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1 Department of Environmental Medicine, University of Rochester, Rochester, NY, USA; Department of Lung Biology and Disease Program, University of Rochester, Rochester, NY, USA
2 Department of Biological Sciences, Stanford University, Stanford, CA, USA
3 Department of Microbiology and Immunology, University of Rochester, Rochester, NY, USA
4 Department of Environmental Medicine, University of Rochester, Rochester, NY, USA; Department of Lung Biology and Disease Program, University of Rochester, Rochester, NY, USA; Division of Pulmonary and Critical Care Medicine, University of Rochester, Rochester, NY, USA
* To whom correspondence should be addressed. E-mail: richard_phipps{at}urmc.rochester.edu.
Cigarette smoke is the principal cause of emphysema. Recent attention has focused on the loss of alveolar fibroblasts in the development of emphysema. Fibroblasts may become damaged by oxidative stress and undergo apoptosis as a result of cigarette smoke exposure. Not all smokers develop lung diseases associated with tobacco smoke, a fact that may reflect individual variation between human fibroblast strains. We hypothesize that fibroblasts from different human beings vary in their ability to undergo apoptosis following cigarette smoke exposure. This could account for emphysematous changes that occur in the lungs of some but not all smokers. Primary human lung fibroblast strains were exposed to cigarette smoke extract (CSE) and assessed for viability, morphological changes and mitochondrial transmembrane potential as indicators of apoptosis. We also examined the generation of intracellular reactive oxygen species (ROS), 4-hydroxy-2-nonenal (4-HNE) and changes in glutathione (GSH) and glutathione disulfide (GSSG) levels. Each human lung fibroblast strain exhibited a differential sensitivity to CSE as judged by changes in mitochondrial membrane potential, viability, ROS generation and glutathione production. Interestingly, the thiol anti-oxidants N-acetylcysteine and GSH eliminated CSE-induced changes in fibroblast morphology such as membrane blebbing, nuclear condensation and cell size and prevented alterations in mitochondrial membrane potential and the generation of ROS. These findings support the concept that oxidative stress and apoptosis are responsible for fibroblast death associated with exposure to tobacco smoke. Variations in the sensitivity of fibroblasts to cigarette smoke may account for the fact that only some smokers develop emphysema.
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