title: Long-term nose-only cigarette smoke exposure induces emphysema and mild skeletal muscle dysfunction in mice.
abstract: Mouse 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.
authors.affiliation: Respiratory Muscle Research Unit, Katholieke Universiteit Leuven, Herestraat 49, Onderwijs en Navorsing 1, bus 706, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Manuela
authors.initials: M
authors.lastname: Rinaldi
authors.forename: Karen
authors.initials: K
authors.lastname: Maes
authors.forename: Stéphanie
authors.initials: S
authors.lastname: De Vleeschauwer
authors.forename: Debby
authors.initials: D
authors.lastname: Thomas
authors.forename: Erik K
authors.initials: EK
authors.lastname: Verbeken
authors.forename: Marc
authors.initials: M
authors.lastname: Decramer
authors.forename: Wim
authors.initials: W
authors.lastname: Janssens
authors.forename: Ghislaine N
authors.initials: GN
authors.lastname: Gayan-Ramirez
mesh_terms: D000818:Animals; D001835:Body Weight; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D066298:In Vitro Techniques; D019570:Inhalation Exposure; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D012129:Respiratory Function Tests; D012907:Smoking / Q000503:physiopathology*; D016019:Survival Analysis; D013997:Time Factors