-infection, with little impact on other inflammation markers. APC-overexpression or treatment with anti-(A)PC antibodies displayed minimal effects during experimental TB. In conclusion, EPCR and APC play a limited role in the host response during experimental pulmonary TB.
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Antígenos CD/metabolismo , Glicoproteínas/metabolismo , Pulmón/metabolismo , Proteína C/metabolismo , Receptores de Superficie Celular/metabolismo , Tuberculosis Pulmonar/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Coagulación Sanguínea , Citocinas/metabolismo , Modelos Animales de Enfermedad , Receptor de Proteína C Endotelial , Femenino , Glicoproteínas/deficiencia , Glicoproteínas/genética , Humanos , Mediadores de Inflamación/metabolismo , Pulmón/inmunología , Pulmón/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Persona de Mediana Edad , Mycobacterium tuberculosis/patogenicidad , Regiones Promotoras Genéticas , Proteína C/genética , Receptor TIE-2/genética , Factores de Tiempo , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/genética , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Regulación hacia ArribaRESUMEN
The lectin-like domain of thrombomodulin (TM) plays an important regulatory role in sterile inflammatory conditions, but its role in severe Gram-positive infectious disease is unknown. Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. The aim of this study was to determine the role of the lectin-like domain of TM in murine pneumococcal pneumonia. Wild-type (WT) mice and mice lacking the lectin-like domain of TM (TM(LeD/LeD)) were infected intranasally with viable S. pneumoniae and either observed in a survival study or euthanised 6, 24 or 48 h after infection. TM(LeD/LeD) mice had a markedly better survival in pneumococcal pneumonia when compared with WT mice. At 48 h post-infection with S. pneumoniae, TM(LeD/LeD) mice had lower bacterial loads in blood and liver, and exhibited less pulmonary inflammation, as shown by having less lung histopathology, less neutrophil influx and lower cytokine and chemokine levels. Plasma levels of pro-inflammatory cytokines were also reduced in TM(LeD/LeD) mice after exposure to the infection. Deletion of the lectin-like domain of TM improves the host defence in pneumococcal pneumonia. The lectin-like domain of TM may have a differential role in response to Gram-positive or Gram-negative bacteria.
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Lectinas/química , Neumonía Neumocócica/inmunología , Trombomodulina/química , Animales , Carga Bacteriana , Coagulación Sanguínea , Lavado Broncoalveolar , Citocinas/sangre , Citocinas/inmunología , Modelos Animales de Enfermedad , Inflamación/inmunología , Hígado/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Neutrófilos/inmunología , Dominios y Motivos de Interacción de Proteínas , Sepsis/metabolismoRESUMEN
The complex biology of asthma compels the use of more relevant human allergens, such as house dust mite (HDM), to improve the translation of animal models into human asthma. LPS exposure is associated with aggravations of asthma, but the mechanisms remain unclear. Here, we studied the effects of increasing LPS doses on HDM-evoked allergic lung inflammation. To this end, mice were intranasally sensitized and challenged with HDM with or without increasing doses of LPS (0.001-10 µg). LPS dose-dependently inhibited HDM-induced eosinophil recruitment into the lungs and mucus production in the airways. LPS attenuated the production of Th2 cytokines (IL-4, IL-5, IL-10, and IL-13) in HDM-challenged lungs, while enhancing the HDM-induced release of IL-17, IL-33, IFN-γ, and TNF-α. The shift toward a Th1 inflammatory response was further illustrated by predominant neutrophilic lung inflammation after LPS administration at higher doses. LPS did not influence HDM-induced plasma IgE concentrations. Although LPS did not significantly affect the activation of coagulation or complement in HDM-challenged lungs, it reduced HDM-initiated endothelial cell activation. This study is the first to provide insights into the effects of LPS in an allergic lung inflammation model making use of a clinically relevant allergen without a systemic adjuvant, revealing that LPS dose-dependently inhibits HDM-induced pulmonary Th2 responses.
