RESUMEN
Premature infants, especially those with bronchopulmonary dysplasia (BPD), develop recurrent severe respiratory viral illnesses. We have shown that hyperoxic exposure of immature mice, a model of BPD, increases lung IL-12-producing Clec9a+ CD103+ dendritic cells (DCs), pro-inflammatory responses, and airway hyperreactivity following rhinovirus (RV) infection. However, the requirement for CD103+ DCs and Clec9a, a DAMP receptor that binds necrotic cell cytoskeletal filamentous actin (F-actin), for RV-induced inflammatory responses has not been demonstrated. To test this, 2-day-old C57BL/6J, CD103+ DC-deficient Batf3-/- or Clec9agfp-/- mice were exposed to normoxia or hyperoxia for 14 days. Also, selected mice were treated with neutralizing antibody against CD103. Immediately after hyperoxia, the mice were inoculated with RV intranasally. We found that compared with wild-type mice, hyperoxia-exposed Batf3-/- mice showed reduced levels of IL-12p40, IFN-γ, and TNF-α, fewer IFN-γ-producing CD4+ T cells, and decreased airway responsiveness following RV infection. Similar effects were observed in anti-CD103-treated and Clec9agfp-/- mice. Furthermore, hyperoxia increased airway dead cell number and extracellular F-actin levels. Finally, studies in preterm infants with respiratory distress syndrome showed that tracheal aspirate CLEC9A expression positively correlated with IL12B expression, consistent with the notion that CLEC9A+ cells are responsible for IL-12 production in humans as well as mice. We conclude that CD103+ DCs and Clec9a are required for hyperoxia-induced pro-inflammatory responses to RV infection. In premature infants, Clec9a-mediated activation of CD103+ DCs may promote pro-inflammatory responses to viral infection, thereby driving respiratory morbidity.
Asunto(s)
Antígenos CD/metabolismo , Células Dendríticas/inmunología , Hiperoxia/fisiopatología , Cadenas alfa de Integrinas/metabolismo , Lectinas Tipo C/fisiología , Pulmón/inmunología , Neumonía/inmunología , Receptores Inmunológicos/fisiología , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Animales , Animales Recién Nacidos , Antígenos CD/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/fisiología , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro/inmunología , Cadenas alfa de Integrinas/genética , Pulmón/metabolismo , Pulmón/patología , Pulmón/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Picornaviridae/complicaciones , Infecciones por Picornaviridae/virología , Neumonía/virología , Proteínas Represoras/fisiología , Síndrome de Dificultad Respiratoria del Recién Nacido/metabolismo , Síndrome de Dificultad Respiratoria del Recién Nacido/patología , Rhinovirus/aislamiento & purificaciónRESUMEN
This study aimed to explore the clinical efficacy of pulmonary surfactant combined with high-frequency oscillatory ventilation (HFOV) on neonatal respiratory distress syndrome (NRDS) and its influence on immune function in children. Children admitted to our hospital from March 2017 to March 2019 who received HFOV combined with pulmonary surfactant therapy as a research group. Sixty-two children received conventional nasal continuous positive pressure combined with pulmonary surfactant therapy as a control group. Clinical efficacy, blood gas and immune function of patients were compared between the two groups. The clinical efficacy of the research group was better than that of the control group (P< 0.050). PaO2 and PaO2/FiO2 were both higher after treatment (P< 0.050). CD3+ and NK cells in the research group were higher than those in the control group, while CD8+ cells and ICAM-1 were lower than those in the control group (P< 0.050). CD3+, CD4+ and NK cells decreased in both groups after treatment, while CD8+ cells and ICAM-1 increased (P< 0.050). HFOV combined with pulmonary surfactant has significant clinical efficacy and high safety on NRDS, and has a certain protective effect on children's immune function. Hence, it is worthy of being the first choice for the clinical treatment of NRDS in the future.
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Antígenos CD/metabolismo , Ventilación de Alta Frecuencia , Molécula 1 de Adhesión Intercelular/metabolismo , Surfactantes Pulmonares/uso terapéutico , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Síndrome de Dificultad Respiratoria del Recién Nacido/terapia , Análisis de los Gases de la Sangre , Niño , Femenino , Humanos , Incidencia , Recién Nacido , Subgrupos Linfocitarios/inmunología , Masculino , Pronóstico , Surfactantes Pulmonares/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND Acute respiratory distress syndrome (ARDS) is a sudden and serious disease with increasing morbidity and mortality rates. Phosphodiesterase 4 (PDE4) is a novel target for inflammatory disease, and ibudilast (IBU), a PDE4 inhibitor, inhibits inflammatory response. Our study investigated the effect of IBU on the pathogenesis of neonatal ARDS and the underlying mechanism related to it. MATERIAL AND METHODS Western blotting was performed to analyze the expression levels of PDE4, CXCR4, SDF-1, CXCR5, CXCL1, inflammatory cytokines, and proteins related to cell apoptosis. Hematoxylin-eosin staining was performed to observe the pathological morphology of lung tissue. Pulmonary edema score was used to assess the degree of lung water accumulation after pulmonary injury. Enzyme-linked immunosorbent assay (ELISA) was used to assess levels of inï¬ammatory factors (TNF-alpha, IL-1ß, IL-6, and MCP-1) in serum. TUNEL assay was used to detect apoptotic cells. RESULTS Increased expression of PDE4 was observed in an LPS-induced neonatal ARDS mouse model, and IBU ameliorated LPS-induced pathological manifestations and pulmonary edema in lung tissue. In addition, IBU attenuated the secretion of inflammatory cytokines by inactivating the chemokine axis in the LPS-induced neonatal ARDS mouse model. Finally, IBU significantly reduced LPS-induced cell apoptosis in lung tissue. CONCLUSIONS IBU, a PDE4 inhibitor, protected against ARDS by interfering with pulmonary inflammation and apoptosis. Our findings provide a novel and promising strategy to regulate pulmonary inflammation in ARDS.
