RESUMO
Glaesserella parasuis (G. parasuis) is a commensal bacterium in the upper respiratory tract of pigs that can also cause the swine Glässer disease, which induces an intensive inflammatory response and results in significant economic losses to the swine industry worldwide. G. parasuis can cause disease through infection of the respiratory tract, resulting in systemic infection, but the mechanism is largely unknown. Recently we showed that Glaesserella parasuis serotype 4 (GPS4) increased swine tracheal epithelial barrier permeability, resulting in easier bacterial translocation. Tight junction proteins (TJ) play a crucial role in maintaining the integrity and impermeability of the epithelial barrier. GPS4 decreased the expression of the TJ ZO-1 and occludin in swine tracheal epithelial cells (STEC). Furthermore, the proinflammatory cytokines IL-6, IL-8 and TNF-α were significantly upregulated in GPS4-infected STEC, and both the MAPK and NF-κB signaling pathways were activated and contributed to the expression of TNF-α. We demonstrate that the production of proinflammatory cytokines, especially TNF-α, during GPS4 infection was involved in barrier dysfunction. Additionally, animal challenge experiments confirmed that GPS4 infection downregulated TJ in the lungs of piglets and induced a severe inflammatory response. In general, G. parasuis infection downregulated the expression of TJ and induced massive secretion of proinflammatory cytokines, resulting in epithelial barrier disruption and favoring bacterial infection. This study allowed us to better understand the mechanism by which G. parasuis crosses the respiratory tract of pigs.
Assuntos
Translocação Bacteriana , Haemophilus parasuis/fisiologia , Infecções por Pasteurellaceae/veterinária , Transdução de Sinais , Doenças dos Suínos/microbiologia , Animais , Células Epiteliais , Infecções por Haemophilus/microbiologia , Infecções por Haemophilus/fisiopatologia , Infecções por Haemophilus/veterinária , Haemophilus parasuis/genética , Infecções por Pasteurellaceae/microbiologia , Infecções por Pasteurellaceae/fisiopatologia , Sorogrupo , Sus scrofa , Suínos , Doenças dos Suínos/fisiopatologiaRESUMO
BACKGROUND: Knowing the individual child's risk is highly useful when deciding on treatment strategies, especially when deciding on invasive procedures. In this study, we aimed to develop a new predictive score for children with bacterial meningitis and compare this with existing predictive scores and individual risk factors. METHODS: We developed the Meningitis Swedish Survival Score (MeningiSSS) based on a previous systematic review of risk factors. From this, we selected risk factors identified in moderate-to-high-quality studies that could be assessed at admission to the hospital. Using data acquired from medical records of 101 children with bacterial meningitis, we tested the overall capabilities of the MeningiSSS compared with four existing predictive scores using a receiver operating characteristic curve (ROC) analysis to assert the area under the curve (AUC). Finally, we tested all predictive scores at their cut-off levels using a Chi-square test. As outcome, we used a small number of predefined outcomes; in-hospital mortality, 30-day mortality, occurrence of neurological disabilities at discharge defined as Pediatric Cerebral Performance Category Scale category two to five, any type of complications occurring during the hospital stay, use of intensive care, and use of invasive procedures to monitor or manage the intracerebral pressure. RESULTS: For identifying children later undergoing invasive procedures to monitor or manage the intracerebral pressure, the MeningiSSS excelled in the ROC-analysis (AUC = 0.90) and also was the only predictive score able to identify all cases at its cut-off level (25 vs 0%, p < 0.01). For intensive care, the MeningiSSS (AUC = 0.79) and the Simple Luanda Scale (AUC = 0.75) had the best results in the ROC-analysis, whereas others performed less well (AUC ≤ 0.65). Finally, while none of the scores' results were significantly associated with complications, an elevated score on the MeningiSSS (AUC = 0.70), Niklasson Scale (AUC = 0.72), and the Herson-Todd Scale (AUC = 0.79) was all associated with death. CONCLUSIONS: The MeningiSSS outperformed existing predictive scores at identifying children later having to undergo invasive procedures to monitor or manage the intracerebral pressure in children with bacterial meningitis. Our results need further external validation before use in clinical practice. Thus, the MeningiSSS could potentially be helpful when making difficult decisions concerning intracerebral pressure management.
