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Increased p21^CIP1/WAF1 and B Cell Lymphoma Leukemia-x_L Expression and Reduced Apoptosis in Alveolar Macrophages from Smokers

Department of Thoracic Medicine, National Heart and Lung Institute at Imperial College School of Science, Technology and Medicine, London, United Kingdom

Correspondence and requests for reprints should be addressed to Ian M. Adcock, Ph.D., Department of Thoracic Medicine, National Heart and Lung Institute at Imperial College, Dovehouse Street, London SW3 6LY, UK. E-mail: ian.adcock{at}ic.ac.uk

Alveolar macrophages (AMs) are the predominant defense cells in the airway, and their numbers are increased in smokers and subjects with chronic obstructive pulmonary disease. This increase may result from increased recruitment, increased proliferation, or reduced cell death. Apoptosis regulates inflammatory cell survival, and p21^CIP1/WAF1 is an important inhibitory regulator of cycle progression after oxidative stress. We have investigated whether chronic smoke exposure influences the expression and localization of cell cycle and apoptotic proteins in AM and bronchial epithelial cells in vivo. The increased numbers of AMs seen in smokers were only partially due to enhanced proliferation. p21^CIP1/WAF1 protein expression was increased in AMs and biopsies isolated from smokers and was found predominantly within the cytoplasm. In addition, B cell lymphoma leukemia (Bcl)-x_L, an antiapoptotic regulator, was also highly expressed in macrophages from smokers compared with nonsmokers and subjects with asthma. Hydrogen peroxide, an oxidative stress, induced cytoplasmic expression of p21^CIP1/WAF1 and failed to induce apoptosis in an in vitro model. These results suggested that AM and bronchial epithelial cells from smokers, in contrast to those from normal subjects and subjects with asthma, have reduced cell death. Thus, oxidative stress induced by cigarette smoking may contribute to the chronicity of inflammation in the airway, through a reduction of apoptosis.

Key Words: p21^CIP1/WAF1 • monocytes/macrophages • apoptosis • cigarette smoke • epithelial cells

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