Respiratory Research - Latest Articles

No evidence of altered alveolar macrophage polarization, but reduced expression of TLR2, in bronchoalveolar lavage cells in sarcoidosis

Maria Wiken — 2010-09-02T00:00:00Z

Background: Sarcoidosis is a granulomatous inflammatory disease, possibly of infectious aetiology. We aimed to investigate whether the degree of functional polarization of alveolar macrophages (AMs), or Toll-like receptor (TLR) expression, is associated with sarcoidosis or with distinct clinical manifestations of this disease. Methods: Total BAL cells (cultured four or 24h in medium, or stimulated 24h with LPS) from 14 patients and six healthy subjects, sorted AMs from 22 patients (Lofgren's syndrome n=11) and 11 healthy subjects, and sorted CD4+ T cells from 26 patients (Lofgren's syndrome n=13) and seven healthy subjects, were included. Using real-time PCR, the relative gene expression of IL-10, IL-12p35, IL-12p40, IL-23p19, CCR2, CCR7, iNOS, CXCL10, CXCL11, CXCL16, CCL18, CCL20, CD80, and CD86, and innate immune receptors TLR2, TLR4, and TLR9, was quantified in sorted AMs, and for selected genes in total BAL cells, while IL-17A was quantified in T cells. Results: We did not find evidence of a difference with regard to alveolar macrophage M1/M2 polarization between sarcoidosis patients and healthy controls. TLR2 gene expression was significantly lower in sorted AMs from patients, particular in Lofgren's patients. CCL18 gene expression in AMs was significantly higher in patients compared to controls. Additionally, the IL-17A expression was lower in Lofgren's patients' CD4+ T cells. Conclusions: Overall, there was no evidence for alveolar macrophage polarization in sarcoidosis. However, there was a reduced TLR2 mRNA expression in patients with Lofgren's syndrome, which may be of relevance for macrophage interactions with a postulated sarcoidosis pathogen, and for the characteristics of the ensuing T cell response.

Reproducibility of the airway response to an exercise protocol standardized for intensity, duration, and inspired air conditions, in subjects with symptoms suggestive of asthma.

Sandra Anderson — 2010-09-01T00:00:00Z

Background: Exercise testing to aid diagnosis of exercise-induced bronchoconstriction (EIB) is commonly performed. Reproducibility of the airway response to a standardized exercise protocol has not been reported in subjects being evaluated with mild symptoms suggestive of asthma but without a definite diagnosis. This study examined reproducibility of % fall in FEV1 and area under the FEV1 time curve for 30 minutes in response to two exercise tests performed with the same intensity and duration of exercise, and inspired air conditions. Methods: Subjects with mild symptoms of asthma exercised twice within approximately 4 days by running for 8 minutes on a motorized treadmill breathing dry air at an intensity to induce a heart rate between 80-90% predicted maximum; reproducibility of the airway response was expressed as the 95% probability interval. Results: Of 373 subjects challenged twice 161 were positive ([greater than or equal to]10% fall FEV1 on at least one challenge). The EIB was mild and 77% of subjects had <15% fall on both challenges. Agreement between results was 76.1% with 56.8% (212) negative (<10% fall FEV1) and 19.3% (72) positive on both challenges. The remaining 23.9% of subjects had only one positive test. The 95% probability interval for reproducibility of the % fall in FEV1 and AUC0-30 min was +/-9.7% and +/-251% for all 278 adults and +/-13.4% and +/-279% for all 95 children. The 95% probability interval for reproducibility of % fall in FEV1 and AUC0-30min for the 72 subjects with two tests [greater than or equal to]10% fall FEV1 was +/-14.6% and +/-373% and for the 34 subjects with two tests [greater than or equal to]15% fall FEV1 it was +/-12.2% and +/-411%. Heart rate and estimated ventilation achieved were not significantly different either on the two test days or when one test result was positive and one was negative. Conclusions: Under standardized, well controlled conditions for exercise challenge, the majority of subjects with mild symptoms of asthma demonstrated agreement in test results. Performing two tests may need to be considered when using exercise to exclude or diagnose EIB, when prescribing prophylactic treatment to prevent EIB and when designing protocols for clinical trials.