Assuntos
Mortalidade Hospitalar , Hipertensão Intracraniana/diagnóstico , Pressão Intracraniana , Meningites Bacterianas/fisiopatologia , Monitorização Fisiológica , Fatores Etários , Área Sob a Curva , Temperatura Corporal , Pré-Escolar , Cuidados Críticos , Sistemas de Apoio a Decisões Clínicas , Craniectomia Descompressiva , Drenagem , Feminino , Estado Funcional , Infecções por Haemophilus/complicações , Infecções por Haemophilus/fisiopatologia , Infecções por Haemophilus/terapia , Humanos , Hipertensão Intracraniana/etiologia , Hipertensão Intracraniana/fisiopatologia , Hipertensão Intracraniana/terapia , Leucopenia/fisiopatologia , Masculino , Meningites Bacterianas/complicações , Meningites Bacterianas/terapia , Meningite Meningocócica/complicações , Meningite Meningocócica/fisiopatologia , Meningite Meningocócica/terapia , Meningite Pneumocócica/complicações , Meningite Pneumocócica/fisiopatologia , Meningite Pneumocócica/terapia , Mortalidade , Curva ROC , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/fisiopatologia , Fatores de Risco , Convulsões/etiologia , Convulsões/fisiopatologia , Choque/etiologia , Choque/fisiopatologia , VentriculostomiaRESUMO
BACKGROUND: Influenza virus infection is often complicated by a bacterial infection, with this coinfection causing severe pneumonia. If not timely treated, the disease can cause death. OBJECTIVE: To demonstrate, in animal models, that coinfection with influenza virus and bacteria that affect the respiratory tract causes multisystemic damage. METHOD: Six groups of mice were formed: a control group, one infected with the influenza virus, two infected with bacteria: Haemophilus influenzae and Streptococcus pneumoniae, respectively; and two co-infected with influenza virus and Haemophilus influenzae or Streptococcus pneumoniae, respectively. RESULTS: Of the six groups of mice, only the group co-infected with influenza virus and Streptococcus pneumoniae showed damage to thoracic and abdominal organs. A decrease in serum cytokine levels was found in all study groups, which was more pronounced in the co-infected mice. CONCLUSIONS: The groups of mice infected with Streptococcus pneumoniae or influenza virus alone showed no damage, which indicates that coexistence of these infections caused the damage in the group of co-infected mice.
ANTECEDENTES: La infección por el virus de la influenza con frecuencia se complica con una infección bacteriana, coinfección que provoca cuadros graves de neumonía, la cual puede ocasionar la muerte si no es tratada en forma oportuna. OBJETIVO: Demostrar en modelos animales que la coinfección por el virus de la influenza y bacterias que afectan el tracto respiratorio ocasiona daño multisistémico. MÉTODO: Se formaron seis grupos de ratones: un grupo control, uno infectado de virus de la influenza, dos infectados de bacterias: Haemophilus influenzae y Streptococcus pneumoniae, respectivamente; y dos coinfectados de virus de la influenza y Haemophilus influenzae y Streptococcus pneumoniae, respectivamente. RESULTADOS: De los seis grupos de ratones, solo en el grupo coinfectado de virus de la influenza y Streptococcus pneumoniae se observó daño en órganos torácicos y abdominales. En todos los grupos se encontró disminución de los niveles séricos de las citocinas, mayor en los ratones coinfectados. CONCLUSIONES: Los grupos de ratones infectados solo de Streptococcus pneumoniae o el virus de la influenza no presentaron daños, lo cual indica que la coexistencia de estas infecciones fue la que ocasionó el daño en el grupo de ratones coinfectados.
Assuntos
Infecções por Haemophilus/fisiopatologia , Infecções por Orthomyxoviridae/fisiopatologia , Infecções Pneumocócicas/fisiopatologia , Animais , Coinfecção/fisiopatologia , Citocinas/sangue , Modelos Animais de Doenças , Infecções por Haemophilus/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/virologia , Infecções Pneumocócicas/microbiologia , Pneumonia/microbiologia , Pneumonia/fisiopatologia , Pneumonia/virologia , Streptococcus pneumoniae/isolamento & purificaçãoRESUMO
Haemophilus influenzae type b (Hib) conjugate vaccines have led to dramatic reductions in Hib disease among young children worldwide. Nontypeable H. influenzae (NTHi) is now the major cause of invasive H. influenzae infections. We investigated the clinical characteristics of invasive NTHi diseases among children in Japan, to clarify the pathogenicity of isolated NTHi strains. The mortality rate was 10.7%, with deaths occurring mainly among children with underlying comorbidities. Biotypes II and III were the most common, and most strains (64.3%) had multiple amino acid substitutions at the Asp-350, Ser-357, Ser-385, and/or Met-377 sites of penicillin-binding protein 3. Two strains were ß-lactamase positive and ampicillin-clavulanate resistant. Biofilm indices varied widely, and IS1016 was detected in 10.7% of the strains tested. Moreover, there was wide variation in the characteristics of invasive NTHi strains. NTHi strains, showing great genetic diversity, are responsible for most invasive H. influenzae infections in children in the postvaccine era. Continuous monitoring of NTHi strains responsible for invasive diseases in children is important to detect changes in the epidemiology of invasive H. influenzae infections in the postvaccine era.
