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Severe adenoviral pneumonia (SAP) can cause post-infectious bronchiolitis obliterans (PIBO) in children. We aimed to investigate the relevant risk factors for PIBO and develop a predictive nomogram for PIBO in children with SAP. This prospective study analysed the clinical data of hospitalised children with SAP and categorised them into the PIBO and non-PIBO groups. Least absolute shrinkage and selection operator (LASSO) regressions were applied to variables that exhibited significant intergroup differences. Logistic regression was adopted to analyse the risk factors for PIBO. Additionally, a nomogram was constructed, and its effectiveness was assessed using calibration curves, C-index, and decision curve analysis. A total of 148 hospitalised children with SAP were collected in this study. Among them, 112 achieved favourable recovery, whereas 36 developed PIBO. Multivariable regression after variable selection via LASSO revealed that aged < 1 year (OR, 2.38, 95% CI, 0.82-6.77), admission to PICU (OR, 24.40, 95% CI, 7.16-105.00), long duration of fever (OR, 1.16, 95% CI, 1.04-1.31), and bilateral lung infection (OR, 8.78, 95% CI, 1.32-195.00) were major risk factors for PIBO. The nomogram model included the four risk factors: The C-index of the model was 0.85 (95% CI, 0.71-0.99), and the area under the curve was 0.85 (95% CI, 0.78-0.92). The model showed good calibration with the Hosmer-Lemeshow test (χ2 = 8.52, P = 0.38) and was useful in clinical settings with decision curve analysis. CONCLUSION: Age < 1 year, PICU admission, long fever duration, and bilateral lung infection are independent risk factors for PIBO in children with SAP. The nomogram model may aid clinicians in the early diagnosis and intervention of PIBO. WHAT IS KNOWN: ⢠Adenoviruses are the most common pathogens associated with PIBO. ⢠Wheezing, tachypnoea, hypoxemia, and mechanical ventilation are the risk factors for PIBO. WHAT IS NEW: ⢠Age < 1 year, admission to PICU, long duration of fever days, and bilateral lung infection are independent risk factors for PIBO in children with SAP. ⢠A prediction model presented as a nomogram may help clinicians in the early diagnosis and intervention of PIBO.
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Bronquiolite Obliterante , Pneumonia Viral , Criança , Humanos , Estudos Prospectivos , Bronquiolite Obliterante/diagnóstico , Bronquiolite Obliterante/etiologia , Pneumonia Viral/complicações , Fatores de RiscoRESUMO
Respiratory syncytial virus (RSV) is the most frequently detected respiratory virus in children with acute lower respiratory tract infection. Previous transcriptome studies have focused on systemic transcriptional profiles in blood and have not compared the expression of multiple viral transcriptomes. Here, we sought to compare transcriptome responses to infection with four common respiratory viruses for children (respiratory syncytial virus, adenovirus, influenza virus, and human metapneumovirus) in respiratory samples. Transcriptomic analysis showed that cilium organization and assembly were common pathways related to viral infection. Compared with other virus infections, collagen generation pathways were distinctively enriched in RSV infection. We identified two interferon-stimulated genes (ISGs), CXCL11 and IDO1, which were upregulated to a greater extent in the RSV group. In addition, a deconvolution algorithm was used to analyze the composition of immune cells in respiratory tract samples. The proportions of dendritic cells and neutrophils in the RSV group were significantly higher than those in the other virus groups. The RSV group exhibited a higher richness of Streptococcus than the other virus groups. The concordant and discordant responses mapped out here provide a window to explore the pathophysiology of the host response to RSV. Last, according to host-microbe network interference, RSV may disrupt respiratory microbial composition by changing the immune microenvironment. IMPORTANCE In the present study, we demonstrated the comparative results of host responses to infection between RSV and other three common respiratory viruses for children. The comparative transcriptomics study of respiratory samples sheds light on the significant roles that ciliary organization and assembly, extracellular matrix changes, and microbial interactions play in the pathogenesis of RSV infection. Additionally, it was demonstrated that the recruitment of neutrophils and dendritic cells (DCs) in the respiratory tract is more substantial in RSV infection than in other viral infections. Finally, we discovered that RSV infection dramatically increased the expression of two ISGs (CXCL11 and IDO1) and the abundance of Streptococcus.