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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Inflamación/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 4/farmacología , Piridinas/farmacología , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Líquido del Lavado Bronquioalveolar , Modelos Animales de Enfermedad , Humanos , Inflamación/diagnóstico , Inflamación/inmunología , Inflamación/patología , Inyecciones Intraperitoneales , Lipopolisacáridos/inmunología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Ratones , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Piridinas/uso terapéutico , Síndrome de Dificultad Respiratoria del Recién Nacido/diagnóstico , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Síndrome de Dificultad Respiratoria del Recién Nacido/patología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunologíaRESUMEN
INTRODUCTION: Preeclampsia complicates about 10-17 % of pregnancies with antiphospholipid syndrome (APS). It is often severe and might occur sometimes at early gestation. The development of preeclampsia before fetal viability is a huge challenge for obstetricians and demands an intensive discussion regarding the therapeutical options. PATIENTS AND METHODS: We retrospectively reviewed the data of 7 women with primary APS who developed preeclampsia before 24 weeks of gestation. Plasma exchange had been performed in four of the cases and two women received corticosteroids. One of the women had received 20 mg of pravastatin daily, starting at 18 weeks of gestation. Neonatal outcome was: live birth in four cases and IUFD in three cases. The main pediatric complications were noted in a 28-week-old premature born boy, who developed severe IRDS and thrombocytopenia. At the present time, the boy continues to have a retarded status. DISCUSSION: This retrospective analysis revealed that women with APS can develop severe preeclampsia even before 20 weeks of gestation. Several management options for prolongation of pregnancy such as plasma exchange, pravastatin, LMHW, hydroxychloroquine/HCQ, or TNF-alpha blocker should be discussed with the patients. Optimal management of preeclampsia before 24 weeks of gestation usually depends on weighing the maternal and fetal complications from expectant management with prolongation of pregnancy versus the predominant fetal and neonatal risks of extreme prematurity from "aggressive" management with immediate delivery.
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Síndrome Antifosfolípido/complicaciones , Preeclampsia/inmunología , Nacimiento Prematuro/inmunología , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Adulto , Síndrome Antifosfolípido/inmunología , Síndrome Antifosfolípido/terapia , Femenino , Viabilidad Fetal/efectos de los fármacos , Viabilidad Fetal/inmunología , Edad Gestacional , Heparina de Bajo-Peso-Molecular/administración & dosificación , Humanos , Hidroxicloroquina/administración & dosificación , Recien Nacido Prematuro , Intercambio Plasmático , Pravastatina/administración & dosificación , Preeclampsia/diagnóstico , Preeclampsia/terapia , Embarazo , Primer Trimestre del Embarazo , Segundo Trimestre del Embarazo , Nacimiento Prematuro/prevención & control , Síndrome de Dificultad Respiratoria del Recién Nacido/prevención & control , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
BACKGROUND Neonatal acute respiratory distress syndrome (ARDS) is a common clinical syndrome caused by lung immaturity and the abnormal synthesis of pulmonary surfactant in preterm newborns, and it has high morbidity and mortality rates. The present study investigated the roles of interleukin-37 (IL-37) in the pathogenesis of neonatal ARDS and the underlying biochemical mechanism. MATERIAL AND METHODS We used 6-day-old neonatal C57BL/6 mice to establish the ARDS model. Inflammatory cytokines levels were measured with enzyme-linked immunosorbent assay (ELISA) Kits. The pathological morphology of lung tissues was observed by hematoxylin-eosin (HE) staining. The expression levels of proteins were assessed by Western blotting and apoptotic cells were detected via TUNEL assay. Further, the expression of nucleotide-bound oligomerization domain (Nod)-like receptor P3 (NLRP3) was detected with immunohistochemistry and Western blotting. RESULTS IL-37 attenuated lipopolysaccharide (LPS)-induced cell apoptosis and excessive inflammatory cytokines levels, including IL-1ß, IL-8, TNF-alpha, and MCP-1, and ameliorated lung pathological manifestations in an LPS-induced neonatal ARDS model. Moreover, IL-37 suppressed the abnormal expression of proteins related to the CXCR4/SDF-1 chemokine axis and NLRP3 inflammasome pathway. CONCLUSIONS The present results suggest that IL-37 protect against LPS-induced lung injury through inhibition of inflammation and apoptosis in lung tissue in an LPS-induced neonatal ARDS model. Hence, IL-37 may be considered as a potential therapeutic agent for neonatal ARDS.
