Modelling COPD co‐morbidities in preclinical models

Chronic obstructive pulmonary disease (COPD) is a major incurable global health burden and is currently the fourth largest cause of death in the world. The burden of COPD in Asia is currently greater than that in the developed Western countries and accounts for the majority of COPD deaths worldwide due to epidemic exposure to tobacco smoke and air pollution. Importantly, much of the disease burden and healthcare utilization in COPD are associated with the management of its co-morbidities (e.g. skeletal muscle wasting, vascular and heart diseases, cognitive dysfunction, anxiety and depression disorders, lung cancer, osteoporosis, metabolic syndrome and diabetes) and infective viral and bacterial acute exacerbations (AECOPD). Moreover, respiratory infections can aggravate these co-morbidities and further deteriorate the patient’s condition. It is currently not clear whether these co-morbidities are independent coexisting conditions (as a result of shared risk factors such as advanced age or smoking history of the patient) or a direct consequence of the progressive lung pathology in COPD patients. Current pharmacological treatments for COPD and its co-morbidities are relatively ineffective and the development of effective therapies has been severely hampered by the lack of understanding of the mechanisms and mediators underlying COPD co-morbidities. Since co-morbidities have a tremendous impact on the prognosis and severity of COPD, the 2015 American Thoracic Society/European Respiratory Society (ATS/ERS) Research Statement on COPD urgently called for studies to elucidate the pathobiological mechanisms linking COPD to its co-morbidities. Consequently, significant research has been channelled towards developing preclinical mouse models of comorbidities associated with COPD to (i) determine the mechanisms underlying these conditions and (ii) identify and test novel therapeutic options for these patients. As cigarette smoke is the major cause of COPD, ‘smoking animal’ models that accurately reflect lung pathophysiology have been established to help identify pathogenic mechanisms. In addition, preclinical models are an integral part of the drug discovery pipeline as they allow for testing of potential therapies. Among the many species (including monkeys, sheep, dogs, guinea pigs and rodents) used, mice have been the most popular choice by investigators given the ability to produce animals with genetic modifications that shed light on specific processes within COPD, the abundance of antibody probes, the availability of many mouse strains with different reactions to cigarette smoke and the low cost. Whilst pathological processes such as airway inflammation and airspace enlargement/emphysema have been successfully targeted in mice, the targeting of systemic co-morbidities in experimental models remain an emerging and topical area of research. We have developed sophisticated preclinical models of cigarette smoke-induced skeletal muscle wasting in mice. Using these models, we have recently shown that mice exposed chronically to cigarette smoke had reduced hind limb skeletal muscles mass (gastrocnemius, tibialis anterior and soleus), grip strength (index of muscle strength) and aerobic endurance. In addition, cigarette smoke altered the expression of a number of genes associated with the regulation of skeletal muscle mass including insulin-like growth factor-I, atrogin-1, MuRF-1 and IL-6. Importantly, we have shown that targeting oxidant-dependent processes that drive cigarette smoke-induced lung inflammation not only reduced lung inflammation but also significantly reduced skeletal muscle wasting (Ivan Bernardo, Steven Bozinovski and Ross Vlahos, unpublished observations). Others have shown that skeletal muscles from cigarette smoke-exposed mice had decreased skeletal muscle capillarization and reduced muscle fibre crosssectional area and exercise tolerance when compared with air-exposed mice. Thus, these studies highlight that chronic exposure to cigarette smoke causes systemic features that closely resemble extrapulmonary manifestations observed in COPD patients, and that these murine models are a useful tool in exploring therapeutics aimed at treating skeletal muscle wasting and dysfunction observed in human COPD. While skeletal muscle wasting and dysfunction is the best developed COPD co-morbidity in mice, we and others are developing clinically relevant animal models to investigate the link between COPD and cardiovascular, cognitive and metabolic co-morbidities. A current limitation is that the smoke exposure mouse models do not cause severe COPD, where a complementary genetic susceptibility strategy may be required to develop a more severe model of COPD co-morbidities. In conclusion, COPD is a complex disease and the mechanisms that drive its induction and progression are poorly understood. Moreover, the mechanisms underlying co-morbidities of COPD are also poorly understood but the identification of common disease pathways may redirect drug discovery research in COPD towards drugs targeting the lung and comorbidities (e.g. skeletal muscle wasting) concurrently. Preclinical models of COPD and its co-morbidities are essential to provide insights into the cellular and molecular mechanisms driving the pathogenesis of COPD co-morbidities and are necessary for the development and testing of new therapies. However, it is