Bacterial Airway Infections Research Articles

Flexible Bronchoscopy in Evaluation of Persistent Wheezing in Children-Experiences from National Pediatric Center.

Background and objectives: Persistent wheezing (PW) is defined as prolonged or recurrent episodes of wheezing despite regular treatment. Flexible bronchoscopy (FB) is recommended to determine the etiology of PW in children. This study aimed to determine the etiology of PW based on FB findings in a national pediatric center. Materials and Methods: Children presenting with PW that underwent flexible bronchoscopy from April 2016 to August 2019 at the Mother and Child Health Institute of Serbia were included in this observational study. After endoscopic evaluation, bronchoalveolar lavage fluid (BALF) samples were taken and further analyzed. Quantitative microbiology, cytological analysis and oil-red staining of specimens were performed to determine cellular constituents and presence of lipid laden macrophages (LLM). Upper gastrointestinal series were performed to exclude gastroesophageal reflux disease, swallowing dysfunction and vascular ring. Results: Pathological findings were revealed in 151 of 172 study participants, with bacterial lower airway infection (BLAI) (48.3%) and primary bronchomalacia (20.4%) as the most common. Younger participants were hospitalized for significantly longer periods (ρ = −0.366, p < 0.001). Study participants with BLAI and associated mucus plugging were notably younger (p < 0.001). Presence of LLM in BALF was not associated with findings of upper gastrointestinal series. All patients with confirmed BLAI were treated with oral antibiotics. Although FB is considered to be invasive, there were no complications associated with the procedure. Conclusions: Flexible bronchoscopy has an exceptional diagnostic value in evaluation of PW. In younger patients with BLAI, presence of mucus plugs may complicate the clinical course, so significant benefits can be achieved with therapeutic lavage during bronchoscopy.

Airway bacterial carriage and childhood respiratory health: A population-based prospective cohort study.

BackgroundAirway bacterial carriage might play a role in respiratory disease. We hypothesize that nasal carriage with Staphylococcus aureus or nasopharyngeal carriage with Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae predisposes individuals to adverse respiratory health.ObjectiveTo examine the association of early‐life airway bacterial carriage with respiratory tract infections and vice versa, and of early‐life airway bacterial carriage with wheezing, lung function, and asthma in later childhood.MethodsWe collected upper airway swabs for bacterial culturing for S aureus, H influenzae, M catarrhalis, and H influenzae at six timepoints between the ages of 6 weeks and 6 years among 945 children participating in a population‐based prospective cohort study. Information on respiratory tract infections and wheezing until age 6 years, and asthma at age 10 years was obtained by questionnaires. Lung function at age 10 years was measured by spirometry. We tested possible bidirectional associations between airway bacterial carriage and respiratory tract infections by cross‐lagged models, and associations of repeatedly measured airway bacterial carriage with wheezing, lung function, and asthma by generalized estimating equations models and regression models.ResultsCross‐lagged modeling showed that early‐life airway bacterial carriage was not consistently associated with upper and lower respiratory tract infections or vice versa. Nasopharyngeal carriage with any bacteria in infancy was associated with an increased risk of wheezing (OR [95% CI]: 1.66 [1.31, 2.10]). Airway bacterial carriage was not consistently associated with school‐age lung function or asthma.ConclusionNasopharyngeal carriage with any bacteria is associated with wheezing, but not respiratory tract infections, asthma, or lung function.

Treatment options in type-2 low asthma.

