Modelling COPD in mice R. Vlahos a, * , S. Bozinovski b , R.C. Gualano a , M. Ernst c , G.P. Anderson a,b a Department of Medicine, Cooperative Research Center for Chronic Inflammatory Diseases, The University of Melbourne, Royal Melbourne Hospital, Parkville, Vic. 3050, Australia b Department of Pharmacology, Cooperative Research Center for Chronic Inflammatory Diseases, The University of Melbourne, Vic. 3010, Australia c Ludwig Institute for Cancer Research, Cooperative Research Center for Chronic Inflammatory Diseases, Royal Melbourne Hospital, Parkville, Vic. 3050, Australia Received 14 February 2005; revised 14 February 2005; accepted 22 February 2005 Abstract Chronic obstructive pulmonary disease (COPD) is characterised by persistent airflow limitation, neutrophilic inflammation, macrophage accumulation, and the production of cytokines, chemokines and proteases. Cigarette smoking is the major cause of COPD and there is currently no satisfactory therapy to help treat individuals with this disease. A better understanding of the cellular and molecular responses triggered by cigarette smoke may provide new molecular targets for the development of therapeutic agents. This brief review highlights some of the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure. q 2006 Elsevier Ltd. All rights reserved. Chronic obstructive pulmonary disease (COPD) is a major global health problem and has been predicted to become the third largest cause of death in the world by 2020 [1]. Cigarette smoking is the major cause of COPD and accounts for more than 95% of cases in industrialized countries [2], but other environmental pollutants are important causes in developing countries [3]. COPD is ‘a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progress- ive and associated with an abnormal inflammatory response of lungs to noxious particles and gases’ [4]. COPD encompasses chronic obstructive bronchiolitis with fibrosis and obstruction of small airways, and emphysema with enlargement of airspaces and destruction of lung parench- yma, loss of lung elasticity, and closure of small airways. Most patients with COPD have all three pathologic conditions (chronic obstructive bronchiolitis, emphysema and mucus plugging), but the relative extent of emphysema and obstructive bronchiolitis within individual patients can vary. 1. Which inflammatory cells are involved in the pathophysiology of COPD? A variety of cell types are involved in the pathophy- siology of COPD, including macrophages, neutrophils and T-lymphocytes. The airways, lung parenchyma, bronchoalveolar lavage fluid (BALF) and sputum of patients with COPD have elevated levels of macrophages compared with normal smokers [5–7]. There is a correlation between macrophage numbers in the airways and the severity of COPD [8]. Macrophages release inflammatory mediators including TNF-a, MCP-1, reac- tive oxygen species and neutrophil chemotactic factors such as LTB 4 and IL-8 in response to cigarette smoke and other irritants. Sputum of COPD patients has increased levels of LTB 4 , IL-8 and TNF-a [6]. Alveolar macrophages also secrete a variety of elastolytic enzymes, including matrix metalloproteinase (MMP)-2, MMP-9, MMP-12, cathepsin K, L and S which destroy lung parenchyma [2]. Histological and bronchial biopsy studies show that patients with COPD have an increased number of neutrophils [7,8]. In addition, a marked increase in neutrophils has been observed in BALF and sputum of COPD patients [5,6]. Neutrophil numbers in bronchial biopsies and induced sputum are correlated with COPD Pulmonary Pharmacology & Therapeutics 19 (2006) 12–17 www.elsevier.com/locate/ypupt 1094-5539/$ - see front matter q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.pupt.2005.02.006 * Corresponding author. Tel.: C61 3 8344 5746; fax: C61 3 8344 0241. E-mail address: rossv@unimelb.edu.au (R. Vlahos).