Assuntos
Infecções por Haemophilus/microbiologia , Haemophilus influenzae/classificação , Haemophilus influenzae/fisiologia , Antibacterianos/farmacologia , Aderência Bacteriana/genética , Técnicas de Tipagem Bacteriana , Biofilmes/crescimento & desenvolvimento , Criança , Pré-Escolar , Elementos de DNA Transponíveis , Farmacorresistência Bacteriana/genética , Variação Genética , Genoma Bacteriano/genética , Infecções por Haemophilus/epidemiologia , Infecções por Haemophilus/mortalidade , Infecções por Haemophilus/fisiopatologia , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/genética , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Testes de Sensibilidade Microbiana , Análise de Sequência de DNARESUMO
Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. COPD is characterized by chronic airway inflammation and lung infections. The airways of patients with COPD are frequently colonized with bacteria [eg, nontypeable Haemophilus influenzae (NTHi)] that cause pulmonary inflammation and exacerbations. Pulmonary adenocarcinomas are frequently associated with an activating mutation in the KRAS gene. We determined the function of Toll-like receptor (TLR) signaling on the progression of Kras-induced early adenomatous lesions in the lung. Wild-type (WT) mice and mice doubly deficient in Tlr-2 and -4 (Tlr2/4-/-), both with an oncogenic Kras allele in lung epithelium, were exposed to NTHi for 4 weeks. Exposure to NTHi resulted in increased tumor proliferation and growth in WT mice, but not in Tlr2/4-/- mice. Alveolar adenomatous hyperplasia and adenocarcinoma were significantly increased in WT mice compared with Tlr2/4-/- mice. The average size of tumors was significantly larger in WT mice, whereas there was no difference in the number of alveolar lesions between WT and Tlr2/4-/- mice. NTHi-induced pulmonary neutrophilic inflammation and tumor-associated neutrophils were reduced in Tlr2/4-/- mice. Thus, subsequent to a driver mutation, NTHi-induced inflammation promotes proliferation of early adenomatous lesions in a TLR-dependent manner.
Assuntos
Genes ras/fisiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Receptor 2 Toll-Like/fisiologia , Receptor 4 Toll-Like/fisiologia , Adenocarcinoma/fisiopatologia , Animais , Proliferação de Células/fisiologia , Infecções por Haemophilus/fisiopatologia , Haemophilus influenzae/fisiologia , Neoplasias Pulmonares/fisiopatologia , Camundongos , Neutrófilos/fisiologia , Doença Pulmonar Obstrutiva Crônica/virologia , Transdução de Sinais/fisiologia , Receptor 2 Toll-Like/deficiência , Receptor 4 Toll-Like/deficiência , Proteínas ras/metabolismoRESUMO
Non-typeable Haemophilus influenzae (NTHi) is the most common pathogen in primary ciliary dyskinesia (PCD) patients. We hypothesised that abnormal ciliary motility and low airway nitric oxide (NO) levels on airway epithelial cells from PCD patients might be permissive for NTHi colonisation and biofilm development.We used a primary epithelial cell co-culture model to investigate NTHi infection. Primary airway epithelial cells from PCD and non-PCD patients were differentiated to ciliation using an air-liquid interface culture and then co-cultured with NTHi.NTHi adherence was greater on PCD epithelial cells compared to non-PCD cells (p<0.05) and the distribution of NTHi on PCD epithelium showed more aggregated NTHi in biofilms (p<0.001). Apart from defective ciliary motility, PCD cells did not significantly differ from non-PCD epithelial cells in the degree of ciliation and epithelial integrity or in cytokine, LL-37 and NO production. Treatment of PCD epithelia using exogenous NO and antibiotic significantly reduced NTHi viability in biofilms compared with antibiotic treatment alone.Impaired ciliary function was the primary defect in PCD airway epithelium underlying susceptibility to NTHi biofilm development compared with non-PCD epithelium. Although NO responses were similar, use of targeted NO with antibiotics enhanced killing of NTHi in biofilms, suggesting a novel therapeutic approach.
