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Extrapulmonary Manifestations of Chronic Obstructive Pulmonary Disease in a Mouse Model of Chronic Cigarette Smoke Exposure

¹ Department of Respiratory Medicine, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands; ² Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; and ³ Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama

Correspondence and requests for reprints should be addressed to Harry R. Gosker, Ph.D., Department of Respiratory Medicine, Maastricht University, NUTRIM, P.O. Box 616, 6,200 MD Maastricht, The Netherlands. E-mail: H.Gosker{at}pul.unimaas.nl

Cigarette smoking is the most commonly encountered risk factor for chronic obstructive pulmonary disease (COPD), reflected by irreversible airflow limitation, frequently associated with airspace enlargement and pulmonary inflammation. In addition, COPD has systemic consequences, including systemic inflammation, muscle wasting, and loss of muscle oxidative phenotype. However, the role of smoking in the development of these extrapulmonary manifestations remains rather unexplored. Mice were exposed to cigarette smoke or control air for 6 months. Subsequently, emphysema was assessed by morphometry of lung tissue, and blood cytokine and chemokine levels were determined by a multiplex assay. Soleus, plantaris, gastrocnemius, and tibialis muscles were dissected and weighed. Muscle fiber typing was performed based on I, IIA, IIB, and IIX myosin heavy-chain isoform composition. Lungs of the smoke-exposed animals showed pulmonary inflammation and emphysema. Moreover, circulating levels of primarily proinflammatory proteins, especially TNF-, were elevated after smoke exposure. Despite an attenuated body weight gain, only the soleus showed a tendency toward lower muscle weight after smoke exposure. Oxidative fiber type IIA proportion was significantly reduced in the soleus. Muscle oxidative enzyme activity was slightly reduced after smoke exposure, being most prominent for citrate synthase in the soleus and tibialis. In this mouse model, chronic cigarette smoke exposure resulted in systemic features that closely resemble the early signs of the extrapulmonary manifestations observed in patients with COPD.

Key Words: cigarette smoking • systemic inflammation • skeletal muscles • murine model • chronic obstructive pulmonary disease

CLINICAL RELEVANCE Cigarette smoke not only leads to pulmonary impairments, but also results in extrapulmonary manifestations frequently observed in chronic obstructive pulmonary disease (COPD). This mouse model is a valuable tool for the further examination of the role of smoking in the systemic pathogenesis in COPD.