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Role of Lung Maintenance Program in the Heterogeneity of Lung Destruction in Emphysema

Division of Cardiopulmonary Pathology, Department of Pathology, and Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine; Department of Environmental Health, School of Public Health, Johns Hopkins University, Baltimore; and Division of Pulmonary, Allergy, Critical Care, and Occupational Medicine, School of Medicine, Indiana University, Indianapolis, Indiana

Correspondence and requests for reprints should be addressed to Rubin M. Tuder, M.D., Division of Cardiopulmonary Pathology, Department of Pathology, Ross Research Building, Room 519, 720 Rutland Avenue, Baltimore, MD 21205. E-mail: rtuder{at}jhmi.edu

ABSTRACT

Centrilobular emphysema caused by chronic cigarette smoking is a heterogeneous disease with a predominance of upper lobe involvement. It is presumed that this heterogeneity indicates a particular susceptibility to cigarette smoke or the fact that the inhaled smoke distributes preferentially to upper lung zones. The less involved areas might therefore retain the capacity for lung regeneration and gain of pulmonary function in terminally ill patients. We propose that the interplay between molecular and cellular switches involved in the lung response to environmental injuries determines the heterogeneous pattern of emphysema due to cigarette smoke. Regional activation of alveolar destruction by apoptosis and oxidative stress coupled with regional failure of defense mechanisms may account for the irregular pattern of lung destruction in cigarette smoke–induced emphysema. Protection afforded by the key antioxidant transcription factor Nrf-2 and the antiproteolytic and antiapoptotic actions of ₁-antitrypsin is central to maintain lung homeostasis and lung structure. As the lung is injured by environmental pollutants, including cigarette smoke, molecular sensors of cellular stress, such as the mTOR/protein translation regulator RTP-801, may engage both inflammation and alveolar cell apoptosis. As injury prevails during the course of this chronic disease, it leads to a more homogeneous pattern of lung disease.

Key Words: aging • apoptosis • emphysema • inflammation • oxidative stress

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