Assuntos
Células Epiteliais/microbiologia , Infecções por Haemophilus/fisiopatologia , Síndrome de Kartagener/microbiologia , Óxido Nítrico/farmacologia , Adolescente , Adulto , Antibacterianos/farmacologia , Aderência Bacteriana , Proteínas de Bactérias/metabolismo , Biofilmes/crescimento & desenvolvimento , Estudos de Casos e Controles , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Haemophilus influenzae/patogenicidade , Haemophilus influenzae/fisiologia , Humanos , Síndrome de Kartagener/fisiopatologia , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Bronchiectasis is a growing health burden both globally and in Australasia. Associated with repeated respiratory infections, the disease often results in hospital admission, impaired quality of life, reduced lung function and shortened life expectancy. We describe the local clinical, physiological and sputum characteristics in patients hospitalized with an infective exacerbation of bronchiectasis. METHODS: This study examined the medical records of all 61 adults admitted to a metropolitan Australian hospital with an infective exacerbation of bronchiectasis in a calendar year. RESULTS: Baseline characteristics include: mean (SD) age of participants was 66 (14) years; 56% were women and 42% were current or ex-smokers. The majority had other coexisting medical conditions, with asthma in 44%, COPD in 59% and both asthma and COPD in 31%. Seventy-two percent were on regular inhaled medication, 23% on cyclical antibiotics and 26% undertook regular respiratory physiotherapy. Bronchodilator reversibility was present in 17% and small airway reversibility in 41%. Sputum demonstrated normal flora in 17%, Pseudomonas aeruginosa in 32%, Haemophilus influenzae in 15% and both organisms in 17%. Mean numbers of exacerbations per year requiring hospitalization was 2.3. Sixty-two percent of subjects had an Index of Relative Socio-Economic Disadvantage in deciles 1-5. Risk factors for exacerbations included a history of asthma or COPD, documented small airway reversibility and presence of P. aeruginosa. CONCLUSION: Patients hospitalized with an infective exacerbation of bronchiectasis are predominantly older with co-morbidities and of lower socio-economic status. Presence of P. aeruginosa was a risk factor for repeated exacerbations, as was a history of asthma, COPD or small airway reversibility.
Assuntos
Asma/epidemiologia , Bronquiectasia/epidemiologia , Coinfecção/epidemiologia , Infecções por Haemophilus/epidemiologia , Infecções por Pseudomonas/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Infecções Respiratórias/epidemiologia , Fumar/epidemiologia , Administração por Inalação , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Australásia/epidemiologia , Austrália/epidemiologia , Bronquiectasia/microbiologia , Bronquiectasia/fisiopatologia , Bronquiectasia/terapia , Coinfecção/microbiologia , Coinfecção/fisiopatologia , Comorbidade , Feminino , Volume Expiratório Forçado , Infecções por Haemophilus/microbiologia , Infecções por Haemophilus/fisiopatologia , Haemophilus influenzae , Hospitalização , Humanos , Masculino , Fluxo Máximo Médio Expiratório , Pessoa de Meia-Idade , Modalidades de Fisioterapia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/fisiopatologia , Pseudomonas aeruginosa , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/terapia , Qualidade de Vida , Terapia Respiratória , Infecções Respiratórias/microbiologia , Infecções Respiratórias/fisiopatologia , Fatores de Risco , Distribuição por Sexo , Fumar/fisiopatologia , Fumar/terapia , Classe Social , EscarroRESUMO
The MAP-LC3 system regulates the intracellular formation of autophagy-associated vacuoles. These vacuoles contain the LC3 protein; thus it has been utilized as a marker to identify autophagosomes. The aim of our study was to investigate whether Haemophilus influenzae strains and their supernatants could activate autophagy in human larynx carcinoma cell line (HEp-2). We demonstrate that higher expression of the LC3B-II protein was induced, particularly by nontypeable Haemophilus influenzae (NTHi) 49766 and by supernatants, containing <50 kDa proteins, of both strains. Ultrastructural studies demonstrate vacuoles with a double membrane and/or membrane material inside, showing similar features to those of autophagic vacuoles. Together, our findings demonstrate that H. influenzae strains and their supernatants trigger an autophagic process.
Assuntos
Autofagia/fisiologia , Infecções por Haemophilus/fisiopatologia , Haemophilus influenzae/fisiologia , Linhagem Celular Tumoral , Humanos , Proteínas Associadas aos Microtúbulos/genética , Regulação para Cima , Vacúolos/ultraestruturaRESUMO
Bacterial coinfection represents a major cause of morbidity and mortality in epidemics of influenza A virus (IAV). The bacterium Haemophilus influenzae typically colonizes the human upper respiratory tract without causing disease, and yet in individuals infected with IAV, it can cause debilitating or lethal secondary pneumonia. Studies in murine models have detected immune components involved in susceptibility and pathology, and yet few studies have examined bacterial factors contributing to coinfection. We conducted genome-wide profiling of the H. influenzae genes that promote its fitness in a murine model of coinfection with IAV. Application of direct, high-throughput sequencing of transposon insertion sites revealed fitness phenotypes of a bank of H. influenzae mutants in viral coinfection in comparison with bacterial infection alone. One set of virulence genes was required in nonvirally infected mice but not in coinfection, consistent with a defect in anti-bacterial defenses during coinfection. Nevertheless, a core set of genes required in both in vivo conditions indicated that many bacterial countermeasures against host defenses remain critical for coinfection. The results also revealed a subset of genes required in coinfection but not in bacterial infection alone, including the iron-sulfur cluster regulator gene, iscR, which was required for oxidative stress resistance. Overexpression of the antioxidant protein Dps in the iscR mutant restored oxidative stress resistance and ability to colonize in coinfection. The results identify bacterial stress and metabolic adaptations required in an IAV coinfection model, revealing potential targets for treatment or prevention of secondary bacterial pneumonia after viral infection.