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Objective: To investigate the relationship between meteorological factors and Human parainfluenza virus type 3 (HPIV-3) infection among hospitalized children. Methods: All hospitalized children with acute lower respiratory tract infections were tested for viral pathogens and enrolled, at the second affiliated hospital of Wenzhou medical university, between 2008 and 2017. Meteorological data were directly obtained from Wenzhou Meteorology Bureau's nine weather stations and expressed as the mean exposure for each 10-day segment (average daily temperatures, average daily relative humidity, rainfall, rainfall days, and wind speed). The correlation between meteorological factors and the incidence of HPIV-3 was analyzed, with an autoregressive integrated moving average model (ARIMA), generalized additive model (GAM), and least absolute shrinkage and selection operator (LASSO). Results: A total of 89,898 respiratory specimens were tested with rapid antigen tests, and HPIV-3 was detected in 3,619 children. HPIV-3 was detected year-round, but peak activities occurred most frequently from March to August. The GAM and LASSO-based model had revealed that HPIV-3 activity correlated positively with temperature and rainfall day, but negatively with wind speed. The ARIMA (1,0,0)(0,1,1) model well-matched the observed data, with a steady R2 reaching 0.708 (Ljung-Box Q = 21.178, P = 0.172). Conclusion: Our study suggests that temperature, rainfall days, and wind speed have significant impacts on the activity of HPIV-3. GAM, ARIMA, and LASSO-based models can well predict the seasonality of HPIV-3 infection among hospitalized children. Further understanding of its mechanism would help facilitate the monitoring and early warning of HPIV-3 infection.
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Introduction: Damage to alveolar epithelial cells caused by uncontrolled inflammation is considered to be the main pathophysiological change in acute lung injury. FGF10 plays an important role as a fibroblast growth factor in lung development and lung diseases, but its protective effect against acute lung injury is unclear. Therefore, this study aimed to investigate protective effect and mechanism of FGF10 on acute lung injury in mice. Methods: ALI was induced by intratracheal injection of LPS into 57BL/6J mice. Six hours later, lung bronchoalveolar lavage fluid (BALF) was acquired to analyse cells, protein and the determination of pro-inflammatory factor levels, and lung issues were collected for histologic examination and wet/dry (W/D) weight ratio analysis and blot analysis of protein expression. Results: We found that FGF10 can prevent the release of IL-6, TNF-α, and IL-1ß, increase the expression of BMP4 and autophagy pathway, promote the regeneration of alveolar epithelial type â ¡ cells, and improve acute lung injury. BMP4 gene knockdown decreased the protective effect of FGF10 on the lung tissue of mice. However, the activation of autophagy was reduced after BMP4 inhibition by Noggin. Additionally, the inhibition of autophagy by 3-MA also lowered the protective effect of FGF10 on alveolar epithelial cells induced by LPS. Conclusions: These data suggest that the protective effect of FGF10 is related to the activation of autophagy and regeneration of alveolar epithelial cells in an LPS-induced ALI model, and that the activation of autophagy may depend on the increase in BMP4 expression.