Asunto(s)
Apoptosis/efectos de los fármacos , Inflamación/tratamiento farmacológico , Interleucina-1/farmacología , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Animales , Animales Recién Nacidos , Apoptosis/inmunología , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Inflamasomas/antagonistas & inhibidores , Inflamasomas/metabolismo , Inflamación/inmunología , Interleucina-1/uso terapéutico , Lipopolisacáridos/inmunología , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunologíaRESUMEN
OBJECTIVE: Micro ribonucleic acids (miRNAs) are crucial to post-transcriptional regulation of the gene expression. Whether miR-26a affects respiratory distress syndrome (RDS) in neonatal rats through the Wnt/ß-catenin signaling pathway was investigated in this study. PATIENTS AND METHODS: The neonatal rat model of RDS was established, and the expressions of miR-26a and glycogen synthase kinase-3ß (GSK-3ß) in RDS in neonatal rats and their correlation were analyzed. The cascade relationship between miR-26a and the Wnt/ß-catenin signaling pathway and the influence of miR-26a on the expression of inflammatory cytokines were subsequently verified. Finally, the influences of miR-26a on the expressions of important markers, receptor for advanced glycation endproducts (RAGE), high mobility group box 1 (HMGB1), and plasminogen activator inhibitor-1 (PAI-1), through the Wnt/ß-catenin signaling pathway were analyzed. RESULTS: Compared with those in normal tissues, the expression of miR-26a in lung tissues of neonatal rats with RDS was significantly decreased (p<0.05), while the expression of GSK-3ß messenger RNAs (mRNAs) was notably increased (p<0.01), and the GSK-3ß expression was negatively correlated with the miR-26a expression (r=-0.6693, p=0.0064). In addition, miR-26a mimics significantly inhibited the GSK-3ß protein expression and activated the Wnt/ß-catenin signaling pathway. Moreover, miR-26a could reduce the expressions of tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and IL-6, as well as RAGE, HMGB1, and PAI-1. CONCLUSIONS: MiR-26a can affect inflammatory responses and markers through the Wnt/ß-catenin signaling pathway in neonatal rats with RDS.
Asunto(s)
Citocinas/metabolismo , MicroARNs/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Vía de Señalización Wnt , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Proteína HMGB1/genética , Inhibidor 1 de Activador Plasminogénico/genética , Ratas , Receptor para Productos Finales de Glicación Avanzada/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunologíaRESUMEN
Acute respiratory distress syndrome (ARDS) is a life-threatening illness characterized by a complex pathophysiology, involving not only the respiratory system but also nonpulmonary distal organs. Although advances in the management of ARDS have led to a distinct improvement in ARDS-related mortality, ARDS is still a life-threatening respiratory condition with long-term consequences. A better understanding of the pathophysiology of this condition will allow us to create a personalized treatment strategy for improving clinical outcomes. In this article, we present a general overview p38 mitogen-activated protein kinase (p38MAPK) and recent advances in understanding its functions. We consider the potential of the pharmacological targeting of p38MAPK pathways to treat ARDS.
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Humanos , Síndrome de Dificultad Respiratoria del Recién Nacido/fisiopatología , Mediadores de Inflamación/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Proteínas Quinasas p38 Activadas por Mitógenos/uso terapéutico , Inflamación/inmunología , Inflamación/metabolismoRESUMEN
Ventilator-induced lung injury is well recognized, and appropriate arterial saturation target is unknown, so gentle modes of ventilation and minimizing oxidative stress have been well studied. Our objective was to analyze any association between the oxygen levels at blood sampling and plasma levels of the interleukins IL-6, IL-1ß, IL-10, and IL-8 and TNF-α in preterm newborns under mechanical ventilation (MV) in their first two days. Methods. Prospective cohort including neonates with severe respiratory distress. Blood samples were collected right before and 2 hours after invasive MV. For analysis purposes, newborns were separated according to oxygen requirement: low oxygen (≤30%) and high oxygen (>30%) groups. Interleukins were measured using a commercially available kit. Results. 20 neonates (gestational age 32.2 ± 3 weeks) were evaluated. Median O2 saturation levels pre-MV were not different in both oxygen groups. In the high oxygen group, IL-6, IL-8, and TNF-α plasma levels increased significantly after two hours under MV. Conclusions. Despite the small sample studied, data showed that there is a relationship between VILI, proinflammatory cytokines, and oxygen-induced lung injury, but a study considering oxidative marker measurements is needed. It seems that less oxygen may keep safer saturation targets playing a less harmful role.
