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Mitochondrial Localization and Function of Heme Oxygenase-1 in Cigarette Smoke–Induced Cell Death

Departments of Pulmonary Diseases and Allergology, University Medical Center Groningen, Groningen, The Netherlands; and Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and Center for Biologic Imaging, Department of Cell Biology and Physiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Augustine M. K. Choi, M.D., Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, MUH 628NW, 3459 Fifth Ave., Pittsburgh, PA 15213. E-mail: Choiam{at}upmc.edu

Cigarette smoke–induced apoptosis and necrosis contribute to the pathogenesis of chronic obstructive pulmonary disease. The induction of heme oxygenase-1 provides cytoprotection against oxidative stress, and may protect in smoking-related disease. Since mitochondria regulate cellular death, we examined the functional expression and mitochondrial localization of heme oxygenase-1 in pulmonary epithelial cells exposed to cigarette smoke extract (CSE), and its role in modulating cell death. Heme oxygenase-1 expression increased dramatically in cytosolic and mitochondrial fractions of human alveolar (A549), or bronchial epithelial cells (Beas-2b) exposed to either hemin, lipopolysaccharide, or CSE. Mitochondrial localization of heme oxygenase-1 was also observed in a primary culture of human small airway epithelial cells. Furthermore, heme oxygenase activity increased dramatically in mitochondrial fractions, and in whole cell extracts of Beas-2b after exposure to hemin and CSE. The mitochondrial localization of heme oxygenase-1 in Beas-2b was confirmed using immunogold-electron microscopy and immunofluorescence labeling on confocal laser microscopy. CSE caused loss of cellular ATP and rapid depolarization of mitochondrial membrane potential. Apoptosis occurred in Beas-2b at low concentrations of cigarette smoke extract, whereas necrosis occurred at high concentrations. Overexpression of heme oxygenase-1 inhibited CSE-induced Beas-2b cell death and preserved cellular ATP levels. Finally, heme oxygenase-1 mRNA expression was elevated in the lungs of mice chronically exposed to cigarette smoke. We demonstrate the functional compartmentalization of heme oxygenase-1 in the mitochondria of lung epithelial cells, and its potential role in defense against mitochondria-mediated cell death during CSE exposure.

Key Words: cigarette smoke • COPD • heme oxygenase-1 • mitochondria

CLINICAL RELEVANCE Cigarette smoke–induced lung cell death contributes to the etiology of chronic obstructive lung disease. This article also contributes to the understanding of the significance of stress protein responses to oxidative stress/injury.

 

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