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Pseudomembranous laryngotracheobronchitis is rarely reported yet potentially life-threatening infectious cause of airway obstruction in children. The causative organisms of this condition are often considered to promote bacterial superinfection following viral infection. We report a case of pseudomembranous laryngotracheobronchitis in a patient caused by human bocavirus 1 and Mycoplasma pneumoniae (M. pneumoniae). A 2-year-old child was admitted to our hospital presenting with cough, hoarseness, and labored breathing. Computed tomography of the chest revealed atelectasis of the right middle lobe of the lung with bronchostenosis and occlusion. Laryngeal edema, pseudomembrane formation and ulceration of the trachea were found during bronchoscopy. Chronic inflammation of the mucosa and local cellulose exudation with acute and chronic inflammatory cell infiltration were confirmed by hematoxylin-eosin staining. Human bocavirus 1 and M. pneumoniae were detected in the bronchoalveolar lavage fluid by next-generation sequencing. The patient tested positive for IgM antibodies against M. pneumoniae. Bronchoscopy was performed three times to clear the secretions in the airway, and azithromycin, ceftriaxone, methylprednisolone, budesonide inhalation, and ambroxol were administered as treatment. The patient's condition improved and she was discharged 21 days after admission. Clinicians should be aware of the potential involvement of human bocavirus 1 and M. pneumoniae in pseudomembranous laryngotracheobronchitis for accurate diagnosis and timely antibiotic administration, and to lower mortality and morbidity rates.
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INTRODUCTION: Human adenovirus (HAdV) is a common pathogen in children with acute respiratory infections (ARIs). The aim was to describe the epidemiology, molecular, and clinical characteristics of HAdV among children hospitalized with ARIs in Wenzhou in southeastern China. METHODOLOGY: From January 2018 to December 2019, nasopharyngeal swab or sputum specimens were prospectively collected from hospitalized children with ARIs. HAdV was detected using direct immunofluorescence. We used a multiplex PCR assay combined with capillary electrophoresis targeting the hexon gene's hypervariable region to identify HAdV types 1, 2, 3, 4, 5, 7, 14, 21, 37, 40, 41, and 55. We analyzed the epidemiological, molecular, and clinical data according to the HAdV type. RESULTS: HAdVs were detected in 1,059 (3.5%) of the total of 30,543 children tested. A total of 947 cases with monotype HAdV identified by the PCR assay were included in the analysis. HAdV-3 (415/947, 43.8%), HAdV-7 (318/947, 33.6%), HAdV-2 (108/947, 11.4%), and HAdV-1 (70/947, 7.4%) were the predominant types. Of the 550 (58.1%) cases detected from December 2018 to August 2019, HAdV-3, and HAdV-7 were the main types. The main diagnoses included 358 cases of pneumonia, 232 cases of tonsillitis, 198 cases of bronchitis, and 159 cases of upper respiratory tract infection (URTI). Among children with pneumonia the main types were HAdV-7 (51.1%), HAdV-3 (36.9%), and HAdV-1 (2.2%). Among children with bronchitis, the main types were HAdV-3 (48.0%), HAdV-7 (28.3%), and HAdV-2 (10.6%). Among children with URTIs, the main types were HAdV-3 (49.7%), HAdV-7 (22.6%), and HAdV-2 (13.2%). Among children with tonsillitis, the main types were HAdV-3 (47.4%), HAdV-2 (22.4%), and HAdV-7 (18.5%). In total, 101 (55.2%) patients required supplemental oxygen, 15 (8.2%) required critical care, and 1 child (0.5%) with HAdV-7 pneumonia died. CONCLUSION: HAdV-3 -7, -2, and -1 were the predominant types identified in hospitalized children with ARIs in Wenzhou. From December 2018 to August 2019, there were outbreaks of HAdV-3 and -7. There were significant differences in HAdV types among children with pneumonia, tonsillitis, bronchitis, and URTI. HAdV-7 can cause more severe pneumonia in children than HAdV-3.
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Bronchial artery-pulmonary artery fistula secondary to pulmonary tuberculosis is an important cause of hemoptysis in adults, but it's relatively rare in children. Bronchial artery-pulmonary artery fistulas are mostly congenital in children and may have no clinical manifestations in the early stage. Congenital bronchial artery-pulmonary fistula with pulmonary tuberculosis can lead to hemoptysis. From 2016 to 2020, two children with pulmonary tuberculosis complicated with bronchial artery and pulmonary artery fistula were admitted and treated in our hospital. We reminded pediatricians to pay attention to a variety of etiology combined with the possibility of children's hemoptysis.