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Estrés Oxidativo , Oxígeno/fisiología , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Lesión Pulmonar Inducida por Ventilación Mecánica/inmunología , Estudios de Cohortes , Citocinas/sangre , Citocinas/metabolismo , Femenino , Humanos , Recién Nacido , Mediadores de Inflamación/metabolismo , Pulmón/metabolismo , Pulmón/patología , Masculino , Estudios Prospectivos , Respiración ArtificialRESUMEN
CHARGE (coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, and ear anomalies/deafness) syndrome is a rare genetic disorder caused by CHD7 mutation and is related to immunodeficiency. A 6-month-old girl with right lung agenesis, congenital heart defects, and ear anomalies developed repeated and serious respiratory infection for a short period. She was clinically diagnosed with typical CHARGE syndrome with severe combined immunodeficiency (T-, B+, NK-); however, CHD7 mutation was not detected. Disseminated BCG infection did not resolve despite administration of anti-tuberculosis drugs and intravenous immune globulins, and she subsequently died of acute respiratory distress syndrome. Pediatr Pulmonol. 2017;52:E4-E6. © 2016 Wiley Periodicals, Inc.
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Adyuvantes Inmunológicos/efectos adversos , Vacuna BCG/efectos adversos , Síndrome CHARGE/complicaciones , Síndrome de Dificultad Respiratoria del Recién Nacido/etiología , Inmunodeficiencia Combinada Grave/inmunología , Tuberculosis Pulmonar/etiología , Anomalías Múltiples/diagnóstico por imagen , Resultado Fatal , Femenino , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/diagnóstico por imagen , Humanos , Lactante , Pulmón/anomalías , Pulmón/diagnóstico por imagen , Enfermedades Pulmonares/complicaciones , Enfermedades Pulmonares/diagnóstico por imagen , Mutación , Mycobacterium bovis , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Inmunodeficiencia Combinada Grave/complicaciones , Tomografía Computarizada por Rayos X , Tuberculosis Pulmonar/diagnóstico por imagen , Tuberculosis Pulmonar/inmunologíaAsunto(s)
Antibacterianos/uso terapéutico , Proteína C-Reactiva/inmunología , Gentamicinas/uso terapéutico , Infecciones por Klebsiella/tratamiento farmacológico , Síndrome de Aspiración de Meconio/terapia , Respiración Artificial , Síndrome de Dificultad Respiratoria del Recién Nacido/terapia , Telemedicina , Femenino , Humanos , Recién Nacido , Infecciones por Klebsiella/inmunología , Síndrome de Aspiración de Meconio/inmunología , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunologíaRESUMEN
Gene-environment interactions likely account for some degree of the variance in response rates that are clinically observed with antenatal corticosteroids, breast milk prophylaxis, surfactant administration, early recognition and treatment of sepsis, utility of non-invasive ventilation, and judicious exposure to supplemental oxygen. While these therapies and practice guidelines have significantly decreased overall neonatal mortality in the NICU, they have not made a marked impact on the frequency and severity of conditions such as bronchopulmonary dysplasia (BPD), necrotizing enterocolitis, and periventricular leukomalacia. One possible explanation is that genetic factors in the neonate modulate response to external intervention or preventative agents, culminating in variable levels of injury and different degrees of resolution and repair. Gene-environment explanations are supported by the observed heritability of BPD in twin studies, but they do not differentiate the interactions between neonate and offending toxin or pathogen, from interactions between neonate and intervention or therapeutic agent. Likely, both kinds of interactions are important in determining outcome.