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Antígenos Dermatofagoides/inmunología , Lipopolisacáridos/farmacología , Pulmón/inmunología , Neumonía/inmunología , Pyroglyphidae/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Animales , Asma/inmunología , Activación de Complemento/inmunología , Citocinas/inmunología , Modelos Animales de Enfermedad , Células Endoteliales/inmunología , Eosinófilos/inmunología , Inmunoglobulina E/inmunología , Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos C57BL , Moco/inmunología , Mucosa Respiratoria/inmunología , Células TH1/inmunologíaRESUMEN
INTRODUCTION: Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia. Protease-activated receptor-1 (PAR-1) is expressed by multiple cell types present in the lungs and can be activated by various proteases generated during acute inflammation. The cellular effect of PAR-1 activation partially depends on the specific protease involved. We here determined the role of PAR-1 in the host response during murine pneumococcal pneumonia. METHODS: Wild-type (WT) and PAR-1 knockout (KO) mice were infected intranasally with viable S. pneumoniae and observed in a survival study or euthanized at 6, 24 or 48 hours of infection. RESULTS: PAR-1 KO mice had a better survival early after infection compared to WT mice. Moreover, PAR-1 KO mice had lower bacterial loads in lungs and blood at 24 hours and in spleen and liver at 48 hours after infection. This favorable response was accompanied by lower lung histopathology scores and less neutrophil influx in PAR-1 KO mice. CONCLUSION: PAR-1 impairs host defense during murine pneumococcal pneumonia.
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Neumonía Neumocócica/inmunología , Receptor PAR-1/fisiología , Animales , Quimiocinas/sangre , Citocinas/sangre , Inmunidad/fisiología , Inflamación/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila/fisiología , Neumonía Neumocócica/mortalidad , Neumonía Neumocócica/fisiopatologíaRESUMEN
CCAAT/enhancer-binding protein δ (C/EBPδ) recently emerged as an essential player in the inflammatory response to bacterial infections. C/EBPδ levels increase rapidly after a proinflammatory stimulus, and increasing C/EBPδ levels seem to be indispensable for amplification of the inflammatory response. Here we aimed to elucidate the role of C/EBPδ in host defense in community-acquired pneumococcal pneumonia. We show that C/EBPδ(-/-) mice are relatively resistant to pneumococcal pneumonia, as indicated by delayed and reduced mortality, diminished outgrowth of pneumococci in lungs, and reduced dissemination of the infection. Moreover, expression of platelet-activating factor receptor (PAFR), which is known to potentiate bacterial translocation of gram-positive bacteria, was significantly reduced during infection in C/EBPδ(-/-) mice compared with WT controls. Importantly, cell stimulation experiments revealed that C/EBPδ potentiates PAFR expression induced by lipoteichoic acid and pneumococci. Thus, C/EBPδ exaggerates bacterial dissemination during Streptococcus pneumoniae-induced pulmonary infection, suggesting an important role for PAFR-dependent bacterial translocation.
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Proteína delta de Unión al Potenciador CCAAT/inmunología , Regulación de la Expresión Génica/fisiología , Glicoproteínas de Membrana Plaquetaria/metabolismo , Neumonía Neumocócica/inmunología , Receptores Acoplados a Proteínas G/metabolismo , Animales , Western Blotting , Proteína delta de Unión al Potenciador CCAAT/genética , Proteína delta de Unión al Potenciador CCAAT/metabolismo , Línea Celular , Ensayo de Inmunoadsorción Enzimática , Técnicas Histológicas , Humanos , Luciferasas , Pulmón/microbiología , Pulmón/patología , Ratones , Ratones Noqueados , Permeabilidad , Neumonía Neumocócica/microbiología , Reacción en Cadena en Tiempo Real de la Polimerasa , Estadísticas no ParamétricasRESUMEN
In severe infection and sepsis, activation of coagulation frequently occurs, which contributes to the development of multiple organ dysfunction. Factor V Leiden is a relatively common mutation resulting in a mild prohemostatic state and consequently with an increased tendency to develop thrombosis. Hypothetically, patients with factor V Leiden may suffer from more severe coagulopathy in cases of severe infection or sepsis. Aggravation of the procoagulant state in sepsis may subsequently result in more severe organ dysfunction and an increased risk of death. In this article we review the experimental and clinical evidence regarding the relationship between the presence of a factor V Leiden mutation and the incidence and outcome of sepsis.