Hypertonic saline increases lung epithelial lining fluid glutathione and thiocyanate: Two protective CFTR-dependent thiols against oxidative injury.

Neal Gould — 2010-08-27T00:00:00Z

Background: Cystic fibrosis is a debilitating lung disease due to mutations in cystic fibrosis transmembrane conductance regulator protein (CFTR) that are associated with chronic infections resulting in elevated myeloperoxidase activity and generation of hypochlorous acid (HOCl). CFTR mutations lead to decreased levels of glutathione (GSH) and thiocyanate (SCN) in the epithelial lining fluid (ELF). Hypertonic saline is used to improve lung function however the mechanism is uncertain. Methods: In the present study, the effect of GSH and SCN on HOCl-mediated cell injury and their changes in the ELF after hypertonic saline nebulization in wild type (WT) and CFTR KO mice was examined. CFTR sufficient and deficient lung cells were assessed for GSH, SCN and corresponding sensitivity towards HOCl-mediated injury, in vitro. Results: CFTR (-) cells had lower extracellular levels of both GSH and SCN and were more sensitive to HOCl-mediated injury. In vivo, hypertonic saline increased ELF GSH in the WT and to a lesser extent in the CFTR KO mice but only SCN in the WT ELF. Finally, potential protective effects of GSH and SCN at concentrations found in the ELF against HOCl toxicity were examined in vitro. Conclusions: While the concentrations of GSH and SCN associated with the WT ELF protect against HOCl toxicity, those found in the CFTR KO mice were less sufficient to inhibit cell injury. These data suggests that CFTR has important roles in exporting GSH and SCN which are protective against oxidants and that hypertonic saline treatment may have beneficial effects by increasing their levels in the lung.

Allergic inflammation does not impact chemical-induced carcinogenesis in the lungs of mice

Konstantinos Doris — 2010-08-26T00:00:00Z

Background: Although the relationship between allergic inflammation and lung carcinogenesis is not clearly defined, several reports suggest an increased incidence of lung cancer in patients with asthma. We aimed at determining the functional impact of allergic inflammation on chemical carcinogenesis in the lungs of mice. Methods: Balb/c mice received single-dose urethane (1 g/kg at day 0) and two-stage ovalbumin during tumor initiation (sensitization: days -14 and 0; challenge: daily at days 6-12), tumor progression (sensitization: days 70 and 84; challenge: daily at days 90-96), or chronically (sensitization: days -14 and 0; challenge: daily at days 6-12 and thrice weekly thereafter). In addition, IL (Interleukin)-5 deficient and wild-type C57BL/6 mice received ten weekly urethane injections. All mice were sacrificed after four months. Primary end-points were number, size, and histology of lung tumors. Secondary end-points were inflammatory cells and mediators in the airspace compartment. Results: Ovalbumin provoked acute allergic inflammation and chronic remodeling of murine airways, evident by airspace eosinophilia, IL-5 up-regulation, and airspace enlargement. Urethane resulted in formation of atypical alveolar hyperplasias, adenomas, and adenocarcinomas in mouse lungs. Ovalbumin-induced allergic inflammation during tumor initiation, progression, or continuously did not impact the number, size, or histologic distribution of urethane-induced pulmonary neoplastic lesions. In addition, genetic deficiency in IL-5 had no effect on urethane-induced lung tumorigenesis. Conclusions: Allergic inflammation does not impact chemical-induced carcinogenesis of the airways. These findings suggest that not all types of airway inflammation influence lung carcinogenesis and cast doubt on the idea of a mechanistic link between asthma and lung cancer.