Asunto(s)
Inmunidad Adaptativa/genética , Displasia Broncopulmonar/tratamiento farmacológico , Enterocolitis Necrotizante/tratamiento farmacológico , Leche Humana/inmunología , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Retinopatía de la Prematuridad/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/inmunología , Enterocolitis Necrotizante/genética , Enterocolitis Necrotizante/inmunología , Femenino , Interacción Gen-Ambiente , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Humanos , Lactante , Mortalidad Infantil , Recién Nacido , Enfermedades del Recién Nacido , Recien Nacido Prematuro , Cuidado Intensivo Neonatal , Ventilación con Presión Positiva Intermitente , Masculino , Leche Humana/efectos de los fármacos , Guías de Práctica Clínica como Asunto , Embarazo , Surfactantes Pulmonares/administración & dosificación , Surfactantes Pulmonares/efectos adversos , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Retinopatía de la Prematuridad/genética , Retinopatía de la Prematuridad/inmunología , Sepsis/inmunología , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIMS: The risk of neonates for severe infection/sepsis is reciprocally proportional to gestational age and birth weight. As monocytes and dendritic cells (DC) are recognised key antigen-presenting immune cells, we aimed to elucidate whether neonatal age is associated with reduced expression of human-leukocyte antigen-DR (HLA-DR) antigens on subsets of monocytes and DCs. METHODS: Forty-three consecutive neonates (20 male, mean gestational age 236.0±26.8 days; mean 1-min Apgar score 7.5±2.0) were included in a monocentric prospective observational analysis. Patients were grouped according to gestational age (n=15 full-term, n=28 pre-term defined as <33 weeks). Ten healthy adult volunteers were assessed also. Flow-cytometric assessment of HLA-DR expression was performed in subsets of peripheral blood myeloid and plasmacytoid DCs (MDC and PDC) and monocytes (CD14brightCD16negative/CD14positiveCD16positive/CD14dimCD16positive). Clinical and routine laboratory data were followed up. RESULTS: At birth, leukocyte counts were increased in full-term neonates. Monocyte counts were significantly increased in neonates when compared with adults (all P<0.05). A significant numerical increase of CD14brightCD16negative and CD14positiveCD16positive monocytes was noted in pre-term and full-term neonates (all P<0.05), while HLA-DR expression in these subsets was significantly diminished (most pronounced in pre-term infants, P<0.0001). MDC and PDC HLA-DR expression was reduced also (all P<0.05). Clinical indices (e.g., pH, days on antibiotics/mechanical ventilation, fever/sepsis) were not found to correlate with immunological indices. CONCLUSIONS: We observed a markedly diminished HLA-DR expression on monocyte and DC subsets in pre-term and full-term neonates, which may contribute to impaired antimicrobial defence mechanisms in the early days of life.
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Células Dendríticas/inmunología , Antígenos HLA-DR/sangre , Recien Nacido Prematuro/sangre , Recien Nacido Prematuro/inmunología , Monocitos/inmunología , Adulto , Células Dendríticas/clasificación , Femenino , Edad Gestacional , Humanos , Tolerancia Inmunológica , Inmunidad Celular , Recién Nacido , Infecciones/sangre , Infecciones/etiología , Infecciones/inmunología , Masculino , Monocitos/clasificación , Embarazo , Estudios Prospectivos , Síndrome de Dificultad Respiratoria del Recién Nacido/sangre , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Adulto JovenRESUMEN
UNLABELLED: Infant respiratory distress syndrome (iRDS) in babies born from women with intrahepatic cholestasis of pregnancy (ICP) has been associated with intrauterine exposure to high bile acid levels. Here, we have investigated the role of macrophages in hypercholanemia-induced changes in maternal and fetal lung. Obstructive cholestasis in pregnant rats (OCP) was maintained from day 14 of gestation to term. Gene expression was determined by RT-QPCR, Western blot, and immunofluorescence. The maternal-fetal bile acid pool was radiolabelled using [(3)H]-taurocholate. OCP resulted in increased bile acids in maternal and fetal organs, including lungs. This was accompanied by structural changes in lung tissue, more marked in fetuses (peribronchial edema, collapse of alveolar spaces and deposits of hyaline material in the alveolar lumen), and infiltration of lung tissue by inflammatory cells. The abundance of macrophages and neutrophils in bronchoalveolar lavage fluid (BALF) was also increased in OCP group. Phospholipase A2-IIA (PLA2), the key enzyme in surfactant degradation, was mainly immunodetected in macrophages, which also expressed the bile acid receptor TGR5. The overall expression of PLA2 was markedly enhanced in maternal and fetal lungs of OCP group and in control maternal BALF cells incubated with bile acids. In neonates born from OCP mothers, the enhanced expression of erythropoietin suggested the presence of hypoxia due to iRDS. In conclusion, these results indicate that the accumulation of bile acids due to maternal cholestasis triggers an inflammatory response in the maternal and fetal lungs together with enhanced macrophage-associated PLA2 expression, which may play an important role in iRDS development. KEY MESSAGES: Maternal cholestasis causes respiratory distress syndrome in rat neonates. Cholestasis in pregnant rats causes bile acid accumulation in the fetal lung. This induces lung macrophages infiltration and inflammatory response. Alveolar macrophages co-express phospholipase A2-IIA and TGR5, but not FXR. Bile acid accumulation stimulates phospholipase A2-IIA, but not TGR5, expression.