Monoclonal antibodies targeting IgE or the type-2 cytokines interleukin (IL)-4, IL-5 and IL-13 are proving highly effective in reducing exacerbations and symptoms in people with severe allergic and eosinophilic asthma, respectively. However, these therapies are not appropriate for 30-50% of patients in severe asthma clinics who present with non-allergic, non-eosinophilic, "type-2 low" asthma. These patients constitute an important and common clinical asthma phenotype, driven by distinct, yet poorly understood pathobiological mechanisms. In this review we describe the heterogeneity and clinical characteristics of type-2 low asthma and summarise current knowledge on the underlying pathobiological mechanisms, which includes neutrophilic airway inflammation often associated with smoking, obesity and occupational exposures and may be driven by persistent bacterial infections and by activation of a recently described IL-6 pathway. We review the evidence base underlying existing treatment options for specific treatable traits that can be identified and addressed. We focus particularly on severe asthma as opposed to difficult-to-treat asthma, on emerging data on the identification of airway bacterial infection, on the increasing evidence base for the use of long-term low-dose macrolides, a critical appraisal of bronchial thermoplasty, and evidence for the use of biologics in type-2 low disease. Finally, we review ongoing research into other pathways including tumour necrosis factor, IL-17, resolvins, apolipoproteins, type I interferons, IL-6 and mast cells. We suggest that type-2 low disease frequently presents opportunities for identification and treatment of tractable clinical problems; it is currently a rapidly evolving field with potential for the development of novel targeted therapeutics.

Lung Function Longitudinal Study by Phenotype and Genotype in Primary Ciliary Dyskinesia

There is considerable variability in the severity and progression of lung disease in primary ciliary dyskinesia (PCD).1-3 Few studies have related progression of lung function to the underlying ultrastructural defect.4,5 We investigated the age-related evolution of spirometry to identify associations between ultrastructural defects, gene mutations, BMI,6 and bacterial airway infections in a longitudinal study of adult and pediatric patients with PCD.

Adenoidal Immune Response in the Context of Inflammation and Allergy

:The mucosal-associated lymphoid tissues of the upper respiratory tract, including adenoids and palatine tonsils, are considered as the first line of defense against respiratory infections, being important effector organs in both mucosal-type and systemic-type adaptive immunity. They are strategically located for mediating both local and regional immune functions, as they are exposed to antigens from both the inhaled air (allergens and pathogens) and the alimentary tract. Adenoids play a major role in the early and effective immune responses against viral and bacterial upper airway infections, as well as in the development of allergic reactions to respiratory allergens, being influenced by several environmental antigens and pollutants, such as tobacco smoke. In addition, recent studies have focused on new immune-modulating strategies for adenoidal cells as a preventive and therapeutic approach for chronic upper airways inflammation.:Herein, we aimed to summarize what is known about the cellular and molecular mechanisms regulating adenoidal immune responses in the context of inflammation and allergy, with particular reference to scientific literature published within the last five years.

Hypoxia-inducible factor and bacterial infections in chronic obstructive pulmonary disease.

COPD is a seriously disabling respiratory condition that inexorably progresses to disability and mortality. It affects approximately 10% of the population globally with a greater prevalence at advanced ages. Airway bacterial infections complicate the disease course in most COPD patients, leading to increased symptoms, more rapid decline in lung function, acute exacerbations and reduced quality of life. With increasing bacterial resistance to antibiotics and adverse effects of conventional treatments, new effective non-antibiotic antimicrobial therapies are urgently needed to manage COPD. Hypoxia-inducible factor (HIF)-1α is an important transcriptional regulator of cellular responses to hypoxia, oxidants and inflammation, and is overexpressed in the lungs of COPD patients. Recent evidence shows that increased HIF-1α expression can upregulate the platelet-activating factor receptor (PAFR) on the airway epithelial surface that is increased in smokers and particularly COPD patients. The receptor is utilized by PAFR-dependent bacteria (Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa) to induce infection in both the respiratory and gastrointestinal (GI) tracts. However, the importance and mechanism of HIF-1α in augmenting PAFR-dependent bacterial infections in COPD are poorly understood. Here, we review the evidence for the roles of local tissue hypoxia-induced inflammation, HIF-1α and PAFR in facilitating bacterial infections in COPD. Blocking PAFR may provide a novel antimicrobial approach to manage bacterial infections in COPD.

Alessandro Moretta and Transporter Associated With Antigen Processing (TAP) Deficiency: On Giant's Shoulders.

