Modelling COPD in mice
Section snippets
Which inflammatory cells are involved in the pathophysiology of COPD?
A variety of cell types are involved in the pathophysiology 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], [6], [7]. There is a correlation between macrophage numbers in the airways and the severity of COPD [8]. Macrophages release inflammatory mediators including TNF-α, MCP-1, reactive oxygen species and
Proteases in COPD
Proteases regulate lung inflammation via the production of cytokines and chemokines and ultimately destroy the extracellular matrix (particularly elastin) of lung parenchyma to produce emphysema [14]. The major proteases involved in COPD include neutrophil elastase and various matrix metalloproteinases, although other serine proteases such as cysteine proteases and proteinase 3 have been implicated [2], [14], [15]. Patients with emphysema have an increase in BALF concentrations and macrophage
Modelling COPD in mice
COPD is a heterogenous disorder consisting of lung inflammation, chronic obstructive bronchiolitis, mucus plugging and emphysema (Fig. 1). Animal models are important in determining the underlying mechanisms of COPD as they address questions involving integrated whole body responses. To date, many species have been used including rodents, dogs, guinea-pigs, monkeys and sheep [23], [24], [25]. Mice offer the greatest ability to investigate the pathogenetic pathways of disease given the advances
Acute exacerbations of COPD
Acute exacerbations of COPD (AECOPD) are a common cause of morbidity and mortality in COPD patients and place a large burden on health care resources. AECOPD may be prolonged, may accelerate the progression of COPD and have a profound effect on the quality of life [37]. The cellular and molecular mechanisms underlying AECOPD are unclear, but there is an increase in neutrophils and concentrations of IL-6, IL-8, TNF-α and LTB4 in sputum during an exacerbation [38], [39] and patients who have
Summary
Cigarette smoking is the major cause of COPD and, apart from smoking cessation, there is currently no treatment that slows the progression of the disease. The characteristic features of human COPD including neutrophilia, the accumulation of macrophages and T-lymphocytes, production of cytokines and chemokines, induction of proteases and the development of emphysema can all be replicated in mice by exposure to cigarette smoke. We and others have proposed that short term responses to cigarette
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2022, Pharmacology and TherapeuticsCitation Excerpt :These models also overcome difficulties with access to clinical samples which often represent a ‘snapshot in time’ and allow for sampling of broncho alveolar lavage fluid, whole lungs and tissues involved in comorbidities (e.g. heart, skeletal muscle, brain) of COPD including cardiovascular disease, skeletal muscle wasting and cognitive decline. We and others have developed pre-clinical models of COPD that accurately replicate the key hallmark characteristics of human COPD such as lung inflammation, bronchiolitis (obstruction of small airways and alveoli), emphysema (enlargement of airspaces and destruction of lung parenchyma), mucus plugging, elevated systemic inflammation and oxidative stress, and impaired lung function (Austin, Crack, Bozinovski, Miller, & Vlahos, 2016; Beckett et al., 2013; Bernardo et al., 2015; Bozinovski et al., 2008; Bozinovski et al., 2011; Brassington et al., 2019; Chan et al., 2019; Chan et al., 2020; Duong et al., 2010; Gosker et al., 2009; Hansen et al., 2013; Hansen et al., 2014; Oostwoud et al., 2016; Passey et al., 2016; Rinaldi et al., 2012; Vlahos et al., 2011; Vlahos et al., 2012; Vlahos & Bozinovski, 2014a; Vlahos, Bozinovski, Gualano, Ernst, & Anderson, 2006). These models have shown that local elevation of cytokines (e.g. IL-6, IL-1β) (Churg et al., 2003; Churg et al., 2004; Hansen et al., 2014; Vlahos et al., 2006), chemokines (e.g. IL-17A, GM-CSF) (Hansen et al., 2014; Vlahos, Bozinovski, Jones, et al., 2006), proteases (e.g. matrix metalloproteinase [MMP]-9, MMP-12, neutrophil elastase) (Churg et al., 2004; Hautamaki, Kobayashi, Senior, & Shapiro, 1997; Morris et al., 2003; Shapiro, 2000; Vlahos & Bozinovski, 2014b), as well as increased oxidative stress, downregulation of antioxidants, and apoptosis of lung cells (Ruwanpura et al., 2011) may be key drivers for the development and progression of COPD.
Integrative characterization of chronic cigarette smoke-induced cardiopulmonary comorbidities in a mouse model
2017, Environmental PollutionPreclinical murine models of Chronic Obstructive Pulmonary Disease
2015, European Journal of PharmacologyCitation Excerpt :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), and Wright et al. (2008)). COPD is a heterogenous disorder consisting of lung inflammation, emphysema, chronic obstructive bronchiolitis and mucus plugging.
Animal models of chronic obstructive pulmonary disease
2015, Archivos de Bronconeumologia