Assuntos
Adaptação Biológica/genética , Coinfecção/microbiologia , Aptidão Genética/genética , Infecções por Haemophilus/fisiopatologia , Haemophilus/genética , Infecções por Orthomyxoviridae/microbiologia , Animais , Coinfecção/virologia , Elementos de DNA Transponíveis/genética , Infecções por Haemophilus/genética , Sequenciamento de Nucleotídeos em Larga Escala , Vírus da Influenza A , Pulmão/microbiologia , Pulmão/virologia , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genéticaRESUMO
Measures of ventilation distribution are promising for monitoring early lung disease in cystic fibrosis (CF). This study describes the cross-sectional and longitudinal impacts of pulmonary inflammation and infection on ventilation homogeneity in infants with CF.Infants diagnosed with CF underwent multiple breath washout (MBW) testing and bronchoalveolar lavage at three time points during the first 2â years of life.Measures were obtained for 108 infants on 156 occasions. Infants with a significant pulmonary infection at the time of MBW showed increases in lung clearance index (LCI) of 0.400 units (95% CI 0.150-0.648; p=0.002). The impact was long lasting, with previous pulmonary infection leading to increased ventilation inhomogeneity over time compared to those who remained free of infection (p<0.05). Infection with Haemophilus influenzae was particularly detrimental to the longitudinal lung function in young children with CF where LCI was increased by 1.069 units for each year of life (95% CI 0.484-1.612; p<0.001).Pulmonary infection during the first year of life is detrimental to later lung function. Therefore, strategies aimed at prevention, surveillance and eradication of pulmonary pathogens are paramount to preserve lung function in infants with CF.
Assuntos
Fibrose Cística/fisiopatologia , Infecções por Haemophilus/fisiopatologia , Pneumonia Bacteriana/fisiopatologia , Infecções por Pseudomonas/fisiopatologia , Aspergilose Pulmonar/fisiopatologia , Infecções Estafilocócicas/fisiopatologia , Testes Respiratórios , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar/imunologia , Pré-Escolar , Estudos Transversais , Fibrose Cística/imunologia , Progressão da Doença , Feminino , Infecções por Haemophilus/imunologia , Haemophilus influenzae , Humanos , Lactente , Recém-Nascido , Interleucina-8/imunologia , Estudos Longitudinais , Masculino , Pneumonia Bacteriana/imunologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa , Aspergilose Pulmonar/imunologia , Ventilação Pulmonar , Infecções Estafilocócicas/imunologia , Staphylococcus aureusRESUMO
BACKGROUND AND OBJECTIVE: Nontuberculous mycobacterial (NTM) lung disease secondary to cystic fibrosis (CF) has been reported, but there is limited data about NTM prevalence in non-CF bronchiectasis. We retrospectively investigated the prevalence of NTM associated with diffuse panbronchiolitis (DPB), a disorder also characterized by reduced mucociliary clearance with bronchiectasis. METHODS: We reviewed mycobacterial cultures, patient characteristics and computed tomography findings of 33 patients with DPB between January 2000 and December 2012. Prevalence was based on at least one positive NTM culture. RESULTS: Mean patient age was 51.5 years. During a mean 162.8-month follow-up, the prevalence of NTM in sputum was 21.2% (seven patients). Of the seven positive patients, six had Mycobacterium avium complex, one had M. kansasii and M. chelonae co-cultured with M. avium complex. Three patients were positive twice, and two had positive smears. The mean time from DPB diagnosis to the first positive result was 194.6 months. NTM-positive patients tended to have lower forced expiratory volume in 1 s (% predicted) than NTM-negative patients (50.0% vs 77.3%, P = 0.03), but there were no radiological or clinical differences between the two groups. CONCLUSIONS: Our observations suggest that NTM is found more often in DPB. Defects of mucociliary clearance may predispose individuals to NTM infection.
