Glaesserella parasuis serotype 4 HPS4-YC disrupts the integrity of the swine tracheal epithelial barrier and facilitates bacterial translocation.

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.

Effect of coinfection with influenza virus and bacteria on host damage / Efecto de la coinfección por virus de la influenza y bacterias en el daño al hospedero

Abstract 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.

Resumen 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.

Inflammation and chronic colonization of Haemophilus influenzae in sputum in COPD patients related to the degree of emphysema and bronchiectasis in high-resolution computed tomography.

The presence of bacteria in the lower airways in COPD results in inflammation, further airway structural damage, and might lead to repeated exacerbations. We have previously shown that chronic colonization of Haemophilus influenzae during stable disease is related to increased inflammation, and we now aimed to relate previous findings of bacterial colonization and inflammation to the degree of radiological findings of bronchiectasis and emphysema. Thirty-nine patients with COPD were included in their stable state, and a high-resolution computed tomography of the lung was performed. They were followed-up monthly for up to a maximum of 6 months or until exacerbation, and they answered questionnaires, performed spirometry, and induced sputum at every visit. Thirty-five patients had emphysema with an emphysema degree of median 20% (interquartile range 10-50), and five patients had bronchiectasis, of which only four could expectorate sputum. The degree of emphysema correlated with several inflammatory mediators in sputum, such as interleukin-8 concentration, myeloperoxidase activity, and Leukotriene B4 concentration. Ten patients were chronically colonized with H. influenzae (ie, had a positive culture for H. influenzae at all visits). The four sputum patients with bronchiectasis were chronically colonized with H. influenzae and showed higher degree of H. influenzae growth compared to patients without bronchiectasis. During exacerbation, there was no longer any correlation between emphysema degree and inflammation, but patients with bronchiectasis showed higher sputum purulence score than patients without bronchiectasis. Emphysema and bronchiectasis in COPD patients show different clinical features. The presence of emphysema is more related to inflammation, while bronchiectasis is associated with bacterial colonization. We believe that both emphysema and bronchiectasis are therefore COPD phenotypes of highest impact and need evaluation to prevent further disease progression.

Primary ciliary dyskinesia ciliated airway cells show increased susceptibility to Haemophilus influenzae biofilm formation.

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.

Nontypeable Haemophilus influenzae-Promoted Proliferation of Kras-Induced Early Adenomatous Lesions Is Completely Dependent on Toll-Like Receptor Signaling.

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.

Patients hospitalized with an infective exacerbation of bronchiectasis unrelated to cystic fibrosis: Clinical, physiological and sputum characteristics.

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.

Haemophilus influenzae triggers autophagy in HEp-2 cells.

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.

Budesonide Inhibits Intracellular Infection with Non-Typeable Haemophilus influenzae Despite Its Anti-Inflammatory Effects in Respiratory Cells and Human Lung Tissue: A Role for p38 MAP Kinase.

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.

Progressive ventilation inhomogeneity in infants with cystic fibrosis after pulmonary infection.

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 2 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.

Nontuberculous mycobacteria in diffuse panbronchiolitis.

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.

[Case of delayed extubation in a woman with low pulmonary function].

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.

Understanding nontypeable Haemophilus influenzae and chronic obstructive pulmonary disease.

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.

Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases.

Macrolide antibiotics have established efficacy in the management of cystic fibrosis and diffuse panbronchiolitis-uncommon lung diseases with substantial morbidity and the potential for rapid progression to death. Emerging evidence suggests benefits of maintenance macrolide treatment in more indolent respiratory diseases including chronic obstructive pulmonary disease and non-cystic fibrosis bronchiectasis. In view of the greater patient population affected by these disorders (and potential for macrolide use to spread to disorders such as chronic cough), widespread use of macrolides, particularly azithromycin, has the potential to substantially influence antimicrobial resistance rates of a range of respiratory microbes. In this Personal View, I explore theories around population (rather than patient) macrolide resistance, appraise evidence linking macrolide use with development of resistance, and highlight the risks posed by injudicious broadening of their use, particularly of azithromycin. These risks are weighed against the potential benefits of macrolides in less aggressive inflammatory airway disorders. A far-sighted approach to maintenance macrolide use in non-cystic fibrosis inflammatory airway diseases is needed, which minimises risks of adversely affecting community macrolide resistance: combining preferential use of erythromycin and restriction of macrolide use to those patients at greatest risk represents an appropriately cautious management approach.

Elastase/LPS-exposed mice exhibit impaired innate immune responses to bacterial challenge: role of scavenger receptor A.

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.

Innate signaling in otitis media: pathogenesis and recovery.

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.

TLR4-mediated induction of TLR2 signaling is critical in the pathogenesis and resolution of otitis media.