The laboratory hosting me for my Ph.D. described in 1994 the first human cases of TAP deficiency in two siblings with recurrent bacterial airway infections and a negative Human Leukocyte Antigen class I (HLA) serotyping. At this time, it became clear that natural killer (NK) cells interact with HLA class I molecules which inhibit them. Inhibitory receptors were postulated, and Alessandro Moretta was the first to generate monoclonal anti-human NK cell antibodies that bound to such molecules, which he characterized in detail (Killer Immunoglobulin-like receptors—KIR). Natural killer cells from healthy donors preferentially kill targets with absent HLA class I molecules (“missing self” concept), whereas we observed that the NK cells from the TAP-deficient patients were hypo-responsive and did not lyse the HLA class I-negative leukemia cell line K562. Moreover, they were not very active in antibody-dependent cellular cytotoxicity assays. To address the question if such NK cells would express KIR or not, my thesis supervisor requested the anti-KIR antibodies from Alessandro Moretta, who was kind enough to provide us generously with aliquots. It turned out that the NK cells from the TAP-deficient individuals expressed most of these inhibitory receptors normally. We then had the privilege to receive almost every new antibody generated in the Moretta lab and to complete the phenotypic studies of the NK cells from our patients. I had the great chance to meet Alessandro Moretta at several occasions. He deeply impressed me each time and strongly influenced my way of thinking.

The monocyte-dependent immune response to bacteria is suppressed in smoking-induced COPD.

COPD patients have an increased susceptibility to bacterial airway infections that can induce exacerbations. In response to infections, circulating monocytes become recruited to the infected tissue and secrete cytokines. We hypothesized that this cytokine response is reduced in COPD. Cultured peripheral blood monocytes of never smokers (NS) and smokers without (S) and with COPD (3 study populations, n = 36-37) were stimulated with extracts of Haemophilus influenzae, Staphylococcus aureus, or Streptococcus pneumoniae or with four different pathogen-associated molecular patterns (PAMPs). Four cytokines and 9 PAMP-related signaling molecules were measured and compared between the groups. Granulocyte-macrophage-colony-stimulating-factor responses to all stimulants were reduced in S and COPD compared to NS. Tumor-necrosis-factor-α responses to all bacterial extracts, peptidoglycan, and lipopolysaccharide were reduced in S and/or COPD. Interleukin-10 responses to S. aureus and lipoteichoic acid were increased in COPD. Correlations to pack-years and lung function were found. The peptidoglycan-receptor NOD2 and the mRNA of the lipopolysaccharide-receptor TLR4 were reduced in S and COPD. Cytokine responses of monocytes to bacteria are suppressed by smoking and in COPD possibly due to NOD2 and TLR4 reduction and/or interleukin-10 increase. This might help to explain the increased susceptibility to bacterial infections. These systemic molecular pathologies might be targets for therapeutic strategies to prevent infection-induced exacerbations. KEY MESSAGES: COPD subjects have an increased susceptibility to bacterial infections. This implies defects in the immune response to bacteria and is critical for disease progression. The cytokine response of monocytes to bacteria is reduced in COPD. This might be due to a reduced NOD2 and TLR4 and an increased IL-10 expression. This can explain the increased susceptibility to infections and help to identify drug targets.

Bioreactor-based mass production of human iPSC-derived macrophages enables immunotherapies against bacterial airway infections

The increasing number of severe infections with multi-drug-resistant pathogens worldwide highlights the need for alternative treatment options. Given the pivotal role of phagocytes and especially alveolar macrophages in pulmonary immunity, we introduce a new, cell-based treatment strategy to target bacterial airway infections. Here we show that the mass production of therapeutic phagocytes from induced pluripotent stem cells (iPSC) in industry-compatible, stirred-tank bioreactors is feasible. Bioreactor-derived iPSC-macrophages (iPSC-Mac) represent a highly pure population of CD45+CD11b+CD14+CD163+ cells, and share important phenotypic, functional and transcriptional hallmarks with professional phagocytes, however with a distinct transcriptome signature similar to primitive macrophages. Most importantly, bioreactor-derived iPSC-Mac rescue mice from Pseudomonas aeruginosa-mediated acute infections of the lower respiratory tract within 4-8 h post intra-pulmonary transplantation and reduce bacterial load. Generation of specific immune-cells from iPSC-sources in scalable stirred-tank bioreactors can extend the field of immunotherapy towards bacterial infections, and may allow for further innovative cell-based treatment strategies.