Helium-oxygen reduces the production of carbon dioxide during weaning from mechanical ventilation

Gordon Flynn — 2010-08-26T00:00:00Z

Background: Prolonged weaning from mechanical ventilation has a major impact on ICU bed occupancy and patient outcome, and has significant cost implications.There is evidence in patients around the period of extubation that helium-oxygen leads to a reduction in the work of breathing. Therefore breathing helium-oxygen during weaning may be a useful adjunct to facilitate weaning. We hypothesised that breathing helium-oxygen would reduce carbon dioxide production during the weaning phase of mechanical ventilation.Materials/patients and methods: We performed a prospective randomised controlled single blinded cross-over trial on 19 adult intensive care patients without significant airways disease who fulfilled criteria for weaning with CPAP. Patients were randomised to helium-oxygen and air-oxygen delivered during a 2 hour period of CPAP ventilation. Carbon dioxide production (VCO2) was measured using a near patient main stream infrared carbon dioxide sensor and fixed orifice pneumotachograph. Results: Compared to air-oxygen, helium-oxygen significantly decreased VCO2 production at the end of the 2 hour period of CPAP ventilation; there was a mean difference in CO2 production of 48.9ml/min (95% CI 18.7-79.2 p=0.003) between the groups. There were no significant differences in other respiratory and haemodynamic parameters. Conclusion: This study shows that breathing a helium-oxygen mixture during weaning reduces carbon dioxide production. This physiological study supports the need for a clinical trial of helium-oxygen mixture during the weaning phase of mechanical ventilation with duration of weaning as the primary outcome.Trial registration: ISRCTN56470948

Genome sequences of human Adenovirus 14 isolates from mild respiratory cases and a fatal pneumonia, isolated during 2006-2007 epidemics in North America

Huo-Shu Houng — 2010-08-25T00:00:00Z

Background: Human adenovirus 14 (HAdV-14) is a recognized causative agent of epidemic febrile respiratory illness (FRI). Last reported in Eurasia in 1963, this virus has since been conspicuously absent in broad surveys, and was never isolated in North America despite inclusion of specific tests for this serotype in surveillance methods. In 2006 and 2007, this virus suddenly emerged in North America, causing high attack rate epidemics of FRI and, in some cases, severe pneumonias and occasional fatalities. Some outbreaks have been relatively mild, with low rates of progression beyond uncomplicated FRI, while other outbreaks have involved high rates of more serious outcomes.Methodology and Findings: In this paper we present the complete genomic sequence of this emerging pathogen, and compare genomic sequences of isolates from both mild and severe outbreaks. We also compare the genome sequences of the recent isolates with those of the prototype HAdV-14 that circulated in Eurasia 30 years ago and the closely related sequence of HAdV-11a, which has been circulating in southeast Asia. Conclusions: The data suggest that the currently circulating strain of HAdV-14 is closely related to the historically recognized prototype throughout its genome, though it does display a couple of potentially functional mutations in the fiber knob and E1A genes. There are no polymorphisms that suggest an obvious explanation for the divergence in severity between outbreak events, suggesting that differences in outcome are more likely environmental or host determined rather than viral genetics.

Female sex hormones mediate the allergic lung reaction by regulating the release of inflammatory mediators and the expression of lung E-selectin in rats

