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Background: Lung densitometry derived from computed tomographic images offers an opportunity to quantify emphysema non-invasively, but a pathological standard cannot be applied to validate its use in longitudinal monitoring studies. Consequently, forced expiratory volume in 1 second (FEV1) remains the standard against which new methods must be judged. We related progression of densitometry (15th percentile point and voxel index, threshold -950 Hounsfield units) to disease stage and FEV1 decline in two studies of subjects with alpha1-antitrypsin deficiency (PiZ). Methods: Consistency of progression, measured using densitometry and FEV1, was assessed in relation to disease stage in a 2 year study of 74 subjects grouped according to the FEV1 criteria employed in the GOLD guidelines. In the second study of a subgroup of subjects with extended data (n=34), summary statistics were applied to measurements performed annually over 3 years and the rate of progression of densitometry was related to FEV1 decline. Results: The progression of percentile point was consistent across a wide spectrum of disease severity, but voxel index progression varied in association with disease stage (p=0.004). In the second study, FEV1 decline correlated with progression of lung densitometry (percentile point: rS=0.527, p=0.001; voxel index: rS=-0.398, p=0.012). Conclusions: 15th percentile point is a more consistent measure of lung density loss across a wide range of physiological impairment than voxel index. However, both methods are valid for use in longitudinal and interventional studies in which emphysema is the major outcome target. [ABSTRACT FROM AUTHOR]

The article focuses on computed tomographic (CT) imaging in α1-antitrypsin deficiency. α1-antitrypsin (AAT) deficiency is characterized by a reduced serum AAT level down to about 20% of the normal level leading to the development of emphysema. CT scanning is the most sensitive method of diagnosing emphysema, determining its subtype and assessing its severity in vivo and both visual and quantitative CT scanning is closely correlated with the pathological extent of emphysema.

Background: It has been suggested that oxidative stress is an important factor in the pathogenesis of chronic obstructive pulmonary disease (COPD). We have shown that an oxidant/antioxidant imbalance occurs in the distal air spaces of smokers and in patients with COPD which is reflected systemically in the plasma. A study was undertaken to determine whether plasma antioxidant status correlated with lung function as assessed by forced expiratory volume in one second (FEV(1)) and forced vital capacity (FVC) in smokers and patients with COPD.Methods: Plasma antioxidant capacity, assessed by the Trolox equivalent antioxidant capacity (TEAC) as an index of overall systemic oxidative stress, and protein thiol levels were measured in 95 patients with stable COPD, in 82 healthy smokers, and in 37 healthy non-smokers.Results: Mean (SE) plasma TEAC levels were significantly decreased in patients with COPD (0.81 (0.03) mmol/l, p<0.001) and in healthy smokers (0.87 (0.04) mmol/l, p<0. 001) compared with healthy non-smokers (1.31 (0.11) mmol/l). The mean differences in plasma antioxidant capacity (mM) were (0.81, 95% confidence interval (CI) 0.22 to 1.48), (0.87, 95% CI 0.2 to 1.46), and (1.31, 95% CI 1.09 to 1.58) in patients with COPD, healthy smokers, and healthy non-smokers, respectively. This reduction was associated with a 29% (95% CI 18 to 38) and a 30% (95% CI 19 to 40) decrease in plasma protein thiol levels in COPD patients and smokers, respectively. Current smoking was not the main contributor to the reduction in antioxidant capacity in patients with COPD as those patients who were still smokers had similar TEAC levels (mean (SE) 0. 78 (0.05); n = 25) to those who had stopped smoking (0.84 (0.02); n = 70). No significant correlations were found between spirometric data measured as FEV(1) % predicted or FEV(1)/FVC % predicted and the plasma levels of TEAC in patients with COPD, healthy smokers, or healthy non-smokers. Similarly, there was no significant correlation between FEV(1) % predicted or FEV(1)/FVC % predicted and the levels of plasma protein thiols in the three groups.Conclusions: These data confirm decreased antioxidant capacity in smokers and patients with COPD, indicating the presence of systemic oxidative stress. However, no relationship was found between protein thiols or TEAC levels and measurements of airflow limitation in either smokers or in patients with COPD. [ABSTRACT FROM AUTHOR]

We have studied the effects of the mucolytic thiol agent mercapto-ethanesulphonate (mesna) on the activity of both polymorphonuclear leucocyte (PMN) elastase and antileucoprotease in vitro. In all tests a specific synthetic substrate was used to measure elastase activity, which was then related to enzyme activity in the absence of mesna. The relative elastase activity decreased to 67.5% of control values after the enzyme had been incubated in a 120 mmol/l mesna solution. In the sol phase of purulent sputum, elastase activity decreased to 45% after the sol phase had been incubated in a 600 mmol/l mesna solution. The inability to reverse the inhibition of mesna by increasing the substrate concentration indicated that mesna acts as a non-competitive inhibitor of PMN elastase. Incubation of elastase with antileucoprotease reduced the relative elastase activity to 21%. When antileucoprotease was preincubated in a 60 mmol/l mesna solution under identical assay conditions, a relative elastase activity of 39% was observed. Inhibition experiments with mesna treated antileucoprotease, in which sulphydryl groups were blocked with iodoacetamide, strongly suggested that the dissociation constant (Ki) of the fraction of antileucoprotease that retains activity after the incubation with mesna was not changed. Elastase inhibitory activity in mucoid sol phase, which can be ascribed mainly to antileucoprotease, decreased to 53% after incubation with mesna at a concentration of 960 mmol/l. Incubation of PMN elastase/antileucoprotease complex with mesna did not result in any release of active PMN elastase from the antileucoprotease. It is concluded that mesna and other thiol compounds, when locally administered, may influence the proteinase-antiproteinase balance in the airways by their effect on both PMN elastase and antileucoprotease. [ABSTRACT FROM AUTHOR]