Small Noncoding Regulatory RNAs from Pseudomonas aeruginosa and Burkholderia cepacia Complex.

Cystic fibrosis (CF) is the most life-limiting autosomal recessive disorder in Caucasians. CF is characterized by abnormal viscous secretions that impair the function of several tissues, with chronic bacterial airway infections representing the major cause of early decease of these patients. Pseudomonas aeruginosa and bacteria from the Burkholderia cepacia complex (Bcc) are the leading pathogens of CF patients’ airways. A wide array of virulence factors is responsible for the success of infections caused by these bacteria, which have tightly regulated responses to the host environment. Small noncoding RNAs (sRNAs) are major regulatory molecules in these bacteria. Several approaches have been developed to study P. aeruginosa sRNAs, many of which were characterized as being involved in the virulence. On the other hand, the knowledge on Bcc sRNAs remains far behind. The purpose of this review is to update the knowledge on characterized sRNAs involved in P. aeruginosa virulence, as well as to compile data so far achieved on sRNAs from the Bcc and their possible roles on bacteria virulence.

In Vivo Biofilm Formation, Gram-Negative Infections and TAS2R38 Polymorphisms in CRSw NP Patients.

Among the predisposing factors implicated in the immune response to airway bacterial infections, genetic variations of the bitter taste receptor TAS2R38, which is expressed in the cilia of the human sinonasal epithelial cells, seem to be associated with susceptibility to chronic rhinosinusitis (CRS) and in vitro biofilm formation. Polymorphisms in TAS2R38 generate two common haplotypes: the nonfunctional AVI (Alanine, Valine, Isoleucine) and the functional PAV (Proline, Alanine, Valine) alleles, with the latter protecting against gram-negative sinonasal infections. The aim of this study is to investigate for the first time the relevance of TAS2R38 genetic variants in the susceptibility to bacterial infections associated with in vivo biofilm formation in chronic rhinosinusitis with nasal polyps (CRSwNP) patients. A prospective study on 100 adult patients undergoing functional endoscopic sinus surgery (FESS) for CRSwNP. Propylthiouracile (PROP) testing and TAS2R38 genotyping were applied to characterize patients for receptor functionality. Sinonasal mucosa samples were processed for microbiological examination and biofilm detection. The nonfunctional genotype is more frequent among CRS patients than in the general population (25% vs. 18.4%, P = 0.034). Airway gram-negative infections are primarily associated with the AVI haplotype (88.9% vs. 11.1% PAV/PAV-functional genotype, P = 0.023). Biofilm formation is prevalent in CRS patients with the AVI nontaster phenotype (62.5% vs. 33.3% PAV taster or supertaster phenotype, P = 0.05). Our findings confirm an inverse correlation between TAS2R38 functionality and gram-negative infections in Italian patients with CRSwNP. In addition, for the first time we demonstrated a relationship between in vivo microbial biofilm and TAS2R38 receptor variants. 2b. Laryngoscope, 128:E339-E345, 2018.

Relationship between the presence of bronchiectasis and acute exacerbation in Thai COPD patients.