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Streptococcus pneumoniae is a major causative agent of pneumonia worldwide and its complex interaction with the lung epithelium has not been thoroughly characterized. In this study, we exploited both RNA-sequencing and microRNA (miRNA)-sequencing approaches to monitor the transcriptional changes in human lung alveolar epithelial cells infected by S. pneumoniae in a time-resolved manner. A total of 1330 differentially expressed (DE) genes and 45 DE miRNAs were identified in all comparisons during the infection process. Clustering analysis showed that all DE genes were grouped into six clusters, several of which were primarily involved in inflammatory or immune responses. In addition, target gene enrichment analyses identified 11 transcription factors that were predicted to link at least one of four clusters, revealing transcriptional coregulation of multiple processes or pathways by common transcription factors. Notably, pharmacological treatment suggested that phosphorylation of p65 is important for optimal transcriptional regulation of target genes in epithelial cells exposed to pathogens. Furthermore, network-based clustering analysis separated the DE genes negatively regulated by DE miRNAs into two functional modules (M1 and M2), with an enrichment in immune responses and apoptotic signaling pathways for M1. Integrated network analyses of potential regulatory interactions in M1 revealed that multiple DE genes related to immunity and apoptosis were regulated by multiple miRNAs, indicating the coordinated regulation of multiple genes by multiple miRNAs. In conclusion, time-series expression profiling of messenger RNA and miRNA provides a wealth of information for global transcriptional changes, and offers comprehensive insight into the molecular mechanisms underlying host-pathogen interactions.
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Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , MicroRNAs , Infecções Pneumocócicas/genética , RNA Mensageiro , Humanos , Análise de Sequência de RNA , Streptococcus pneumoniaeRESUMO
This study investigated the seasonality and secular trends in the etiology of viral lower respiratory tract infections (LRTIs) among hospitalized children in Wenzhou, southeastern China. A retrospective review was conducted concerning viral LRTIs in children hospitalized at a university hospital between January 1, 2008 and December 31, 2017. Direct immunofluorescence was used to detect respiratory syncytial virus (RSV), adenovirus (AdV), influenza A virus (Inf A), influenza B virus (Inf B), and human parainfluenza virus types 1 to 3 (hPIV1-3). Of 89 898 children tested, at least one viral respiratory pathogen was identified in 25.6% and multiple pathogens were identified in 0.4%. RSV (17.6%), hPIV3 (4.0%), and AdV (2.2%) were the most frequently detected pathogens. The proportion of positive samples varied with age and was the highest in children aged <6 months (36.2%). Seasonal differences were observed in RSV, AdV, Inf A, Inf B, hPIV1, and hPIV3 infections. There was a declining trend in the proportion of positive samples over time, primarily due to a decrease in RSV and hPIV3 infections. RSV, hPIV3, and AdV were the most common viral respiratory pathogens identified among hospitalized children with LRTIs. The distribution of viruses varied with age and season.