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Factor V/genética , Infecciones/genética , Mutación , Sepsis/genética , Animales , Humanos , Infecciones/sangre , Ratones , Sepsis/sangre , Trombofilia/sangre , Trombofilia/genética , Trombofilia/microbiologíaRESUMEN
Recombinant human activated protein C (APC), which has both anticoagulant and anti-inflammatory properties, improves survival of patients with severe sepsis. This beneficial effect is especially apparent in patients with pneumococcal pneumonia. Earlier treatment with APC in sepsis has been associated with a better therapeutic response as compared to later treatment. In a mouse model it was recently confirmed that recombinant murine (rm-)APC decreases coagulation activation and improves survival in pneumococcal pneumonia; however, APC did not impact on the inflammatory response. The aim of this study was to determine the effect of APC treatment instigated early in infection on activation of coagulation and inflammation after induction of pneumococcal pneumonia. Mice were infected intranasally with viable S. pneumoniae . Mice were treated with rm-APC (125 µg) or vehicle intraperitoneally 12 hours after infection and were sacrificed after 20 hours, after which blood and organs were harvested for determination of bacterial outgrowth, coagulation activation and inflammatory markers. In this early treatment model, rm-APC treatment inhibited pulmonary and systemic activation of coagulation as reflected by lower levels of thrombin-antithrombin complexes and D-dimer. Moreover, rm-APC reduced the levels of a large number of cytokines and chemokines in the lung. When administered early in pneumococcal pneumonia, rm-APC inhibits systemic and pulmonary activation of coagulation and moreover exerts various anti-inflammatory effects in the lung.
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Pulmón/efectos de los fármacos , Neumonía Neumocócica/inmunología , Proteína C/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Streptococcus pneumoniae/inmunología , Animales , Antiinflamatorios/administración & dosificación , Antitrombina III/metabolismo , Biomarcadores/metabolismo , Coagulación Sanguínea/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Humanos , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Péptido Hidrolasas/metabolismo , Neumonía Neumocócica/sangre , Streptococcus pneumoniae/crecimiento & desarrollo , Streptococcus pneumoniae/patogenicidadRESUMEN
BACKGROUND: Streptococcus pneumoniae is the most frequently isolated pathogen responsible for community-acquired pneumonia. Osteopontin is involved in inflammation during both innate and adaptive immunity. METHODS: To determine the role of osteopontin in the host response during pneumococcal pneumonia, osteopontin knockout (KO) and normal wild-type (WT) mice were intranasally infected with viable S. pneumoniae. RESULTS: Pneumonia was associated with a rapid increase in pulmonary osteopontin concentrations in WT mice from 6 h onward. Osteopontin KO mice showed a prolonged survival relative to WT mice, which was accompanied by diminished pulmonary bacterial growth and reduced dissemination to distant body sites. In addition, at 48 h after infection pulmonary inflammation was decreased in osteopontin KO mice as reflected by lower inflammation scores and reduced chemokine concentrations. In contrast to pneumococcal pneumonia, osteopontin deficiency did not influence bacterial growth in primary pneumococcal sepsis induced by direct intravenous infection, suggesting that the detrimental effect of osteopontin on antibacterial defense during pneumonia primarily is exerted in the pulmonary compartment. Moreover, recombinant osteopontin stabilized S. pneumoniae viability in vitro. CONCLUSIONS: These results suggest that the pneumococcus misuses osteopontin in the airways for optimal growth and to cause invasive disease after entering the lower airways.
Asunto(s)
Osteopontina/inmunología , Neumonía Neumocócica/inmunología , Streptococcus pneumoniae/inmunología , Animales , Citocinas/análisis , Interleucinas/análisis , Estimación de Kaplan-Meier , Pulmón/microbiología , Pulmón/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteopontina/análisis , Osteopontina/genética , Fagocitosis , Neumonía Neumocócica/fisiopatologíaRESUMEN
Influenza accounts for 5-10% of community-acquired pneumonia cases, and is a major cause of mortality. Sterile and bacterial lung injury are associated with procoagulant and inflammatory derangements in the lungs and down-regulation of the protein C (PC) pathway has been correlated with disease severity and mortality in severe bacterial pneumonia and sepsis. In addition, during lethal influenza pneumonia, pulmonary and systemic coagulation are activated, which can be attenuated by the administration of recombinant activated (A) PC. We here determined the role of endogenous PC in lethal H1N1 influenza A infection. Male C57BL/6 mice pretreated with an inhibitory monoclonal antibody directed against murine PC or a control antibody were intranasally infected with a lethal dose of a mouse-adapted H1N1 influenza A strain. Mice were killed at 48 or 96 hours after infection, after which lungs and bronchoalveolar lavage fluid were harvested, or observed for up to 9 days. Anti-PC antibody treatment aggravated pulmonary activation of coagulation as compared with control antibody treatment, as reflected by increased lung concentrations of thrombin-antithrombin complexes and fibrin degradation products, as well as intravascular thrombus formation. Anti-PC antibody treatment aggravated lung histopathology, but lowered bronchoalveolar neutrophil influx and total protein levels, and delayed mortality. In conclusion, endogenous PC has strong effects on the host response to lethal influenza A infection, inhibiting pulmonary coagulopathy and inflammation on the one hand, but facilitating neutrophil influx and protein leak and accelerating mortality on the other hand.