Assuntos
Bronquiectasia/epidemiologia , Bronquiolite/epidemiologia , Infecções por Haemophilus/epidemiologia , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Micobactérias não Tuberculosas , Adolescente , Adulto , Idoso de 80 Anos ou mais , Bronquiectasia/diagnóstico por imagem , Bronquiectasia/microbiologia , Bronquiolite/diagnóstico por imagem , Bronquiolite/microbiologia , Bronquiolite/fisiopatologia , Fibrose Cística/microbiologia , Feminino , Volume Expiratório Forçado , Infecções por Haemophilus/diagnóstico por imagem , Infecções por Haemophilus/microbiologia , Infecções por Haemophilus/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Depuração Mucociliar , Infecções por Mycobacterium não Tuberculosas/diagnóstico por imagem , Infecções por Mycobacterium não Tuberculosas/fisiopatologia , Prevalência , Estudos Retrospectivos , Escarro/microbiologia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Inhaled corticosteroids (ICS) are widely used in the treatment of obstructive lung diseases. Recent data suggest a higher pneumonia risk in chronic obstructive pulmonary disease (COPD) patients treated with ICS. OBJECTIVE: Since non-typeable Haemophilus influenzae (NTHi) is the most common pathogen associated with acute exacerbations of COPD, we investigated the effects of budesonide (BUD) on NTHi-induced inflammation and invasive infection. METHODS: The alveolar epithelial cell line A549 and specimens of human lung tissue (HLT) were used in our experiments. Intracellular infection was determined by a lysis/culture assay of infected cells. Activated p38 mitogen-associated protein kinase (MAPK) was assessed using Western blotting and immunohistochemistry, expression of toll-like receptor 2 (TLR2) was determined by PCR, and CXCL-8 levels were measured using ELISA. Immunohistochemistry was used for detection of CXCL-8, platelet-activating factor receptor (PAF-R) and NTHi. RESULTS: BUD significantly reduced CXCL-8 secretion in A549 cells and lung tissue infected with NTHi. Furthermore, BUD decreased the expression of PAF-R in HLT and A549 cells. In A549 cells and HLT, BUD inhibited intracellular infection and - synergistically with NTHi - increased the expression of TLR2 (in A549 cells). TLR2 stimulation did not influence the intracellular infection of A549 cells, but p38 MAPK inhibition resulted in a significant reduction of infection. CONCLUSION: The present study adds new insights into the effects of glucocorticoids on pulmonary host defence after NTHi infection. Although the inflammatory response to infection is suppressed by BUD, interestingly, the intracellular infection is also inhibited. This effect seems to depend on the inhibition of p38 MAPK - a key enzyme in many pro-inflammatory pathways - as well as of PAF-R expression.
Assuntos
Budesonida/farmacologia , Haemophilus influenzae/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Administração por Inalação , Anti-Inflamatórios/farmacologia , Western Blotting , Budesonida/efeitos adversos , Células Cultivadas , Meios de Cultivo Condicionados , Indução Enzimática/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/efeitos dos fármacos , Infecções por Haemophilus/etiologia , Infecções por Haemophilus/fisiopatologia , Humanos , Imuno-Histoquímica , Reação em Cadeia da Polimerase , Doença Pulmonar Obstrutiva Crônica/microbiologia , Sensibilidade e Especificidade , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: Bacteria are frequently implicated in acute exacerbations of chronic obstructive pulmonary disease (COPD), but their influence on airway inflammation remains unclear. This review will focus on nontypeable Haemophilus influenzae (NTHi), its impact on host immune responses, and the potential for vaccination strategies in COPD. RECENT FINDINGS: NTHi is associated with impaired immune function in patients with COPD. Features of the bacterium itself potentiate its ability to colonize the lower airways. An imbalance between bacterial load and host immunity may lend itself to the development of exacerbations. Oral immunotherapy may be a method of augmenting the host immune response and could provide protection from exacerbations. SUMMARY: A causal link between NTHi and COPD exacerbations has not been clearly established. However, colonization of the lower airways by NTHi likely plays a significant role in the inflammatory state of COPD.
Assuntos
Infecções por Haemophilus/imunologia , Haemophilus influenzae/patogenicidade , Doença Pulmonar Obstrutiva Crônica/imunologia , Infecções Respiratórias/imunologia , Imunidade Adaptativa , Aderência Bacteriana/imunologia , Progressão da Doença , Infecções por Haemophilus/microbiologia , Infecções por Haemophilus/fisiopatologia , Haemophilus influenzae/isolamento & purificação , Humanos , Imunoterapia/métodos , Imunoterapia/tendências , Inflamação/imunologia , Inflamação/microbiologia , Doença Pulmonar Obstrutiva Crônica/microbiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Mucosa Respiratória/imunologia , Infecções Respiratórias/microbiologia , Infecções Respiratórias/fisiopatologia , Vacinação/tendênciasRESUMO
A 78-year-old woman with low pulmonary function (forced expiratory volume in 1 second of 450 ml) underwent an open incisional pulmonary tissue biopsy for suspected diffuse panbronchiolitis and anti-neutrophil cytoplasmic antibody-associated vasculitis. She was intubated with a double-lumen tracheal tube after receiving 0.57 mg x kg(-1) of rocuronium and 0.9 mg kg(-1) of propofol. Under one-lung ventilation, the PaCO2 was 54-74 mmHg and PaO2 was 121-127 mmHg until 50 min after lung recruitment, after which the PaCO2 decreased to 62-66 mmHg and PaO2 increased to 283-382 mmHg. The operation ended uneventfully. Although the rocuronium-induced neuromuscular blockade was reversed by 2.0 mg x kg(-1) of sugammadex (train-of-four ratio, nearly 100%), it seemed a little difficult to extubate the patient just after the operation because blood gas analysis showed a pH 7.39, PaCO2 of 66 mmHg and PaO2 382 mmHg with FIO2 1.0. The blood gas analysis revealed pH 7.52, PaCO2 44.5 mmH and PaO2 144 mmHg with FIO2 of 0.4. The patient was successfully extubated with no respiratory complication 10 h after the end of the operation on the first postoperative day.