BackgroundThe prevalence rate of bronchiectasis in COPD is variable. Coexisting bronchiectasis and COPD may influence COPD severity and exacerbation.ObjectiveWe investigated whether bronchiectasis is associated with frequent or severe COPD exacerbation. Lower airway bacterial and mycobacterial infections are a possible mechanism for bronchiectasis.Materials and methodsA cross-sectional study was conducted in 2013–2014. COPD exacerbations and hospitalizations were reviewed. Spirometry and CT were performed. COPD symptoms were assessed by using the COPD assessment test (CAT) and modified Medical Research Council (mMRC) dyspnea scale. Sputum inductions were performed and specimens were sent for microbiology.ResultsWe recruited 72 patients. Global Initiative for Chronic Obstructive Lung Disease (GOLD) A, B, C, and D, were noted in 20%, 27.1%, 14.3%, and 38.6% of the patients, respectively. Frequent exacerbations (≥2) and/or ≥1 hospitalization in the previous year were observed in 40.3% of patients. Median mMRC of COPD with frequent and non-frequent exacerbations was 1.0 (range 1–2) and 2.0 (range 1–3), (p=0.002), respectively. Median CAT of COPD with frequent and non-frequent exacerbations was 20.5 (3–37) and 11.0 (2–32), (p=0.004), respectively. CT-detected bronchiectasis was observed in 47.2% of patients. Median mMRC of COPD with and without bronchiectasis was 1.0 (0–4) and 1.0 (0–4) (p=0.22), respectively. Median CAT of COPD with and without bronchiectasis was 16.2 (95% CI: 12.9–19.6) and 13.0 (3–37), (p=0.49), respectively. The lower post-bronchodilator forced expiratory volume in 1 second (FEV1) of COPD with frequent exacerbations than those without was noted (p=0.007). The post-bronchodilator forced expiratory volume at 1 second percent in patients with and without bronchiectasis was not different (p=0.91). After adjusting for gender, severity of airflow obstruction, severity of COPD symptoms, the odds ratio for bronchiectasis with frequent and/or severe exacerbation was 4.99 (95% CI: 1.31–18.94), (p=0.018). Neither bacterial nor mycobacterial airway infection was associated with bronchiectasis or frequent exacerbation.ConclusionsBronchiectasis is common in Thai COPD. It was associated with frequent exacerbation or hospitalization. Mycobacterial tuberculosis in COPD patients with bronchiectasis was uncommon.

Reduced nontypeable Haemophilus influenzae lower airway infection in children with chronic endobronchial suppuration vaccinated with the 10-valent pneumococcal H. influenzae protein D conjugate vaccine

BackgroundNontypeable Haemophilus influenzae (NTHi), the most common bacterial lower airway infection in children with protracted bacterial bronchitis, is associated with progression to bronchiectasis. We determined whether vaccination with 10-valent pneumococcal NTHi protein-D conjugate vaccine (PHiD-CV) reduced NTHi lower airway infection compared to children not PHiD-CV-vaccinated. Our unique childhood vaccination schedule and prospective 9-year bronchoalveolar lavage (BAL) collection provided an exclusive opportunity to examine this hypothesis. MethodsPaired BAL fluids and nasopharyngeal (NP) swabs were collected from 543 children (2007–2016) undergoing bronchoscopy for chronic cough. Children who received a primary course of ≥2 doses of one pneumococcal conjugate vaccine (PCV) and <2 doses of another PCV were included in each vaccine group. Logistic regression determined associations between NTHi lower airway infection (≥104 colony-forming units/mL BAL) and age, sex, Indigenous status, antibiotic exposure, and PHiD-CV vaccination. ResultsOf 262 PCV7-vaccinated, 53 PHiD-CV-vaccinated and 166 PCV13-vaccinated children (62 had mixed schedules, <2 PCV doses or missing vaccination data), NTHi lower airway infection was detected in 89 (34%), 9 (17%) and 47 (28%), respectively. On multivariate regression, significant independent factors associated with reduced NTHi lower airway infection were PHiD-CV vaccination (ORadjusted = 0.42, 95%CI 0.19–0.93), macrolide use (ORadjusted = 0.57, 95%CI 0.35–0.93) and increasing age (ORadjusted = 0.88, 95%CI 0.80–0.96). PHiD-CV vaccination had no impact on NTHi NP carriage. ConclusionsPHiD-CV-vaccinated children were significantly less likely to have NTHi lower airway infection than children not PHiD-CV-vaccinated. PHiD-CV is likely an effective intervention for reducing NTHi endobronchial infection in children at risk of chronic suppurative lung diseases.

Asthma Exacerbation Caused by Bacterial Infection in Two Elderly Patients

Background: The role of airway bacterial infection in the asthma exacerbation has been reported in addition to that of viral infection. However, the effect of bacterial infections on asthma exacerbation has received less attention than that of viral infections, and clinical features have not been well reported.Case presentation: Here, we describe the clinical features of two cases of asthma exacerbation that were thought to involve airway and/or lung bacterial infection and that improved with treatment including antibiotics, glucocorticoids and bronchodilators.Conclusion: The examination data suggested that neutrophilic inflammation caused by bacterial infections may have an important role in the development of asthma exacerbations.