Asunto(s)
Coagulación Sanguínea , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Lesión Pulmonar/virología , Pulmón/virología , Infecciones por Orthomyxoviridae/virología , Neumonía Viral/virología , Proteína C/metabolismo , Trombosis/virología , Células Epiteliales Alveolares/inmunología , Células Epiteliales Alveolares/virología , Animales , Anticuerpos Monoclonales/administración & dosificación , Antitrombina III/metabolismo , Líquido del Lavado Bronquioalveolar/química , Modelos Animales de Enfermedad , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Inyecciones Intraperitoneales , Pulmón/irrigación sanguínea , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Lesión Pulmonar/sangre , Lesión Pulmonar/inmunología , Lesión Pulmonar/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila , Infecciones por Orthomyxoviridae/sangre , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/patología , Péptido Hidrolasas/metabolismo , Neumonía Viral/sangre , Neumonía Viral/inmunología , Neumonía Viral/patología , Proteína C/inmunología , Trombosis/sangre , Trombosis/inmunología , Trombosis/patología , Factores de Tiempo , Carga ViralRESUMEN
Patients with acute lung injury or respiratory distress syndrome often require supplemental oxygen to maintain tissue oxygenation; however, this treatment can cause or worsen lung inflammation. CD44 is a transmembrane adhesion molecule that is present on a wide variety of cell types, including leukocytes and parenchymal cells, and is an important player in leukocyte trafficking. The aim of this study was to determine the role of CD44 during hyperoxia-induced (> 95% oxygen) acute lung injury. Whereas all wild-type mice survived the 72-hour observation period, 37.5% of CD44 knockout (KO) mice died. CD44 deficiency was associated with a profound influx of neutrophils into the bronchoalveolar space, in the presence of similar or even lower neutrophil numbers in lung parenchyma, suggesting that CD44 is important for containing neutrophils in the pulmonary interstitium during hyperoxia. In addition, CD44 deficiency resulted in increased IL-6 and keratinocyte-derived chemokine release into bronchoalveolar lavage fluid (BALF). CD44 KO mice further displayed evidence for increased vascular leak and injury of type II respiratory epithelial cells. CD44 protected against bronchial epithelial cell death, as shown by increased epithelial cell necrosis and a trend toward increased BALF nucleosome levels in CD44 KO mice. CD44 can bind and internalize hyaluronic acid (HA), which acts proinflammatory. Concentrations of HA increased in BALF from CD44 KO but not wild-type mice during hyperoxia. These data suggest that CD44 protects against hyperoxia-induced lung injury and mortality by a mechanism that at least in part relies on its ability to clear HA from the bronchoalveolar space.
Asunto(s)
Receptores de Hialuranos/genética , Receptores de Hialuranos/fisiología , Hiperoxia , Lesión Pulmonar/metabolismo , Pulmón/metabolismo , Animales , Líquido del Lavado Bronquioalveolar , Ácido Hialurónico/química , Inflamación , Interleucina-6/metabolismo , Leucocitos/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/citología , Neutrófilos/metabolismoRESUMEN
BACKGROUND: Recombinant human activated protein C (APC) improves survival of patients with severe sepsis; this beneficial effect is especially apparent in patients with pneumococcal pneumonia. The aim of this study was to determine the effect of APC treatment initiated after induction of pneumococcal pneumonia on pulmonary coagulation, inflammation, and survival, with or without concurrent antibiotic therapy. METHODS: Mice were infected intranasally with viable Streptococcus pneumoniae and were treated intraperitoneally after 24 h of infection with vehicle, recombinant mouse (rm) APC (125 µg), ceftriaxone (500 µg), or rm-APC plus ceftriaxone. Treatment with rm-APC or vehicle was repeated every 8 h for a maximum of 96 h. Animals were either killed 48 h after infection or were monitored in a survival study (with an extra dose of ceftriaxone given after 72 h). RESULTS: Rm-APC treatment inhibited pulmonary activation of coagulation, as reflected by lower levels of thrombin-antithrombin complexes and D-dimer. Rm-APC did not affect the pulmonary levels of 55 inflammatory mediators in the context of antibiotic therapy. Rm-APC added to ceftriaxone markedly improved survival, compared with ceftriaxone treatment alone. CONCLUSIONS: Rm-APC inhibits pulmonary activation of coagulation and, when added to antibiotic therapy, improves survival in murine pneumococcal pneumonia.