Assuntos
Extubação/métodos , Anestesia Geral , Biópsia/métodos , Pulmão/cirurgia , Testes de Função Respiratória , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/fisiopatologia , Bronquiolite/complicações , Bronquiolite/diagnóstico , Bronquiolite/patologia , Bronquiolite/fisiopatologia , Feminino , Volume Expiratório Forçado/fisiologia , Infecções por Haemophilus/complicações , Infecções por Haemophilus/diagnóstico , Infecções por Haemophilus/patologia , Infecções por Haemophilus/fisiopatologia , Humanos , Intubação Intratraqueal/métodos , Pulmão/patologia , Respiração Artificial/métodos , Fatores de TempoRESUMO
Nontypeable Haemophilus influenzae (NTHi) is an important bacterial pathogen associated with lower respiratory tract colonization and with acute exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). Why the immune system fails to eliminate NTHi and the exact contribution of the organism to COPD progression are not well understood, in part because we lack an animal model that mimics all aspects of COPD. For this study, we used an established murine model that exhibits typical features of COPD. Elastase/LPS-exposed mice infected with NTHi showed persistence of bacteria up to 5 days after infection, whereas mice exposed to elastase, LPS, or PBS cleared all bacteria by 3 days. Elastase/LPS-exposed mice also showed sustained lung neutrophilic inflammation, goblet cell metaplasia, airway hyperresponsiveness, and progression of emphysema at 15 days after infection. Alveolar macrophages isolated from elastase/LPS-exposed mice showed impaired bacterial phagocytosis, reduced expression of MARCO and of mannose receptor, and absent expression of scavenger receptor-A (SR-A). Neutralization of SR-A significantly decreased phagocytosis of NTHi by normal alveolar macrophages. Our results suggest that elastase/LPS-exposed mice show impaired bacterial clearance and sustained lung inflammation. Lack of SR-A expression may, in part, be responsible for impaired phagocytosis of bacteria by alveolar macrophages of elastase/LPS-exposed mice. These data validate the suitability of elastase/LPS model for investigating NTHi pathogenesis and progression of disease in COPD.
Assuntos
Infecções por Haemophilus/imunologia , Imunidade Inata/fisiologia , Lipopolissacarídeos/farmacologia , Elastase Pancreática/farmacologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Receptores Depuradores Classe A/fisiologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Linhagem Celular , Citocinas/metabolismo , Infecções por Haemophilus/fisiopatologia , Haemophilus influenzae/imunologia , Medidas de Volume Pulmonar , Macrófagos Alveolares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Muco/metabolismo , Fagocitose/imunologia , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/microbiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/imunologia , Enfisema Pulmonar/microbiologiaRESUMO
Otitis media (OM) is the most prevalent childhood disease in developed countries. Involvement of innate immunity mediated by Toll-like receptors (TLRs) in OM has been implicated primarily in cell lines and by association studies of innate immune gene polymorphisms with OM prevalence. However, the precise role of innate immunity in OM is incompletely understood. We review recent research that has advanced our understanding of how innate immunity in the middle ear is mediated by the interaction of pathogen molecules with receptors such as the TLRs, leading to the activation of adaptor molecules and production of proinflammatory cytokines. TLR genes and signaling molecules are upregulated in OM in a murine model. Deletion of several key innate immune genes results in persistent OM in mice, coupled with an inability to clear bacterial infection from the middle ear. It is concluded that an intact innate immune signaling system is critical to recovery from bacterial OM.
