Airway mucociliary regeneration and function are key players for airway defense and are impaired in chronic obstructive pulmonary disease (COPD). Using transcriptome analysis in COPD-derived... Show moreAirway mucociliary regeneration and function are key players for airway defense and are impaired in chronic obstructive pulmonary disease (COPD). Using transcriptome analysis in COPD-derived bronchial biopsies, we observed a positive correlation between cilia-related genes and microRNA-449 (miR449). In vitro, miR449 was strongly increased during airway epithelial mucociliary differentiation. In vivo, miR449 was upregulated during recovery from chemical or infective insults. miR0449(-/-) mice (both alleles are deleted) showed impaired ciliated epithelial regeneration after naphthalene and Haemophilus influenzae exposure, accompanied by more intense inflammation and emphysematous manifestations of COPD. The latter occurred spontaneously in aged miR449(-/-) mice. We identified Aurora kinase A and its effector target HDAC6 as key mediators in miR449-regulated ciliary homeostasis and epithelial regeneration. Aurora kinase A is downregulated upon miR449 overexpression in vitro and upregulated in miR449(-/-) mouse lungs. Accordingly, imaging studies showed profoundly altered cilia length and morphology accompanied by reduced mucociliary clearance. Pharmacological inhibition of HDAC6 rescued cilia length and coverage in miR449(-/-) cells, consistent with its tubulin-deacetylating function. Altogether, our study establishes a link between miR449, ciliary dysfunction, and COPD pathogenesis. Show less
In this thesis, we developed methods focusing on quantifying pulmonary vascular diseases and assessing treatment effects, based on CT images. A lung vessel segmentation method was proposed in... Show moreIn this thesis, we developed methods focusing on quantifying pulmonary vascular diseases and assessing treatment effects, based on CT images. A lung vessel segmentation method was proposed in Chapter 2, as accurately extracting lung vessels is an essentialstep for pulmonary vessel analysis. An automatic method for pulmonary vessel quantification was developed in Chapter 3, where two imaging biomarkers were proposed for quantifying the vascular morphology. In Chapter 4, the relation between these imaging biomarkers and pulmonary function were investigated in a selected SSc patient group, who had reductions in gas transfer but did not have fibrosis. The densitometry changes in pulmonary vasculature and parenchyma were studied by comparing CTPA scans before and after treatment for CTEPH patients treated with BPA, in Chapter 5. A vascular tree matching method was proposed for matching pulmonaryvasculature trees, for quantifying changes in vascular morphology for CTEPH patients in Chapter 6. Show less
Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath... Show moreConcentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4-way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation. EBC and plasma samples were collected postdose and analysed for drug concentrations. Sample dilution, calculated using urea concentrations, was used to estimate the epithelial lining fluid concentration. Salbutamol and tobramycin were largely undetectable in EBC after intravenous administration and were detectable after inhaled administration in all subjects in 50.8 and 51.5% of EBC samples, respectively. Correction of EBC concentrations for sample dilution did not explain the high variability. This high variability of EBC drug concentrations seems to preclude EBC as a matrix for pharmacokinetic analysis of tobramycin and salbutamol. Show less
Purpose: Gas exchange in systemic sclerosis (SSc) is known to be affected by fibrotic changes in the pulmonary parenchyma. However, SSc patients without detectable fibrosis can still have impaired... Show morePurpose: Gas exchange in systemic sclerosis (SSc) is known to be affected by fibrotic changes in the pulmonary parenchyma. However, SSc patients without detectable fibrosis can still have impaired gas transfer. We aim to investigate whether pulmonary vascular changes could partly explain a reduction in gas transfer of SSc patients without fibrosis. Materials and Methods: We selected 77 patients whose visual computed tomography (CT) scoring showed no fibrosis. Pulmonary vessels were detected automatically in CT images, and their local radii were calculated. The frequency of occurrence for each radius was calculated, and, from this radius histogram, 2 imaging biomarkers (alpha and beta) were extracted, wherein alpha reflects the relative contribution of small vessels compared with large vessels, and beta represents the vessel tree capacity. Correlations between imaging biomarkers and gas transfer [single-breath diffusion capacity for carbon monoxide corrected for hemoglobin concentration (DLCOc) %predicted] were evaluated with Spearman correlation. Multivariable stepwise linear regression was performed with DLCOc %predicted as the dependent variable and age, BMI, sPAP, FEV1 %predicted, TLC %predicted, FVC %predicted, alpha, beta, voxel size, and CT-derived lung volume as independent variables. Results: Both alpha and beta were significantly correlated with gas transfer (R=-0.29, P-value=0.011 and R=0.32, P-value=0.004, respectively). The multivariable stepwise linear regression analysis selected sPAP [coefficient=-0.78; 95% confidence interval (CI)=-1.07, -0.49; P-value<0.001], beta (coefficient=8.6; 95% CI=4.07, 13.1; P-value<0.001), and FEV1% predicted (coefficient=0.3; 95% CI=0.12, 0.48; P-value=0.001) as significant independent predictors of DLCOc %predicted (R=0.71, P-value<0.001). Conclusions: In SSc patients without detectable pulmonary fibrosis, impaired gas exchange is associated with alterations in pulmonary vascular morphology. Show less