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Colestasis Intrahepática/inmunología , Macrófagos/inmunología , Neumonía/inmunología , Complicaciones del Embarazo/inmunología , Animales , Ácidos y Sales Biliares , Proteínas Portadoras/metabolismo , Eritropoyetina/genética , Eritropoyetina/metabolismo , Femenino , Feto/inmunología , Feto/metabolismo , Expresión Génica , Humanos , Hígado/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Peroxidasa/metabolismo , Fosfolipasas A2/metabolismo , Embarazo , Ratas Wistar , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Síndrome de Dificultad Respiratoria del Recién Nacido/metabolismoRESUMEN
BACKGROUND: As a protective response to an inflammatory stimulus, the antigen-presenting molecules (human leukocyte antigen-DR (HLA-DR)) on monocytes are downregulated. If severe, the response may lead to immunodepression or immunoparalysis, associated with an increased rate of morbidity and mortality in adults. In very low birth weight (VLBW) infants, birth and intensive care present major immunological challenges. METHODS: We measured monocyte HLA-DR expression by flow cytometry and determined 13 plasma cytokines in 56 VLBW infants (gestational age (GA): 23.7-31.8 wk) and 25 controls (GA: 34.1-41.4 wk). RESULTS: HLA-DR expression decreased postnatally both in VLBW and in control infants. In VLBW infants, GA and respiratory distress syndrome (RDS) both showed associations with HLA-DR nadir on day 3, when 45% of them met the criteria of immunodepression. HLA-DR expression was lower in those infants subsequently developing infection (74 vs. 49% (day 3) and 85 vs. 68% (day 7); both P = 0.002). Interleukin (IL)-6 on day 1 was a predictor of the HLA-DR nadir. CONCLUSION: VLBW infants are in a state of immunodepression postnatally. This immunodepression correlated with GA and was a predisposing factor for late infections. The downregulation of HLA-DR during RDS probably indicates an RDS-induced antigen load on the immune system.
Asunto(s)
Antígenos HLA-DR/sangre , Tolerancia Inmunológica , Recien Nacido Extremadamente Prematuro/inmunología , Recien Nacido Prematuro/inmunología , Recién Nacido de muy Bajo Peso/inmunología , Monocitos/inmunología , Biomarcadores/sangre , Estudios de Casos y Controles , Regulación hacia Abajo , Femenino , Citometría de Flujo , Edad Gestacional , Humanos , Recien Nacido Extremadamente Prematuro/sangre , Recién Nacido , Recien Nacido Prematuro/sangre , Recién Nacido de muy Bajo Peso/sangre , Mediadores de Inflamación/sangre , Unidades de Cuidado Intensivo Neonatal , Interleucina-6/sangre , Masculino , Infecciones Oportunistas/sangre , Infecciones Oportunistas/inmunología , Estudios Prospectivos , Síndrome de Dificultad Respiratoria del Recién Nacido/sangre , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Factores de Riesgo , Factores de TiempoRESUMEN
OBJECTIVE: To investigate the effect of pulmonary surfactant (PS) on the Th1/Th2 balance and serum levels of interleukin-4 (IL-4), interferon-γ (IFN-γ) and IgE in neonates with respiratory distress syndrome (RDS). METHODS: A total of 58 neonates with RDS were divided into control (n=20) and PS treatment groups (n=38). The control group underwent mechanical ventilation and other conventional treatment, while the PS treatment group received with bovine PS treatment within 1 hour of being admitted to the hospital together with mechanical ventilation and other conventional treatment. Enzyme-linked immunosorbent assay was used to measure serum levels of IL-4, IFN-γ and IgE before treatment and 24, 48 and 72 hours after treatment. Simultaneously, arterial blood gas, respiratory system compliance, and other ventilator parameters were recorded. RESULTS: Compared with the control group, the PS treatment group showed significantly shorter duration of mechanical ventilation and oxygen exposure time (P<0.05), significantly better respiratory system compliance and significantly lower oxygenation index 24, 48 and 72 hours after treatment (P<0.05). At 48 and 72 hours after treatment, serum levels of IFN-γ were significantly lower in the PS treatment group than in the control group (120±46 ng/L vs 229±59 ng/L, P<0.05; 141±40 ng/L vs 282±44 ng/L, P<0.05), and serum levels of IL-4 were significantly higher in the PS treatment group than in the control group (263±48 pg/mL vs 152±45 pg/mL, P<0.05; 417±49 pg/mL vs 201±46 pg/mL, P<0.05). At 72 hours after treatment, serum level of IgE was significantly lower in the PS treatment group than in the control group (115±44 pg/mL vs 199±43 ng/mL; P<0.05). CONCLUSIONS: PS treatment can shorten the duration of mechanical ventilation and oxygen exposure time, regulate serum levels of IFN-γ, IL-4 and IgE, and influence Th1/Th2 balance in neonates with RDS, thus inhibiting lung inflammatory response and reducing lung injury.