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Infecções por Adenovirus Humanos/epidemiologia , Influenza Humana/epidemiologia , Infecções por Paramyxoviridae/epidemiologia , Infecções Respiratórias/virologia , Infecções por Adenovirus Humanos/virologia , Adenovírus Humanos/isolamento & purificação , Adolescente , Distribuição por Idade , Fatores Etários , Criança , Pré-Escolar , China/epidemiologia , Coinfecção/virologia , Hospitalização , Humanos , Lactente , Vírus da Influenza A/isolamento & purificação , Vírus da Influenza B/isolamento & purificação , Influenza Humana/virologia , Vírus da Parainfluenza 1 Humana , Vírus da Parainfluenza 2 Humana/isolamento & purificação , Vírus da Parainfluenza 3 Humana/isolamento & purificação , Infecções por Paramyxoviridae/virologia , Infecções por Vírus Respiratório Sincicial/epidemiologia , Vírus Sinciciais Respiratórios/isolamento & purificação , Infecções Respiratórias/epidemiologia , Estudos Retrospectivos , Estações do AnoRESUMO
INTRODUCTION: Respiratory syncytial virus (RSV) infection is a major cause of hospitalization in children. Meteorological factors are known to influence seasonal RSV epidemics, but the relationship between meteorological factors and RSV infection in children is not well understood. We aimed to explore the relationship between meteorological factors and RSV infections among hospitalized children, using different statistical models. METHODS: We conducted a retrospective review concerning children with RSV infections admitted to a tertiary pediatric hospital in Wenzhou, China, between January 2008 and December 2017. The relationship between meteorological factors (average daily temperatures, average daily relative humidity, rainfall, rainfall days, and wind speed) and the incidence of RSV in hospitalized children was analyzed using three time-series models, namely an autoregressive integrated moving average (ARIMA) model, a generalized additive model (GAM), and a least absolute shrinkage and selection operator (LASSO)-based model. RESULTS: In total, 15 858 (17.6%) children tested positive for RSV infection. The ARIMA model revealed a marked seasonal pattern in the RSV detection rate, which peaked in winter and spring. The model was a good predictor of RSV incidence (R2 : 83.5%). The GAM revealed that a lower temperature and higher wind speed preceded increases in RSV detection. The LASSO-based model revealed that temperature and relative humidity were negatively correlated with RSV detection. CONCLUSIONS: Seasonality of RSV infection in hospitalized children correlated strongly with temperature. The LASSO-based model can be used to predict annual RSV epidemics using weather forecast data.
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Conceitos Meteorológicos , Infecções por Vírus Respiratório Sincicial/epidemiologia , Criança , Criança Hospitalizada , China/epidemiologia , Feminino , Hospitais Pediátricos , Humanos , Incidência , Masculino , Estudos RetrospectivosRESUMO
INTRODUCTION: Lower respiratory tract infections (LRTIs), particularly those acquired in hospitals, are an important cause of childhood morbidity and mortality. Understanding the aetiology and epidemiology of LRTIs is necessary for clinical management, reduction of antibiotic usage, vaccine development and prevention of nosocomial infection. AIM: In this study, we aimed to detect 13 viruses and atypical bacteria in nasopharyngeal secretion specimens from hospitalized children with LRTIs. METHODOLOGY: From January 2014 to December 2016, nasopharyngeal secretion specimens were prospectively collected from 3232 children aged between 1 and 72 months. Nucleic acid was extracted and analysed using the SureX13 respiratory pathogen multiplex kit as per the manufacturer's instructions. RESULTS: A total of 2874 (88.9 %) children tested positive for viral and/or atypical bacterial infections, and 965 (29.9 %) were co-infected with multiple pathogens. The most frequently detected respiratory tract pathogens (RTPs) were rhinovirus, respiratory syncytial virus, parainfluenza virus and adenoviruses. The rates of RTP and co-infection positivity in the toddler group were significantly higher than those in the infant and preschool groups. CONCLUSION: The SureX13 respiratory pathogen multiplex kit has the ability to effectively detect a range of RTPs in hospitalized paediatric patients with LRTIs.
