We conclude that online determination of exhaled aerosols from the human lungs is a prerequisite to standardize the assessment of nonvolatile mediators by normalization to the aerosol emission rate.
SUMMARYThe pathogenesis of pulmonary sarcoidosis has been related to an increased production of Th1-like cytokines. However, cytokine expression in sarcoidosis has not been systematically studied at a singlecell level. We therefore investigated the expression of IL-2, IL-4, IL-13, tumour necrosis factor-alpha (TNF-a ) and interferon-gamma (IFN-g) intracellularly in bronchoalveolar lavage (BAL) and peripheral blood CD31 T lymphocytes from patients with pulmonary sarcoidosis (radiologic stage II±III, n 8) and normal controls (n 9) by flow cytometry. In contrast to IL-4 and IL-13, the percentage of T lymphocytes expressing intracellular IL-2 (49´3^21´3% versus 14´5^15´6%), IFN-g (75´5^14´9% versus 32´6^18´7%) and TNF-a (68´3^18´7% versus 36´8^20´8%) was significantly higher in patients with sarcoidosis than in normal controls (each P , 0´005). In contrast to BAL lymphocytes, expression of these cytokines in peripheral blood lymphocytes did not differ between patients with sarcoidosis and normal controls. Close correlations were observed between the percentages of BAL lymphocytes expressing intracellular IL-2, IFN-g and TNF-a , but not for IL-4 or IL-13. Analysis of the expression of these cytokines in T lymphocyte subsets revealed IL-2, IFN-g, and TNF-a in CD41 as well as CD8 1 T lymphocytes, suggesting a contribution of TC1 cells to the production of proinflammatory cytokines in sarcoidosis. We conclude that a Th1-like cytokine pattern can be observed in CD41 as well as in CD8 1 BAL T lymphocytes in patients with pulmonary sarcoidosis.
The deletion (D)/insertion (I) polymorphism in intron 16 of the angiotensinconverting enzyme (ACE) gene has the greatest impact on serum ACE level in Caucasians of any factor yet discovered. The aim of the present study was to establish new ACE genotype-corrected normal ranges for serum ACE level in a population of central European origin.After a medical examination, 159 healthy Caucasians volunteered to donate blood for the study. ACE genotypes were assessed by PCR and serum ACE levels were determined using two different kinetic tests.The distribution of the D/I polymorphism of the ACE gene was in accordance with the HardyWeinberg equilibrium. Serum ACE levels and ACE genotypes correlated significantly, with the highest serum ACE levels in subjects with ACE genotype D/D, and the lowest serum ACE levels in subjects with genotype I/I (mean¡SD, assay 1: D/D 59.3¡15.1 U?L -1 , D/I 45.5¡15.2 U?L -1
Airway obstruction does not change the number flux or size distribution of particles in exhaled breath. The high intersubject variability of particle emission supports the concept of online determination of aerosol properties (primarily number flux, during exhaled breath) during breath condensate sampling to properly normalize the results of biochemical analysis. As high dilution and variable dilution are the main challenges of biomarker assessment in exhaled breath condensate, this normalization procedure would significantly add to the value of the technique.
COPD is a highly prevalent disease. With regard to the increasing life expectancy and the change of smoking habits of the population, a further increase of morbidity and mortality due to COPD must be expected, especially in women.
BackgroundInhalation of endotoxin (LPS) induces a predominantly neutrophilic airway inflammation and has been used as model to test the anti-inflammatory activity of novel drugs. In the past, a dose exceeding 15–50 μg was generally needed to induce a sufficient inflammatory response. For human studies, regulatory authorities in some countries now request the use of GMP-grade LPS, which is of limited availability. It was therefore the aim of this study to test the effect and reproducibility of a low-dose LPS challenge (20,000 E.U.; 2 μg) using a flow- and volume-controlled inhalation technique to increase LPS deposition.MethodsTwo to four weeks after a baseline sputum induction, 12 non-smoking healthy volunteers inhaled LPS on three occasions, separated by at least 4 weeks. To modulate the inflammatory effect of LPS, a 5-day PDE4 inhibitor (Roflumilast) treatment preceded the last challenge. Six hours after each LPS inhalation, sputum induction was performed.ResultsThe low-dose LPS inhalation was well tolerated and increased the mean percentage of sputum neutrophils from 25% to 72%. After the second LPS challenge, 62% neutrophils and an increased percentage of monocytes were observed. The LPS induced influx of neutrophils and the cumulative inflammatory response compared with baseline were reproducible. Treatment with Roflumilast for 5 days did not have a significant effect on sputum composition.ConclusionThe controlled inhalation of 2 μg GMP-grade LPS is sufficient to induce a significant neutrophilic airway inflammation in healthy volunteers. Repeated low-dose LPS challenges potentially result in a small shift of the neutrophil/monocyte ratio; however, the cumulative response is reproducible, enabling the use of this model for “proof-of-concept” studies for anti-inflammatory compounds during early drug development.Trial registrationClinicaltrials.gov: NCT01400568
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