Comprehensive gene expression profiling of rat lung reveals distinct acute and chronic responses to cigarette smoke inhalation

• Published in: American journal of physiology. Lung cellular and molecular physiology 2007-11, Vol.293 (5), p.L1183-L1193
• Main Authors: Stevenson, Christopher S, Docx, Cerys, Webster, Ruth, Battram, Cliff, Hynx, Debra, Giddings, June, Cooper, Philip R, Chakravarty, Probir, Rahman, Irfan, Marwick, John A, Kirkham, Paul A, Charman, Christine, Richardson, Delwood L, Nirmala, N. R, Whittaker, Paul, Butler, Keith
• Format: Article
• Language: English
• Subjects: Airway management; Animals; Biomarkers - metabolism; Bronchoalveolar Lavage Fluid - chemistry; Chronic obstructive pulmonary disease; Cigarettes; Gene expression; Gene Expression Profiling; Lung - metabolism; Lungs; Male; Oligonucleotide Array Sequence Analysis; Rats; Rats, Sprague-Dawley; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Smoking - metabolism; Tobacco smoke
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00105.2007

1 Respiratory Disease Area, Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom; 2 Genome and Proteome Sciences, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts; 3 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; 4 Airway Disease, Department of Cardiothoracic Surgery, National Heart and Lung Institute, London, United Kingdom; and 5 Department of Environmental Medicine, Division of Lung Biology and Disease, University of Rochester Medical Center, Rochester, New York Submitted 19 March 2007 ; accepted in final form 13 August 2007 Chronic obstructive pulmonary disease (COPD) 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 that 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 mo. 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 upregulated. 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 wk, which was followed by the chronic phase of the response. During this phase, gene sets related to immunity and defense 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. chronic obstructive pulmonary disease; metabolic pathways; oxidant stress Address for reprint requests and other correspondence: C. S. Stevenson, Imperial College London National Heart an