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Bactérias/isolamento & purificação , Reação em Cadeia da Polimerase Multiplex/normas , Kit de Reagentes para Diagnóstico/normas , Infecções Respiratórias/diagnóstico , Vírus/isolamento & purificação , Fatores Etários , Bactérias/classificação , Bactérias/genética , Criança Hospitalizada/estatística & dados numéricos , Pré-Escolar , China/epidemiologia , Coinfecção/diagnóstico , Coinfecção/epidemiologia , Coinfecção/microbiologia , Coinfecção/virologia , Feminino , Humanos , Lactente , Masculino , Nasofaringe/microbiologia , Nasofaringe/virologia , Prevalência , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/microbiologia , Infecções Respiratórias/virologia , Análise de Sequência de DNA , Vírus/classificação , Vírus/genéticaRESUMO
Adiponectin plays a role in asthma and obesity, but its effects and mechanism in obesity-related asthma remain elusive. This study aimed to evaluate the effects of adiponectin on airway inflammation and oxidative stress and to determine its mechanism in obesity-related asthma. Male C57BL6/J mice fed with a high-fat diet to induce obesity were sensitized and challenged with ovalbumin to induce asthma, and treated with adiponectin (1â¯mg/kg) and AMP-activated protein kinase (AMPK) inhibitor compound C (20â¯mg/kg) twice before the first ovalbumin challenge. We found exogenous adiponectin significantly reduced airway resistance, inflammatory infiltration in lung tissue, and cell counts in bronchoalveolar lavage fluid. Adiponectin inhibited great levels of eotaxin, myeloperoxidase, tumor necrosis factor-α, 8hydroxy2'deoxyguanosine, and nitric oxide in obesity-related asthma mice. Moreover, we found increased nuclear factor kappa B p65, inducible nitric oxide synthase and B-cell lymphoma 2 protein expression were down-regulated with adiponectin administration. Additionally, adiponectin elevated the lower levels of pAMPK and AMPK activity in lung tissue. These protective effects of adiponectin were reversed after treatment with the AMPK inhibitor compound C. Thus, we conclude that adiponectin alleviates exacerbation of airway inflammation and oxidative stress in a murine model of obesity-related asthma partly through AMPK signaling pathway.
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Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/farmacologia , Asma/tratamento farmacológico , Obesidade/complicações , 8-Hidroxi-2'-Desoxiguanosina , Proteínas Quinases Ativadas por AMP/genética , Animais , Antioxidantes/metabolismo , Asma/induzido quimicamente , Asma/etiologia , Quimiocina CCL11/metabolismo , Desoxiguanosina/análogos & derivados , Imunoglobulina E , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico , Estresse Oxidativo , Distribuição AleatóriaRESUMO
AIM: To explore the role of tumor necrosis factor-alpha (TNF-α) on Staphylococcus aureus-induced necroptosis in alveolar epithelial cells. MAIN METHODS: The A549 alveolar epithelial cell line was pretreated with small interfering RNA (siRNA) against receptor interacting protein-3 (RIP3) and then stimulated by S. aureus, where some cells were pretreated with TNF-α or TNF-α with anti-TNF-α antibody simultaneously. A549 cell death was assessed using lactate dehydrogenase (LDH) leakage and flow cytometry analyses. The protein expressions of RIP1, RIP3, cleaved caspase-1, and cleaved caspase-8 were analyzed by western blot. KEY FINDINGS: S. aureus-induced LDH release was increased significantly by TNF-α. In addition, flow cytometry showed that TNF-α increased A549 cell apoptosis and necrosis in S. aureus-infected cell cultures. Levels of RIP3 and cleaved caspase-1 protein in A549 cells infected with S. aureus increased at 12â¯h post-infection, as shown by western blot. Significant additional increases in RIP3 expression were observed following the addition of TNF-α. Decreasing RIP3 levels by siRNA significantly suppressed the release of LDH induced by TNF-α and S. aureus. RIP3 siRNA also significantly suppressed A549 cell necrosis induced by S. aureus and TNF-α at 6 and 12â¯h post-infection as shown by flow cytometry analysis. SIGNIFICANCE: TNF-α enhances the damage of S. aureus on lung epithelial cells, and its mechanism is associated with RIP3 mediated necroptosis.