Defining lower airway bacterial infection in children with chronic endobronchial disorders.

BackgroundDifferentiating lower airway bacterial infection from possible upper airway contamination in children with endobronchial disorders undergoing bronchoalveolar lavage (BAL) is important for guiding management. A diagnostic bacterial load threshold based on inflammatory markers has been determined to differentiate infection from upper airway contamination in infants with cystic fibrosis, but not for children with protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD), or bronchiectasis.MethodsBAL samples from children undergoing bronchoscopy underwent quantitative bacterial culture, cytologic examination, and respiratory virus testing; a subset also had interleukin‐8 examined. Geometric means (GMs) of total cell counts (TCCs) and neutrophil counts were plotted by respiratory pathogen bacterial load. Logistic regression determined associations between age, sex, Indigenous status, antibiotic exposure, virus detection and bacterial load, and elevated TCCs (>400 × 103 cells/mL) and airway neutrophilia (neutrophils >15% BAL leukocytes).ResultsFrom 2007 to 2016, 655 children with PBB, CSLD, or bronchiectasis were enrolled. In univariate analyses, Indigenous status and bacterial load ≥105 colony‐forming units (CFU)/mL were positively associated with high TCCs. Viruses and bacterial load ≥104 CFU/mL were positively associated with neutrophilia; negative associations were seen for Indigenous status and macrolides. In children who had not received macrolide antibiotics, bacterial load was positively associated in multivariable analyses with high TCCs at ≥104 CFU/mL and with neutrophilia at ≥105 CFU/mL; GMs of TCCs and neutrophil counts were significantly elevated at 104 and 105 CFU/mL compared to negative cultures.ConclusionsOur findings support a BAL threshold ≥104 CFU/mL to define lower airway infection in children with chronic endobronchial disorders.

The Nonantibiotic Macrolide EM703 Improves Survival in a Model of Quinolone-Treated Pseudomonas aeruginosa Airway Infection

Macrolide antibiotics are used as anti-inflammatory agents, e.g., for prevention of exacerbations in chronic obstructive pulmonary disease and cystic fibrosis. Several studies have shown improved outcomes after the addition of macrolides to β-lactam antibiotics for treatment of severe community-acquired pneumonia. However, a beneficial effect of macrolides in treating Gram-negative bacterial airway infections, e.g., those caused by Pseudomonas aeruginosa, remains to be shown. Macrolide antibiotics have significant side effects, in particular, motility-stimulating activity in the gastrointestinal tract and promotion of bacterial resistance. In this study, EM703, a modified macrolide lacking antibiotic and motility-stimulating activities but with retained anti-inflammatory properties, was used as an adjunct treatment for experimental P. aeruginosa lung infection, in combination with a conventional antibiotic. Airway infections in BALB/cJRj mice were induced by nasal instillation of P. aeruginosa; this was followed by treatment with the quinolone levofloxacin in the absence or presence of EM703. Survival, inflammatory responses, and cellular influx to the airways were monitored. Both pretreatment and simultaneous administration of EM703 dramatically improved survival in levofloxacin-treated mice with P. aeruginosa airway infections. In addition, EM703 reduced the levels of proinflammatory cytokines, increased the numbers of leukocytes in bronchoalveolar lavage fluid, and reduced the numbers of neutrophils present in lung tissue. In summary, the findings of this study show that the immunomodulatory properties of the modified macrolide EM703 can be important when treating Gram-negative pneumonia, as exemplified by P. aeruginosa infection in this study.

Long-term nicotine exposure dampens LPS-induced nerve-mediated airway hyperreactivity in murine airways.

