Preclinical murine models of Chronic Obstructive Pulmonary Disease

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and is the 4th leading cause of death worldwide. It is believed that an exaggerated inflammatory response to cigarette smoke causes progressive airflow limitation. This inflammation, where macrophages, neutrophils and T lymphocytes are prominent, leads to oxidative stress, emphysema, small airway fibrosis and mucus hypersecretion. Much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and infectious (viral and bacterial) exacerbations (AECOPD). Comorbidities, defined as other chronic medical conditions, in particular skeletal muscle wasting and cardiovascular disease markedly impact on disease morbidity, progression and mortality. The mechanisms and mediators underlying COPD and its comorbidities are poorly understood and current COPD therapy is relatively ineffective. Thus, there is an obvious need for new therapies that can prevent the induction and progression of COPD and effectively treat AECOPD and comorbidities of COPD. Given that access to COPD patients can be difficult and that clinical samples often represent a “snapshot” at a particular time in the disease process, many researchers have used animal modelling systems to explore the mechanisms underlying COPD, AECOPD and comorbidities of COPD with the goal of identifying novel therapeutic targets. This review highlights the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure and the recent advances in modelling infectious exacerbations and comorbidities of COPD.

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and is the 4th leading cause of death worldwide (WHO, 2014). COPD is a “disease characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of lungs to noxious particles and gases” (Pauwels et al., 2001) (Fig. 1). Cigarette smoking is the major cause of COPD and accounts for more than 95% of cases in industrialized countries (Barnes et al., 2003), but other environmental pollutants are important causes in developing countries (Dennis et al., 1996). COPD encompasses chronic obstructive bronchiolitis with fibrosis and obstruction of small airways, and emphysema with enlargement of airspaces and destruction of lung parenchyma, 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. As the disease worsens, patients experience progressively more frequent and severe exacerbations, which are due to viral and bacterial chest infections (Hurst et al., 2010, Rohde et al., 2003, Seemungal et al., 2001, Sethi, 2004) (Fig. 1). Patients are also increasingly disabled by disease comorbidities, such as cardiovascular disease and skeletal muscle wasting, which further reduce their quality of life (Barnes and Celli, 2009, Cavailles et al., 2013, Maltais et al., 2014). In addition, respiratory infections can worsen these comorbidities and further impact on the patient׳s life (Cavailles et al., 2013).

Current forms of therapy for COPD are relatively ineffective and the development of effective treatments for COPD have been severely hampered as the mechanisms and mediators that drive the induction and progression of chronic inflammation, emphysema, altered lung function, defective lung immunity, musculoskeletal derangement and markedly worsened cardiovascular risk remain only poorly understood. Given that cigarette smoke is the major cause of COPD, “smoking mouse” models that accurately reflect disease pathophysiology have been developed and have made rapid progress in identifying candidate pathogenic mechanisms and new therapies (reviewed in Churg et al., 2008, Fricker et al., 2014, Goldklang et al., 2013, Mercer et al., 2015, Stevenson and Belvisi, 2008, Stevenson and Birrell, 2011, Vlahos and Bozinovski, 2014, Vlahos et al., 2006a, Wright and Churg, 2010, Wright et al., 2008).