Asunto(s)
Surfactantes Pulmonares/uso terapéutico , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Células TH1/inmunología , Células Th2/inmunología , Recuento de Linfocito CD4 , Femenino , Humanos , Inmunoglobulina E/sangre , Recién Nacido , Interferón gamma/sangre , Interleucina-4/sangre , Masculino , Surfactantes Pulmonares/farmacología , Respiración Artificial , Síndrome de Dificultad Respiratoria del Recién Nacido/complicaciones , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunologíaRESUMEN
BACKGROUND: As compared with constant respiratory rate (RR) and tidal volume (V(T)) during controlled conventional mechanical ventilation (CV), variable ventilation (VV) using the same breath-to-breath minute volume but variable V(T) and RRs enhances ventilation efficiency in preterm lambs. We hypothesized that if V(T) was adjusted to target permissive hypercarbia, VV would result in more efficient gas exchange without increasing inflammatory and injurious responses in the lung. METHODS: Preterm lambs at 129 d gestation were anesthetized, tracheotomized, and randomized to either CV (n = 8) or VV (n = 8) using the same initial average V(T) and RR. Lung mechanics and gas exchange were measured intermittently, and average V(T) was adjusted to target partial pressure of arterial carbon dioxide (PaCO2) of 40-50 mm Hg for 3 h. Lung injury and inflammation were assessed from bronchoalveolar lavage fluid, lung tissue, and peripheral blood. RESULTS: VV achieved permissive hypercarbia using a lower average V(T), peak inspiratory pressure, and elastance (increased compliance) as compared with CV. Oxygenation and markers of lung tissue inflammation or injury were not different apart from a lower wet:dry tissue ratio in the VV lungs. CONCLUSIONS: VV improves ventilation efficiency and in vivo lung compliance in the ovine preterm lung without increasing lung inflammation or lung injury.
Asunto(s)
Pulmón/fisiopatología , Neumonía/prevención & control , Ventilación Pulmonar , Respiración Artificial/métodos , Síndrome de Dificultad Respiratoria del Recién Nacido/terapia , Lesión Pulmonar Inducida por Ventilación Mecánica/prevención & control , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Edad Gestacional , Mediadores de Inflamación/metabolismo , Pulmón/inmunología , Pulmón/patología , Rendimiento Pulmonar , Neumonía/etiología , Neumonía/inmunología , Neumonía/patología , Neumonía/fisiopatología , Intercambio Gaseoso Pulmonar , Respiración Artificial/efectos adversos , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Síndrome de Dificultad Respiratoria del Recién Nacido/patología , Síndrome de Dificultad Respiratoria del Recién Nacido/fisiopatología , Frecuencia Respiratoria , Ovinos , Volumen de Ventilación Pulmonar , Factores de Tiempo , Lesión Pulmonar Inducida por Ventilación Mecánica/etiología , Lesión Pulmonar Inducida por Ventilación Mecánica/inmunología , Lesión Pulmonar Inducida por Ventilación Mecánica/patología , Lesión Pulmonar Inducida por Ventilación Mecánica/fisiopatologíaRESUMEN
BACKGROUND: Acute inflammatory responses to supplemental oxygen and mechanical ventilation have been implicated in the pathophysiological sequelae of respiratory distress syndrome (RDS). Although surfactant replacement therapy (SRT) has contributed to lung stability, the effect on lung inflammation is inconclusive. Lucinactant contains sinapultide (KL4), a novel synthetic peptide that functionally mimics surfactant protein B, a protein with anti-inflammatory properties. We tested the hypothesis that lucinactant may modulate lung inflammatory response to mechanical ventilation in the management of RDS and may confer greater protection than animal-derived surfactants. METHODS: Preterm lambs (126.8 ± 0.2 SD d gestation) were randomized to receive lucinactant, poractant alfa, beractant, or no surfactant and studied for 4 h. Gas exchange and pulmonary function were assessed serially. Lung inflammation biomarkers and lung histology were assessed at termination. RESULTS: SRT improved lung compliance relative to no SRT without significant difference between SRT groups. Lucinactant attenuated lung and systemic inflammatory response, supported oxygenation at lower ventilatory requirements, and preserved lung structural integrity to a greater degree than either no SRT or SRT with poractant alfa or beractant. CONCLUSION: These data suggest that early intervention with lucinactant may more effectively mitigate pulmonary pathophysiological sequelae of RDS than the animal-derived surfactants poractant alfa or beractant.
Asunto(s)
Antiinflamatorios/farmacología , Alcoholes Grasos/farmacología , Pulmón/efectos de los fármacos , Fosfatidilgliceroles/farmacología , Neumonía/prevención & control , Proteínas/farmacología , Surfactantes Pulmonares/farmacología , Respiración Artificial/efectos adversos , Síndrome de Dificultad Respiratoria del Recién Nacido/terapia , Animales , Productos Biológicos/farmacología , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Combinación de Medicamentos , Edad Gestacional , Mediadores de Inflamación/metabolismo , Pulmón/inmunología , Pulmón/patología , Pulmón/fisiopatología , Rendimiento Pulmonar/efectos de los fármacos , Fosfolípidos/farmacología , Neumonía/inmunología , Neumonía/patología , Neumonía/fisiopatología , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Síndrome de Dificultad Respiratoria del Recién Nacido/patología , Síndrome de Dificultad Respiratoria del Recién Nacido/fisiopatología , Ovinos , Factores de Tiempo , Lesión Pulmonar Inducida por Ventilación Mecánica/inmunología , Lesión Pulmonar Inducida por Ventilación Mecánica/patología , Lesión Pulmonar Inducida por Ventilación Mecánica/fisiopatologíaRESUMEN
Immaturity of the pulmonary and immune systems represents an important risk factor for increased morbidity and mortality in neonates. Surfactant protein (SP)-A and SP-D, linking molecules between these two systems, are critical for lung homeostasis as they regulate surfactant metabolism and host immunodefense activities in innate and adaptive immunity. Preterm neonates with respiratory distress syndrome showed lower concentrations of SP-A and SP-D, and the administration of exogenous surfactant was found to strengthen the secretion of SPs. Low levels of SP-A and SP-D also correlated with a higher risk of infection and development of bronchopulmonary dysplasia. Moreover, SP-A- and SP-D-enriched surfactant formulations were more resistant to the inhibitory action of the plasmatic proteins in animal models. Based on these assumptions, new-generation surfactants, enriched with SP-A and/or SP-D, may enhance the function of immune system and lungs in neonates, potentially improving the clinical outcome.
