Current Respiratory Medicine Reviews , 2005, 1, 33-41 33 Apoptosis in COPD Sandra Hodge*, Greg Hodge, Mark Holmes and Paul N. Reynolds Department of Thoracic Medicine, Royal Adelaide Hospital, and Lung Research, Hanson Institute, North Terrace, Adelaide, South Australia 5001 Abstract: Chronic obstructive pulmonary disease (COPD) is a highly prevalent airway disease that causes serious morbidity and mortality. Despite its importance, the cellular and molecular mechanisms that contribute to COPD pathogenesis have only recently been investigated. COPD is characterised by chronic inflammation, and loss of structural integrity throughout the lung from conducting airways, to the alveolar walls. Apoptosis is an active biochemical process, associated with minimal inflammation or disruption of neighbouring tissue. Apoptosis is considered to play an important role in effective repair of an injured airway epithelium, and resolution of inflammation. However, disorders in the apoptotic process, including increased rates of epithelial cell apoptosis or defective clearance of apoptotic cells by neighbouring phagocytes, are associated with tissue injury in several conditions, including liver injury and heart disease. Increasingly, the role of apoptosis in the pathogenesis of COPD is being recognised. Several studies have reported increased apoptosis of airway epithelial cells, and defective clearance of these cells by alveolar macrophages in COPD, although how this relates to the disease process is still largely unknown. Cigarette smoking directly induces apoptosis of airway epithelial cells. However, the increased rate of apoptosis does not appear to diminish with cessation of cigarette smoking. In this regard, factors that relate to perpetuation of the chronic inflammatory response in COPD may also contribute to increased apoptosis in the airways. These include the high level of oxidative stress, release of proteolytic enzymes as a result of increased numbers of neutrophils, cytotoxic T-cells, activation of TNF-α , TGF-β and Fas pathways, and inflammatory responses to colonisation of the airways with bacteria. Understanding the role of apoptosis and phagocytosis in the airways in COPD is likely to lead to novel therapeutic approaches for this extremely common, yet, often neglected disease. Keywords: Apoptosis, COPD, bronchial epithelial cell, alveolar macrophage. Chronic obstructive pulmonary disease (COPD) is an incapacitating, highly prevalent airway disease, that arises as a result of noxious injury to the lungs, most commonly due to cigarette smoking. The disease causes serious morbidity and mortality [1, 2]. It is an increasing global health problem, predicted to become the third most prevalent cause of death in the world, by 2020 [3]. The presence of COPD is independently linked to an increased risk of lung cancer [4,5], with over 80% of lung cancer cases occurring in smokers or ex-smokers [6]. In addition, patients with COPD have a 2- to 3- fold increased risk of cardiovascular disease [7]. Despite this high prevalence and an urgent need for more effective therapies, COPD research is markedly under- funded, relative to global burden. There have been some incremental improvements in the application of pharmacotherapies for COPD recently, but in the main treatments remain poorly efficacious and have been limited to extrapolations of treatments for asthma, with little attention paid to COPD-specific pathogenesis. Thus new therapeutic options are needed, based on improved knowledge of the underlying pathogenic mechanisms, especially as distinct from the effects of smoking per se. disease is self-inflicted, end stage, chronic and irreversible, and that little needs to be done, other than encourage patients to stop smoking. In the last few years however, with an increasing understanding of the specific inflammatory basis of this disease, attitudes toward COPD management have shifted from therapeutic nihilism and “victim blaming”, to a realization that accurate diagnosis and specific therapy for COPD is essential. This shift is exemplified in the recent ‘GOLD’ guidelines for COPD management [8]. This landmark document clearly highlights the importance of more attention to research in COPD, for the development of specific therapies. REPAIR OF THE NORMAL AIRWAY Lung injury causes physical changes to the epithelium. Portions of the basement membrane are exposed as a result of loss of cells, and an inflammatory response is instigated. In the normal airway, repair of an injured epithelium is a highly regulated process. A provisional matrix, derived from plasma proteins including fibrin and fibronectin, is rapidly formed. Residual basal cells release cytokines that initiate inflammatory responses (eg., interleukin (IL-) 8 and tumour necrosis factor (TNF-) α ), and upregulate production of fibronectin and collagen (eg., transforming growth factor (TGF-) β). Simultaneously, cytokines such as epidermal growth factor (EGF), macrophage chemotactic protein (MCP-) 1 and granulocyte macrophage colony stimulating factor (GMCSF), induce de-differentiation and proliferation The lack of priority given to COPD research and development, has arisen largely due to a perception that the *Address correspondence to this author at the Department of Thoracic Medicine, Royal Adelaide Hospital, and Lung Research, Hanson Institute, North Terrace, Adelaide, South Australia 5001; Tel: 08 82223452; Fax: 08 81616043; E-mail: sandy.hodge@imvs.sa.gov.au 1573-398X/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.