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Rob Janssen,1 Emiel FM Wouters,2 Wim Janssens,3 Willeke F Daamen,4 Paul Hagedoorn,5 Hugo AJM de Wit,6 Jef Serré,3 Ghislaine Gayan-Ramirez,3 Frits ME Franssen,2 Niki L Reynaert,2 Jan H von der Thüsen,7 Henderik W Frijlink5 1Department of Pulmonary Medicine, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands; 2Department of Respiratory Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands; 3Laboratory of Respiratory Diseases, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium; 4Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; 5Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, Groningen, University of Groningen, Groningen, The Netherlands; 6Department of Clinical Pharmacy, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands; 7Department of Pathology, Erasmus Medical Center, Rotterdam, The NetherlandsCorrespondence: Rob JanssenDepartment of Pulmonary Medicine, Canisius-Wilhelmina Hospital, Weg Door Jonkerbos 100, Nijmegen, SZ 6532, The NetherlandsEmail rob.janssen@cwz.nlAbstract: Current pharmacotherapy of chronic obstructive pulmonary disease (COPD) aims at reducing respiratory symptoms and exacerbation frequency. Effective therapies to reduce disease progression, however, are still lacking. Furthermore, COPD medications showed less favorable effects in emphysema than in other COPD phenotypes. Elastin fibers are reduced and disrupted, whereas collagen levels are increased in emphysematous lungs. Protease/antiprotease imbalance has historically been regarded as the sole cause of emphysema. However, it is nowadays appreciated that emphysema may also be provoked by perturbations in the sequential repair steps following elastolysis. Essentiality of fibulin-5 and lysyl oxidase-like 1 in the elastin restoration process is discussed, and it is argued that copper deficiency is a plausible reason for failing elastin repair in emphysema patients. Since copper-dependent lysyl oxidases crosslink elastin as well as collagen fibers, copper supplementation stimulates accumulation of both proteins in the extracellular matrix. Restoration of abnormal elastin fibers in emphysematous lungs is favorable, whereas stimulating pulmonary fibrosis formation by further increasing collagen concentrations and organization is detrimental. Heparin inhibits collagen crosslinking while stimulating elastin repair and might therefore be the ideal companion of copper for emphysema patients. Efficacy and safety considerations may lead to a preference of pulmonary administration of copper-heparin over systemic administration.Keywords: collagen, copper, desmosine, elastin, emphysema, fibulin-5, heparin, lysyl oxidase, lysyl oxidase-like protein 1, tropoelastin

This document contains supplementary Tables S1 and S2, as referred to in the text. Table S1 is The change (post - pre) in all pulmonary function parameters evoked by the provocation. Table S2 shows Spearmanâ s univariate correlation of the change in Borg dyspnea score with gender, smoking status, and all pulmonary function parameters. (DOCX 27â kb)

Table S1. Baseline characteristics. Table S2. Baseline values of measurements of small airways dysfunction. Table S3. Difference in Î PD20 adenosine in patients with and without small airways dysfunction after treatment with QVAR, Clenil and Flixotide. Table S4. Univariate linear regression analysis of baseline variables and change in airway hyperresponsiveness (Î PD20) in patients treated with QVAR, Clenil and Flixotide. Figure S1. Scatterplots of significant correlations between baseline variables and Î PD20 adenosine. (PDF 731 kb)