Ana Paula Ligeiro de Oliveira — 2010-08-24T00:00:00Z

Background: Fluctuations of estradiol and progesterone levels caused by the menstrual cycle worsen asthma symptoms. Conflicting data are reported in literature regarding pro and anti-inflammatory properties of estradiol and progesterone. Methods: Female Wistar rats were ovalbumin (OVA) sensitized 1 day after resection of the ovaries (OVx). Control group consisted of sensitized-rats with intact ovaries (Sham-OVx). Allergic challenge was performed by aerosol (OVA 1%, 15 min) two weeks later. Twenty four hours after challenge, BAL, bone marrow and total blood cells were counted. Lung tissues were used as explants, for expontaneous cytokine secretion in vitro or for immunostaining of E-selectin. Results: We observed an exacerbated cell recruitment into the lungs of OVx rats, reduced blood leukocytes counting and increased the number of bone marrow cells. Estradiol-treated OVx allergic rats reduced, and those treated with progesterone increased, respectively, the number of cells in the BAL and bone marrow. Lungs of OVx allergic rats significantly increased the E-selectin expression, an effect prevented by estradiol but not by progesterone treatment. Systemically, estradiol treatment increased the number of peripheral blood leukocytes in OVx allergic rats when compared to non treated-OVx allergic rats. Cultured-BAL cells of OVx allergic rats released elevated amounts of LTB4 and nitrites while bone marrow cells increased the release of TNF-alpha and nitrites. Estradiol treatment of OVx allergic rats was associated with a decreased release of TNF-alpha, IL-10, LTB4 and nitrites by bone marrow cells incubates. In contrast, estradiol caused an increase in IL-10 and NO release by cultured-BAL cells. Progesterone significantly increased TNF- alpha by cultured BAL cells and bone marrow cells. Conclusions: Data presented here suggest that upon hormonal oscillations the immune sensitization might trigger an allergic lung inflammation whose phenotype is under control of estradiol. Our data could contribute to the understanding of the protective role of estradiol in some cases of asthma symptoms in fertile ans post-menopausal women clinically observed.

The presence of serum anti-Ascaris lumbricoides IgE antibodies and of Trichuris trichiura infection are risk factors for wheezing and/or atopy in preschool-aged Brazilian children

Neuza Alcantara-Neves — 2010-08-23T00:00:00Z

Background: The elucidation of factors that trigger the development of transient wheezing in early childhood may be an important step toward understanding the pathogenesis of asthma and other allergic diseases later in life. Transient wheezing has been mainly attributed to viral infections, although sensitisation to aeroallergens and food allergens may occur at an early age. In developing countries, intestinal helminthic infections have also been associated with allergy or atopy-related disorders.ObjectiveThe aim of this study was to explore the association of Trichuris trichiura and Ascaris lumbricoides infections with wheezing and atopy in early childhood.Study design: A cross-sectional study using a Portuguese-language ISAAC phase I questionnaire, adapted for preschool-aged children, nested in a cohort study of childhood diarrhoea, was conducted on 682 children. Two faecal samples per child were examined for the presence of intestinal helminthic infection. IgE antibodies against three allergenic preparations (Dermatophagoides pteronyssinus, Blomia tropicalis and common child food), as well as against A. lumbricoides antigens, were measured in a sub-sample of these children, whose parents allowed the procedure. Atopy was defined by the presence of levels of serum IgE antibodies [greater than or equal to] 0.35 kU/L against at least one of the three tested allergenic preparations. Results: Active T. trichiura infection but not A. lumbricoides infection was positively associated with wheezing in the total studied children population [adjusted OR=2.60; CI=1.54;4.38] and in the atopic children sub-population [adjusted OR=3.07; CI=1.00;9.43]. The association with atopy was also positive and statistically significant only in the brute analysis [OR= 2.13; CI=1.03;4.40]. Anti-A. lumbricoides IgE antibodies, but not current A. lumbricoides infection, were positively associated with wheezing in atopic children [adjusted OR=2.01; CI= 1.00;4.50] and in non-atopic children [adjusted OR=3.07; CI=1.13;8.35] and it was also associated with atopy [adjusted OR=7.29; CI=3.90; 13.4]. On the other hands, reports of wheezing were not significantly associated with atopy. Conclusions: These data corroborate previous studies showing that wheezing is predominantly associated with infection in early childhood and shows that anti-A. lumbricoides IgE antibodies, but not active Ascaris infections, are associated with wheezing and atopy. Additionally, the data demonstrate that T. trichiura infection may play a role in the pathogenesis of atopic wheezing in early childhood.

