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1 Respiratory Disease, Novartis Institutes for BioMedical Research, Horsham, United Kingdom
2 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
3 Department of Cardiothoracic Surgery, Airway Disease, National Heart & Lung Institute, London, United Kingdom
4 Dept of Environmental Medicine, Division of Lung Biology and Disease, University of Rochester Medical Center, Rochester, New York, United States
5 Genome and Proteome Sciences, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: c.stevenson{at}imperial.ac.uk.
Chronic obstructive pulmonary disease is a smoking-related disease that lacks effective therapies due partly to the poor understanding of disease pathogenesis. The aim of this study was to identify molecular pathways which could be responsible for the damaging consequences of smoking. To do this, we employed Gene Set Enrichment Analysis to analyze differences in global gene expression, which we then related to the pathological changes induced by cigarette smoke (CS). Sprague-Dawley rats were exposed to whole-body CS for 1 day and for various periods up to 8 months. Gene Set Enrichment Analysis of microarray data identified that metabolic processes were most significantly increased early in the response to CS. Gene sets involved in stress response and inflammation were also up-regulated. CS exposure increased neutrophil chemokines, cytokines, and proteases (MMP-12) linked to the pathogenesis of COPD. After a transient acute response, the CS-exposed rats developed a distinct molecular signature after 2 weeks which was followed by the chronic phase of the response. During this phase, gene sets related to immunity and defence progressively increased and predominated at the later time-points in smoke-exposed rats. Chronic CS inhalation recapitulated many of the phenotypic changes observed in COPD patients including oxidative damage to macrophages, a slowly resolving inflammation, epithelial damage, mucus hypersecretion, airway fibrosis, and emphysema. As such, it appears that metabolic pathways are central to dealing with the stress of CS exposure; however, over time, inflammation and stress response gene sets become the most significantly affected in the chronic response to CS.
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