COPD is characterised by tissue destruction and inflammation. Given the lack of curative treatments and the progressive nature of the disease, new treatments for COPD are highly relevant. In vitro cell culture and animal studies have demonstrated that mesenchymal stromal cells (MSCs) have the capacity to modify immune responses and to enhance tissue repair. These properties of MSCs provided a rationale to investigate their potential for treatment of a variety of diseases, including COPD. Preclinical models support the hypothesis that MSCs may have clinical efficacy in COPD. However, although clinical trials have demonstrated the safety of MSC treatment, thus far they have not provided evidence for MSC efficacy in the treatment of COPD. In this review, we discuss the rationale for MSC-based cell therapy in COPD, the main findings from in vitro and in vivo preclinical COPD model studies, clinical trials in patients with COPD and directions for further research., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Chronic obstructive pulmonary disease (COPD) is a respiratory disorder with increasing prevalence and mortality. It is associated with airway obstruction, increased airway hyper-responsiveness (AHR), and ongoing airway and lung inflammation dominated by CD8 lymphocytes and neutrophils. Single-nucleotide polymorphisms (SNPs) in a disintegrin and metalloprotease 33 (ADAM33) gene have been associated with AHR and COPD., Objective: To assess whether SNPs in ADAM33 are associated with the severity of AHR and airway inflammation in COPD., Methods: Eight SNPs in ADAM33 (F+1, Q-1, S&#95;1, S&#95;2, ST+5, T&#95;1, T&#95;2, V&#95;4) were genotyped in 111 patients with COPD (96 males, 69 current smokers, mean (standard deviation (SD)), aged 62 (8) years, median pack-years 42 (IQR 31-55), mean postbronchodilator forced expiratory volume in 1 s (FEV(1))% predicted 63 (9). Provocative concentration of methacholine causing a decrease in FEV(1) of 20% (PC(20) methacholine), sputum and bronchial biopsies were collected., Results: Patients with the ST+5 AA genotype had more severe AHR, higher numbers of sputum inflammatory cells and CD8 cells in bronchial biopsies than patients with the GG genotype (p = 0.03, 0.05 and 0.01, respectively). CD8 cell numbers were lower in patients carrying the minor allele of SNP T&#95;1 and T&#95;2, and homozygotic minor variants of SNP S&#95;2 compared with the wild type (p = 0.02, 0.01 and 0.02, respectively)., Conclusions: This is the first study revealing that SNPs in a gene that confers susceptibility to COPD in the general population-that is, ADAM33-are associated with AHR and airway inflammation in COPD. These findings constitute an important step forward in linking gene polymorphisms with COPD pathophysiology, thereby possibly contributing to better treatments for this progressive and disabling disease in the future.

Computed tomographic scanning may replace lung function tests as the golden standard for assessing the response to known and novel treatments for alpha1-antitrypsin deficiency.

Background: There is increasing recognition that questionnaires of health status and lung density measurements are more sensitive tools for assessing progression of emphysema than forced expiratory volume in 1 second (FEV(1)) and transfer coefficient (KCO). A study was undertaken to investigate prospectively the correlation between annual change in health status and computer tomography (CT) derived lung density in subjects with alpha(1)-antitrypsin deficiency., Methods: Twenty two patients of mean (SD) age 40.7 (9.2) years with ZZ type alpha(1)-antitrypsin deficiency were investigated at baseline and 30 months later by FEV(1) and KCO, St George Respiratory Questionnaire (SGRQ), and by a spiral CT scan of the chest. CT data of chest images were analysed using software designed for automated lung contour detection and lung density measurements. The density data were corrected for changes in inspiration levels., Results: Changes in lung density, expressed as 15th percentile point or relative area below -950 HU, correlated well with changes in health status (SGRQ total score): R = -0.56, p = 0.007 or R = 0.6, p = 0.003. Neither changes in health status nor changes in lung density correlated significantly with changes in FEV(1) or changes in KCO., Conclusions: The SGRQ total score (which is a global measure in COPD) and lung density (a specific measure of emphysema) are sensitive to deterioration in patients with alpha(1)-antitrypsin deficiency. This finding may facilitate future studies with new drugs specific for emphysema, a frequently occurring component of COPD.