Decline in air pollution and change in prevalence in respiratory symptoms and chronic obstructive pulmonary disease in elderly women

Tamara Schikowski — 2010-08-22T00:00:00Z

Background: While adverse effects of exposure to air pollutants on respiratory health are well studied, little is known about the effect of a reduction in air pollutants on chronic respiratory symptoms and diseases. We investigated whether different declines in air pollution levels in industrialised and rural areas in Germany were associated with changes in respiratory health over a period of about 20 years. Methods: We used data from the SALIA cohort study in Germany (Study on the influence of Air pollution on Lung function, Inflammation and Aging) to assess the association between the prevalence of chronic obstructive pulmonary disease (COPD) and chronic respiratory symptoms and the decline in air pollution exposure. In 1985-1994, 4874 women aged 55-years took part in the baseline investigation. Of these, 2116 participated in a questionnaire follow-up in 2006 and in a subgroup of 402 women lung function was tested in 2008-2009. Generalized estimating equation (GEE) models were used to estimate the effect of a reduction in air pollution on respiratory symptoms and diseases. Results: Ambient air concentrations of particulate matter with aerodynamic size < 10um (PM10) declined in average by 20mug/m3. Prevalence of chronic cough with phlegm production and mild COPD at baseline investigation compared to follow-up was 9.5% vs. 13.3% and 8.6% vs. 18.2%, respectively. A steeper decline of PM10 was observed in the industrialized areas in comparison to the rural area, this was associated with a weaker increase in prevalence of respiratory symptoms and COPD. Among women who never smoked, the prevalence of chronic cough with phlegm and mild COPD was estimated at 21.4% and 39.5%, respectively, if no air pollution reduction was assumed, and at 13.3% and 17.5%, respectively, if air pollution reduction was assumed. Conclusion: We concluded that parallel to the decline of ambient air pollution over the last 20 years in the Ruhr area the age-related increase in chronic respiratory diseases and symptoms appears to attenuate in the population of elderly women.

Nordic Walking improves daily physical activities in COPD: a randomised controlled trial

Marie-Kathrin Breyer — 2010-08-22T00:00:00Z

Background: In patients with COPD progressive dyspnoea leads to a sedentary lifestyle. To date, no studies exist investigating the effects of Nordic Walking in patients with COPD. Therefore, the aim was to determine the feasibility of Nordic Walking in COPD patients at different disease stages. Furthermore we aimed to determine the short- and long-term effects of Nordic Walking on COPD patients' daily physical activity pattern as well as on patients exercise capacity. Methods: Sixty COPD patients were randomised to either Nordic Walking or to a control group. Patients of the Nordic Walking group (n = 30; age: 62 ± 9 years; FEV1: 48 ± 19% predicted) underwent a three-month outdoor Nordic Walking exercise program consisting of one hour walking at 75% of their initial maximum heart rate three times per week, whereas controls had no exercise intervention. Primary endpoint: daily physical activities (measured by a validated tri-axial accelerometer); secondary endpoint: functional exercise capacity (measured by the six-minute walking distance; 6MWD). Assessment time points in both groups: baseline, after three, six and nine months. Results: After three month training period, in the Nordic Walking group time spent walking and standing as well as intensity of walking increased (Δ walking time: +14.9 ± 1.9 min/day; Δ standing time: +129 ± 26 min/day; Δ movement intensity: +0.40 ± 0.14 m/s2) while time spent sitting decreased (Δ sitting time: -128 ± 15 min/day) compared to baseline (all: p < 0.01) as well as compared to controls (all: p < 0.01). Furthermore, 6MWD significantly increased compared to baseline (Δ 6MWD: +79 ± 28 meters) as well as compared to controls (both: p < 0.01). These significant improvements were sustained six and nine months after baseline. In contrast, controls showed unchanged daily physical activities and 6MWD compared to baseline for all time points. Conclusions: Nordic Walking is a feasible, simple and effective physical training modality in COPD. In addition, Nordic Walking has proven to positively impact the daily physical activity pattern of COPD patients under short- and long-term observation.Clinical trial registrationNordic Walking improves daily physical activities in COPD: a randomised controlled trial - ISRCTN31525632