Assuntos
Imunidade Inata , Otite Média/imunologia , Receptores Toll-Like/imunologia , Animais , Criança , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Infecções por Haemophilus/genética , Infecções por Haemophilus/imunologia , Infecções por Haemophilus/fisiopatologia , Haemophilus influenzae , Humanos , Camundongos , Otite Média/genética , Otite Média/fisiopatologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Although previous studies using human cytokines in rabbits and rats have provided evidence of the participation of tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) in the meningeal inflammatory cascade, the results obtained by several groups of investigators have been discordant or, at times, contradictory. In the present study, homologous cytokines were applied to the rabbit meningitis model. Intracisternal administration of 10(2)-10(5) IU of purified rabbit TNF-alpha (RaTNF-alpha) produced significant cerebrospinal fluid (CSF) inflammation. A similar response was observed after intracisternal inoculation of 5-200 ng of rabbit recombinant IL-1 beta (rrIL-1 beta). Preincubation of these two mediators with their specific antibodies resulted in an almost complete suppression of the CSF inflammatory response. In animals with Haemophilus influenzae type b lipooligosaccharide-induced meningitis, intracisternal administration of anti-rrIL-1 beta, anti-RaTNF-alpha, or both resulted in a significant modulation of meningeal inflammation. Simultaneous administration of 10(3) IU of RaTNF-alpha and 5 ng of rrIL-1 beta resulted in a synergistic inflammatory response manifested by a more rapid and significantly increased influx of white blood cells into the CSF compared with results after each cytokine given alone. These data provide evidence for a seminal role of TNF-alpha and IL-1 beta in the initial events of meningeal inflammation.
Assuntos
Infecções por Haemophilus/fisiopatologia , Interleucina-1/farmacologia , Meningite/fisiopatologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Anticorpos/administração & dosagem , Modelos Animais de Doenças , Haemophilus influenzae/patogenicidade , Imunização Passiva , Inflamação , Contagem de Leucócitos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Coelhos , Proteínas Recombinantes/farmacologiaRESUMO
The use of dexamethasone (DXM) as adjunctive therapy for bacterial meningitis (BM) in infants and children has remained controversial for 20 years. In spite of solid pathophysiological arguments, the limited number of patients, methodological flaws in clinical studies taken individually and pooled into meta-analyses, and the emergence of pneumococcal cephalosporin-resistance did not allow to reach a consensus on the effectiveness of DXM in the prevention of neurological sequelae, in the course of non Haemophilus influenzae b (Hib) BM. A recent meta-analysis conducted with an adequate number of patients (2,750 patients including 2,074 infants and children below 15 years of age) demonstrated that DXM prevented mortality and sequelae in adults with pneumococcal meningitis and suggested that this efficacy could also apply to infants and children. Data from the active surveillance networks of pediatric BM and pneumococcal resistance in France suggested that DXM anti-inflammatory effect on antibiotic CSF penetration would not have a significant impact on the bactericidal efficacy if recommended dosages of cefotaxime (300 mg/kg per day) and vancomycin (60 mg/kg per day) were used. DXM could be considered in the early treatment of pneumococcal BM in infants and children in industrialized countries. But there is no proven efficacy of DXM in meningococcal meningitis in infants and children.
Assuntos
Corticosteroides/uso terapêutico , Dexametasona/uso terapêutico , Meningites Bacterianas/tratamento farmacológico , Adolescente , Anti-Inflamatórios/uso terapêutico , Criança , Pré-Escolar , Países Desenvolvidos , Infecções por Haemophilus/tratamento farmacológico , Infecções por Haemophilus/fisiopatologia , Haemophilus influenzae , Humanos , Lactente , Meningites Bacterianas/fisiopatologiaRESUMO
Otitis media caused by nontypeable Haemophilus influenzae (NTHi) is a common and recurrent bacterial infection of childhood. The structural variability and diversity of H. influenzae lipopolysaccharide (LPS) glycoforms are known to play a significant role in the commensal and disease-causing behavior of this pathogen. In this study, we determined LPS glycoform populations from NTHi strain 1003 during the course of experimental otitis media in the chinchilla model of infection by mass spectrometric techniques. Building on an established structural model of the major LPS glycoforms expressed by this NTHi strain in vitro (M. Månsson, W. Hood, J. Li, J. C. Richards, E. R. Moxon, and E. K. Schweda, Eur. J. Biochem. 269:808-818, 2002), minor isomeric glycoform populations were determined by liquid chromatography multiple-step tandem electrospray mass spectrometry (LC-ESI-MS(n)). Using capillary electrophoresis ESI-MS (CE-ESI-MS), we determined glycoform profiles for bacteria from direct middle ear fluid (MEF) samples. The LPS glycan profiles were essentially the same when the MEF samples of 7 of 10 animals were passaged on solid medium (chocolate agar). LC-ESI-MS(n) provided a sensitive method for determining the isomeric distribution of LPS glycoforms in MEF and passaged specimens. To investigate changes in LPS glycoform distribution during the course of infection, MEF samples were analyzed at 2, 5, and 9 days postinfection by CE-ESI-MS following minimal passage on chocolate agar. As previously observed, sialic acid-containing glycoforms were detected during the early stages of infection, but a trend toward more-truncated and less-complex LPS glycoforms that lacked sialic acid was found as disease progressed.