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Morte Celular/efeitos dos fármacos , Proteína Serina-Treonina Quinases de Interação com Receptores/fisiologia , Staphylococcus aureus/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Células A549 , Células Epiteliais Alveolares , Caspase 8/genética , Caspase 8/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , Necrose/induzido quimicamente , Necrose/patologia , Complexo de Proteínas Formadoras de Poros Nucleares/efeitos dos fármacos , Complexo de Proteínas Formadoras de Poros Nucleares/fisiologia , Proteínas de Ligação a RNA/efeitos dos fármacos , Proteínas de Ligação a RNA/fisiologia , Proteína Serina-Treonina Quinases de Interação com Receptores/efeitos dos fármacosRESUMO
Antibiotic-induced immunopathology associated with the release of bacterial cell wall components has been suggested to contribute to poor outcomes in bacterial pneumonia. Adjunctive systemic glucocorticoid steroid (GC) therapy for pneumonia has been a controversial issue. In the present study, we first found that dexamethasone (2.5 mg/kg/day) in combination with oxacillin was beneficial for improving lung injury in mice inoculated intratracheally with live Staphylococcus aureus, and did not interfere with bacterial clearance. Alleviation of lung injury was evidenced by attenuated lung pathology, reduced total protein levels, soluble receptor for advanced glycation end-products (sRAGE), tumor necrosis factor alpha (TNF-α), and keratinocyte chemoattractant (KC) and interleukin (IL)-6 in bronchoalveolar lavage fluid (BALF). It was further confirmed by inhibition of receptor interacting protein-3 (RIP3) expression in pulmonary tissues. As in the live S. aureus experiments, dexamethasone (2.5 mg/kg/day) improved lung injury in mice challenged with heat-killed S. aureus (HKSA). In conclusion, our results demonstrated that an appropriate dose of adjunctive dexamethasone (2.5 mg/kg/day) with oxacillin alleviated experimental S. aureus-induced lung injury via its inhibition of inflammatory cytokine release and RIP3 expression.
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Anti-Inflamatórios/uso terapêutico , Dexametasona/uso terapêutico , Lesão Pulmonar/prevenção & controle , Pneumonia Estafilocócica/tratamento farmacológico , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Staphylococcus aureus , Animais , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Anti-Inflamatórios/administração & dosagem , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Dexametasona/administração & dosagem , Quimioterapia Combinada , Feminino , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/etiologia , Lesão Pulmonar/imunologia , Camundongos Endogâmicos C57BL , Oxacilina/administração & dosagem , Oxacilina/uso terapêutico , Pneumonia Estafilocócica/complicações , Pneumonia Estafilocócica/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Staphylococcus aureus/efeitos dos fármacosRESUMO
Streptococcus pneumoniae is an important pathogen of pneumonia in human. Human alveolar epithelium acts as an effective barrier and is an active participant in host defense against invasion of bacterial by production of various mediators. Sirtuin 1 (SIRT1), the prototypic class III histone deacetylase, is involved in the molecular control of lifespans and immune responses. This study aimed at examining the role of SIRT1 in mediating S. pneumoniae-induced human ß-defensin-2 (hBD2) and interleukin-8(IL-8) expression in the alveolar epithelial cell line A549 and the underlying mechanisms involved. A549 cells were infected with S. pneumoniae for indicated times. Exposure of A549 cells to S. pneumoniae increased the expressions of SIRT1 protein, hBD2 and IL-8 mRNA, and protein. The SIRT1 activator resveratrol enhanced S. pneumoniae-induced gene expression of hBD2 but decreased IL-8 mRNA levels. Blockade of SIRT1 activity by the SIRT1 inhibitors nicotinamide reduced S. pneumoniae-induced hBD2 mRNA expression but increased its stimulatory effects on IL-8 mRNA. S. pneumoniae-induced activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). SIRT1 expression was attenuated by selective inhibitors of ERK and p38 MAPK. The hBD2 mRNA production was decreased by pretreatment with p38 MAPK inhibitor but not with ERK inhibitor, whereas the IL-8 mRNA expression was controlled by phosphorylation of ERK. These results suggest that SIRT1 mediates the induction of hBD2 and IL-8 gene expression levels in A549 cell by S. pneumoniae. SIRT1 may play a key role in host immune and defense response in A549.