Asunto(s)
Recien Nacido Prematuro , Enfermedades Pulmonares/inmunología , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Proteína D Asociada a Surfactante Pulmonar/metabolismo , Síndrome de Dificultad Respiratoria del Recién Nacido/metabolismo , Inmunidad Adaptativa , Displasia Broncopulmonar/tratamiento farmacológico , Displasia Broncopulmonar/inmunología , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/patología , Humanos , Inmunidad Innata , Recién Nacido , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/metabolismo , Enfermedades Pulmonares/patología , Unión Proteica , Mapeo de Interacción de Proteínas , Proteína A Asociada a Surfactante Pulmonar/inmunología , Proteína A Asociada a Surfactante Pulmonar/farmacología , Proteína D Asociada a Surfactante Pulmonar/inmunología , Proteína D Asociada a Surfactante Pulmonar/farmacología , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Síndrome de Dificultad Respiratoria del Recién Nacido/patología , Relación Estructura-ActividadRESUMEN
Respiratory distress syndrome (RDS) is a common problem and the leading cause of death in premature infants (PI). The introduction of surfactant treatment for RDS management has lowered mortality and morbidity; nevertheless, some neonates do not improve and are at increased risk of pulmonary hemorrhage. Inflammation, not only local but also systemic, seems to play an important role in the pathogenesis of RDS. To determine whether cytokine patterns characterize RDS and its outcome, we measured type-1 (IL-2, TNF-α, IFN-γ, IL-6) and type-2 (IL-4, IL-5, IL-10, TGF-ß1) serum cytokines of 47 PI with established RDS and a control group of 30 healthy, appropriate for gestational age, full-term neonates. Cord blood samples were obtained at the time of delivery from PI and controls. Venous blood samples were collected from PI who received surfactant treatment and/or developed pulmonary hemorrhage. Significantly elevated cord blood cytokine levels were observed in PI at time of delivery, compared to controls, except for IL-5 and TNF-α levels that were within control range. The type-1/type-2 cytokine ratio was significantly increased in PI vs controls. Neonates who developed pulmonary hemorrhage between 2 and 3 days of life and/or died, presented the strongest Th1 and type-1 cytokine polarization that was mainly due to increased IFN-γ and TNF-α, and decreased TGF-ß1. The majority of these PI were female with very low gestational age. Overall, PI with RDS present a Th1/type-1 cytokine polarization, which persists irrespective of the treatment provided, and is amplified when complications appear. Th1 polarization is associated with poor prognosis.
Asunto(s)
Citocinas/sangre , Recien Nacido Prematuro , Síndrome de Dificultad Respiratoria del Recién Nacido/inmunología , Células TH1/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Sangre Fetal/metabolismo , Humanos , Recién Nacido , Masculino , Pronóstico , Síndrome de Dificultad Respiratoria del Recién Nacido/sangreRESUMEN
OBJECTIVES: To evaluate the clinical significance of Ureaplasma urealyticum recovery from umbilical cord blood, using Polymerase Chain Reaction (PCR), and its association with umbilical cord interleukin-6 (IL-6) levels and neonatal morbidity in preterm infants. METHODS: Cord blood PCR for Ureaplasma urealyticum, and IL-6 were assessed in relation to neonatal outcomes of 30 preterm deliveries of less than 35 weeks' gestation. RESULTS: Ureaplasma urealyticum was present in 43.3% of the examined cord blood samples. Positive neonatal Ureaplasma urealyticum was more common in association with premature rupture of membranes, chorioamnionitis, antenatal maternal use of antibiotics, and earlier gestation. Ureaplasma urealyticum was also associated with an early pro-inflammatory immune response (i.e. elevated IL-6 and positive C-reactive protein). Cutoff level of interleukin-6 of 240 pg% predicts the occurrence of respiratory distress syndrome (RDS), in neonates with positive PCR for Ureaplasma urealyticum. CONCLUSIONS: Preterm patients with positive cord blood PCR for Ureaplasma urealyticum were more likely to have premature rupture of membrane, antenatal antibiotics, chorioamnionitis, earlier gestation, pro-inflammatory response, and RDS than those with a negative PCR. High IL-6 is more likely associated with RDS in Ureaplasma urealyticum positive neonates.