Otitis media is the most prevalent childhood disease in developed countries. The involvement of Toll-like receptors (TLRs) in otitis media pathophysiology has been implicated by studies in cell lines and association studies of TLR gene polymorphisms. However, precise functions of TLRs in the etiology of otitis media in vivo have not been examined. We investigated the inflammatory response to nontypeable Haemophilus influenzae using a model of otitis media in wild-type, TLR2(- /-) and TLR4(-/ -) mice by gene microarray, qPCR, immunohistochemistry, Western blot analysis and histopathology. Toll-like receptor-2(- /-) and TLR4(- /-) mice exhibited a more profound, persistent inflammation with impaired bacterial clearance compared to controls. While wild-type mice induced tumor necrosis factor-a (TNF) after non-typeable H. influenzae challenge, TLR2(-/-) and TLR4(-/-) mice lack TNF induction in the early phase of otitis media. Moreover, lack of TLR2 resulted in a late increase in IL-10 expression and prolonged failure to clear bacteria. Toll-like receptor-4(-/- ) mice showed impaired early bacterial clearance and loss of TLR2 induction in early otitis media. Our results demonstrate that both TLR2 and TLR4 signalling are critical to the regulation of infection in non-typeable H. influenzae-induced otitis media. Toll-like receptor-4 signalling appears to induce TLR2 expression, and TLR2 activation is critical for bacterial clearance and timely resolution of otitis media.

[Physiopathology of cystic fibrosis and of infections associated to this disease]. / Aspecte ale fiziopatologiei mucoviscidozei si a infectiilor bronhopulmonare asociate acesteia.

Cystic fibrosis (CF) is one of the most common lethal inherited diseases in the caucasian population. The hope of understanding the physiopathology of CF appeared after identification of the gene which encodes CF. The alteration in CFTR protein breaks the hydric balance of the mucosal secretions, producing mucus with increased viscosity. Broncho-pulmonary infections are constant encountered because of the stasis of the mucus. The most common bacterial pathogens in the sputum of patients with MV are Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia. MV remains a severe, incurable disease, but the evolution is getting better because of the improvements of care methods.

Microbiologic determinants of exacerbation in chronic obstructive pulmonary disease.

BACKGROUND: The culture of bronchial secretions from the lower airway has been reported to be positive for potentially pathogenic microorganisms (PPMs) in patients with stable chronic obstructive pulmonary disease (COPD), but the determinants and effects of this bacterial load in the airway are not established. METHODS: To determine the bronchial microbial pattern in COPD and its relationship with exacerbation, we pooled analysis of crude data from studies that used protected specimen brush sampling, with age, sex, smoking, lung function, and microbiologic features of the lower airway as independent variables and exacerbation as the outcome, using logistic regression modeling. RESULTS: Of 337 study participants, 70 were healthy, 181 had stable COPD, and 86 had exacerbated COPD. Differences in the microbial characteristics in the participating laboratories were not statistically significant. A cutoff point of 10(2) colony-forming units (CFU) per milliliter or greater for the identification of abnormal positive culture results for PPMs was defined using the 95th percentile in the pooled analysis of healthy individuals. Bronchial colonization of 10(2) CFU/mL or greater by PPMs was found in 53 patients with stable COPD (29%) and in 46 patients with exacerbated COPD (54%) (P<.001, chi(2) test), with a predominance of Haemophilus influenzae and Pseudomonas aeruginosa. Higher microbial loads were associated with exacerbation and showed a statistically significant dose-response relationship after adjustment for covariates (odds ratio, 3.62; 95% confidence interval, 1.47-8.90), but P aeruginosa persisted as a statistically significant risk factor after adjustment for microbial load (odds ratio, 11.12; 95% confidence interval, 1.17-105.82). CONCLUSIONS: One quarter of the patients with COPD are colonized by PPMs during their stable periods. Exacerbation is associated with the overgrowth of PPMs and with the appearance of P aeruginosa in the lower airway, which is associated with exacerbation symptoms independent of load.

Exploitation of host epithelial signaling networks by respiratory bacterial pathogens.

Although tremendous effort has been put towards identifying the surface molecules of nontypeable Haemophilus influenzae (NTHi) for vaccine development over the past decades, it is only recently that we have begun to appreciate the intricate host epithelial signaling networks activated by NTHi, an important human pathogen causing respiratory infections. From what has been reported, it is evident that NTHi activates multiple signaling pathways in host epithelial cells that, in turn, inadvertently contribute to the pathogenesis. Among those signaling pathways, activation of NF-kappaB leads to up-regulation of IL-1beta, IL-8 and TNF-alpha, mucin MUC2 and Toll-like receptor 2 (TLR2), whereas activation of p38 MAP kinase mediates not only up-regulation of inflammatory mediators and mucin MUC5AC but also down-regulation of TLR2. Interestingly, NTHi-induced activation of the PI3K-Akt pathway, however, leads to inhibition of p38 mitogen-activated protein (MAP) kinase. Moreover, the TGF-beta-Smad signaling pathway cooperates with NF-kappaB to mediate up-regulation of mucin MUC2. Finally, glucocorticoids synergistically enhance NTHi-induced TLR2 expression via specific up-regulation of the MAP kinase phosphatase-1 that, in turn, leads to inactivation of p38 MAP kinase, the negative regulator for TLR2 expression. These studies may bring new insights into the molecular pathogenesis of NTHi-induced infections and open up novel therapeutic targets for these diseases.