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Células Epiteliais/enzimologia , Células Epiteliais/microbiologia , Interleucina-8/metabolismo , Alvéolos Pulmonares/enzimologia , Alvéolos Pulmonares/microbiologia , Sirtuína 1/metabolismo , Streptococcus pneumoniae/patogenicidade , beta-Defensinas/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática , Ativadores de Enzimas/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Interações Hospedeiro-Patógeno , Humanos , Interleucina-8/genética , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/imunologia , RNA Mensageiro/metabolismo , Transdução de Sinais , Sirtuína 1/genética , Streptococcus pneumoniae/imunologia , Fatores de Tempo , Regulação para Cima , beta-Defensinas/genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Curcumin, a natural product derived from the plant Curcuma longa, has been found to have anti-inflammatory, antineoplastic and antifibrosis effects. It has been reported that curcumin attenuates allergic airway inflammation in mice through inhibiting NF-κB and its downstream transcription factor GATA3. It also has been proved the antineoplastic effect of curcumin through down-regulating Notch1 receptor and its downstream nuclear transcription factor NF-κB levels. In this study, we aimed to investigate the anti-inflammatory effect of curcumin on acute allergic asthma and its underlying mechanisms. 36 male BALB/c mice were randomly divided into four groups (normal, asthma, asthma+budesonide and asthma+curcumin groups). BALF (bronchoalveolar lavage fluid) and lung tissues were analyzed for airway inflammation and the expression of Notch1, Notch2, Notch3, Notch4 and the downstream transcription factor GATA3. Our findings showed that the levels of Notch1 and Notch2 receptors were up-regulated in asthma group, accompanied by the increased expression of GATA3. But the expression of Notch2 receptor was lower than Notch1 receptor. Curcumin pretreatment improved the airway inflammatory cells infiltration and reversed the increasing levels of Notch1/2 receptors and GATA3. Notch3 receptor was not expressed in all of the four groups. Notch4 receptor protein and mRNA expression level in the four groups had no significant differences. The results of the present study suggested that Notch1 and Notch2 receptor, major Notch1 receptor, played an important role in the development of allergic airway inflammation and the inhibition of Notch1-GATA3 signaling pathway by curcumin can prevent the development and deterioration of the allergic airway inflammation. This may be a possible therapeutic option of allergic asthma.
Assuntos
Asma/prevenção & controle , Curcuma , Curcumina/uso terapêutico , Fator de Transcrição GATA3/antagonistas & inibidores , Receptor Notch1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Curcumina/farmacologia , Fator de Transcrição GATA3/biossíntese , Inflamação/metabolismo , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Receptor Notch1/biossíntese , Transdução de Sinais/fisiologiaRESUMO
OBJECTIVE: To study the clinical characteristics of children who suffered from Streptococcus pneumoniae (SP) septicemia and the drug sensitivity of SP strains. METHODS: A retrospective analysis was performed on the clinical data of 25 children with SP septicemia between January 2009 and December 2012. RESULTS: Of the 25 cases, 16 (64%) were aged under 2 years, 5 (20%) were aged 2-5 years, and 4 (16%) were aged over 5 years. Fourteen cases (56%) were complicated by infection of other organs, and 5 cases (20%) had underlying chronic diseases. Fever was the most common clinical manifestation, and the majority presented with remittent fever. Eight patients with pneumonia or pyothorax had pulmonary symptoms. Five patients with purulent meningitis had neurological symptoms, five cases had hepatosplenomegaly and two cases had septic shock. Nineteen cases (76%, 19/25) had significantly elevated white blood cell (WBC) counts, twenty-one cases (84%, 21/25) had significantly elevated serum C-reactive protein (CRP) levels, and eight cases (50%, 8/16) had significantly elevated serum procalcitonin (PCT) levels. The drug sensitivity analysis showed that invasive SP had high resistance rates to penicillin (96%), clindamycin hydrochloride (88%) and erythromycin (84%), and it was completely sensitive to imipenem, vancomycin, levofloxacin and linezolid. The multi-drug resistance rate of invasive SP was up to 88%. Twenty-three cases (92%) were cured or improved after active treatment. CONCLUSIONS: SP septicemia is commonly seen in children aged under 2 years. The most common clinical manifestation is fever, accompanied by elevated WBC count, CRP level and PCT level, and it is usually complicated by pulmonary or brain infection. Resistance to multiple antibiotics is very common in SP strains, so it is important to properly use antibiotics according to drug sensitivity test results. Patients who receive active treatment have a good clinical outcome.