Abstract
SUMMARYMouse models of chronic obstructive pulmonary disease (COPD) focus on airway inflammation and lung histology, but their use has been hampered by the lack of pulmonary function data in their assessment. Systemic effects such as muscle dysfunction are also poorly modeled in emphysematous mice. We aimed to develop a cigarette-smoke-induced emphysema mouse model in which serial lung function and muscular dysfunction could be assessed, allowing the disease to be monitored more appropriately. C57Bl6 mice were nose-only exposed to cigarette smoke or filtered air for 3–6 months. Lung function tests were repeated in the same mice after 3 and 6 months of cigarette smoke or air exposure and compared with lung histological changes. Contractile properties of skeletal muscles and muscle histology were also determined at similar time points in separate groups of mice. Serial lung function measurements documented hyperinflation after 3 and 6 months of cigarette smoke exposure, with a significant 31–37% increase in total lung capacity (TLC) and a significant 26–35% increase in compliance (Cchord) when compared with animals exposed to filtered air only (P<0.001 after 3 and after 6 months). These functional changes preceded the changes in mean linear intercept, which became only significant after 6 months of cigarette smoke exposure and which correlated very well with TLC (r=0.74, P=0.004) and Cchord (r=0.79, P=0.001). After 6 months of cigarette smoke exposure, a significant fiber-type shift from IIa to IIx/b was also observed in the soleus muscle (P<0.05), whereas a 20% reduction of force was present at high stimulation frequencies (80 Hz; P=0.09). The extensor digitorum longus (EDL) muscle was not affected by cigarette smoke exposure. These serial pulmonary function variables are sensitive outcomes to detect emphysema progression in a nose-only cigarette-smoke-exposed animal model of COPD. In this model, muscular changes became apparent only after 6 months, particularly in muscles with a mixed fiber-type composition.
Highlights
Chronic obstructive pulmonary disease (COPD) is a slowly progressive disease characterized by airflow limitation that is not fully reversible and by an abnormal inflammatory response in the lung (Pauwels and Rabe, 2004; Rabe et al, 2007)
Importantly, the present study demonstrated that emphysema progression in mouse models can be monitored over a prolonged period of time by serial invasive measurements of total lung capacity (TLC) and Cchord within the same animal
We have previously shown that semi-quasistatic measurements of compliance with Scireq-Flexivent, as used by others, are less reliable than compliance (Cchord) measurements obtained with the Buxco as in the present study, and that measures of compliance and TLC are probably the best markers for mouse models of emphysema (Vanoirbeek et al, 2010)
Summary
Chronic obstructive pulmonary disease (COPD) is a slowly progressive disease characterized by airflow limitation that is not fully reversible and by an abnormal inflammatory response in the lung (Pauwels and Rabe, 2004; Rabe et al, 2007). Besides the presence of lung inflammation, COPD is characterized by several systemic consequences, including weight loss, skeletal muscle wasting and muscle dysfunction (Pauwels and Rabe, 2004; Decramer et al, 2005; Gea and Barreiro, 2008). Skeletal muscle dysfunction is accepted as a very important systemic consequence of COPD because it is associated with exacerbations of the disease, reduced quality of life and decreased prognosis (Pitta et al, 2005; Swallow et al, 2007). Physical inactivity is likely to be the most important factor for developing muscle dysfunction because it sneaks in at the very early stages of COPD and further develops as the disease progresses (Pitta et al, 2005; Watz et al, 2008; Watz et al, 2009; Troosters et al, 2010b). For a better understanding of the mechanisms that lead to disease progression, including the development of muscle dysfunction, improving existing animal models is fundamental
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