Nicotine is a major component of cigarette smoke. It causes addiction and is used clinically to aid smoke cessation. The aim of the present study is to investigate the effect of nicotine on lipopolysaccharide (LPS)-induced airway hyperreactivity (AHR) and to explore the potential involvement of neuronal mechanisms behind nicotine's effects in murine models in vivo and in vitro. BALB/c mice were exposed to nicotine in vivo via subcutaneous Alzet osmotic minipumps containing nicotine tartate salt solution (24 mg·kg-1·day-1) for 28 days. LPS (0.1 mg/ml, 20 µl) was administered intranasally for 3 consecutive days during the end of this period. Lung functions were measured with flexiVent. For the in vitro experiments, mice tracheae were organcultured with either nicotine (10 μM) or vehicle (DMSO, 0.1%) for 4 days. Contractile responses of the tracheal segments were measured in myographs following electric field stimulation (EFS; increasing frequencies of 0.2 to 12.8 Hz) before and after incubation with 10 µg/ml LPS for 1 h. Results showed that LPS induced AHR to methacholine in vivo and increased contractile responses to EFS in vitro. Interestingly, long-term nicotine exposure markedly dampened this LPS-induced AHR both in vitro and in vivo. Tetrodotoxin (TTX) inhibited LPS-induced AHR but did not further inhibit nicotine-suppressed AHR in vivo. In conclusion, long-term nicotine exposure dampened LPS-induced AHR. The effect of nicotine was mimicked by TTX, suggesting the involvement of neuronal mechanisms. This information might be used for evaluating the long-term effects of nicotine and further exploring of how tobacco products interact with bacterial airway infections.

Ciprofloxacin-loaded lipid-core nanocapsules as mucus penetrating drug delivery system intended for the treatment of bacterial infections in cystic fibrosis

Treatment of bacterial airway infections is essential for cystic fibrosis therapy. However, effectiveness of antibacterial treatment is limited as bacteria inside the mucus are protected from antibiotics and immune response. To overcome this biological barrier, ciprofloxacin was loaded into lipid-core nanocapsules (LNC) for high mucus permeability, sustained release and antibacterial activity. Ciprofloxacin-loaded LNC with a mean size of 180nm showed a by 50% increased drug permeation through mucus. In bacterial growth assays, the drug in the LNC had similar minimum inhibitory concentrations as the free drug in P. aeruginosa and S. aureus. Interestingly, formation of biofilm-like aggregates, which were observed for S. aureus treated with free ciprofloxacin, was avoided by exposure to LNC.With the combined advantages over the non-encapsulated drug, ciprofloxacin-loaded LNC represent a promising drug delivery system with the prospect of an improved antibiotic therapy in cystic fibrosis.

A prospective, observational cohort study of the seasonal dynamics of airway pathogens in the aetiology of exacerbations in COPD

BackgroundThe aetiology of acute exacerbations of COPD (AECOPD) is incompletely understood. Understanding the relationship between chronic bacterial airway infection and viral exposure may explain the incidence and seasonality of these...

Insulin signaling via the PI3-kinase/Akt pathway regulates airway glucose uptake and barrier function in a CFTR-dependent manner.

Cystic fibrosis-related diabetes is the most common comorbidity associated with cystic fibrosis (CF) and correlates with increased rates of lung function decline. Because glucose is a nutrient present in the airways of patients with bacterial airway infections and because insulin controls glucose metabolism, the effect of insulin on CF airway epithelia was investigated to determine the role of insulin receptors and glucose transport in regulating glucose availability in the airway. The response to insulin by human airway epithelial cells was characterized by quantitative PCR, immunoblot, immunofluorescence, and glucose uptake assays. Phosphatidylinositol 3-kinase/protein kinase B (Akt) signaling and cystic fibrosis transmembrane conductance regulator (CFTR) activity were analyzed by pharmacological and immunoblot assays. We found that normal human primary airway epithelial cells expressed glucose transporter 4 and that application of insulin stimulated cytochalasin B-inhibitable glucose uptake, consistent with a requirement for glucose transporter translocation. Application of insulin to normal primary human airway epithelial cells promoted airway barrier function as demonstrated by increased transepithelial electrical resistance and decreased paracellular flux of small molecules. This provides the first demonstration that airway cells express insulin-regulated glucose transporters that act in concert with tight junctions to form an airway glucose barrier. However, insulin failed to increase glucose uptake or decrease paracellular flux of small molecules in human airway epithelia expressing F508del-CFTR. Insulin stimulation of Akt1 and Akt2 signaling in CF airway cells was diminished compared with that observed in airway cells expressing wild-type CFTR. These results indicate that the airway glucose barrier is regulated by insulin and is dysfunctional in CF.