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Increased p53 Level, Bax/Bcl-x_L Ratio, and TRAIL Receptor Expression in Human Emphysema

¹ Centre de Recherche de l'Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Quebec City, Canada

Correspondence and requests for reprints should be addressed to Julie Milot, M.D., Ph.D., Hôpital Laval, 2725 Chemin Sainte-Foy, Québec, PQ, Canada G1V 4G5. E-mail: julie.milot{at}crhl.ulaval.ca

Rationale: Emphysema is mainly known for the complex inflammatory processes associated with its development. In addition to lung inflammation, it is now accepted that increased alveolar cell apoptosis is also part of emphysema pathophysiology. However, little is known about the mechanisms involved in alveolar apoptosis. We postulate that oxidative stress and proinflammatory cytokines could lead to p53 accumulation, Bax/Bcl-x_L ratio elevation, and higher tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) receptor levels in the emphysematous lung.

Objectives: To evaluate the expression of p53, Bax, Bcl-x_L, TRAIL, and TRAIL receptors in lung parenchyma from nonemphysematous nonsmokers and smokers and emphysematous smokers and ex-smokers and to determine whether H₂O₂ and/or TNF can modulate the expression of these apoptotic proteins.

Methods: p53, Bax, Bcl-x_L, and TRAIL receptor protein levels in lung parenchyma were measured by Western blot, and TRAIL mRNA levels were measured by real-time polymerase chain reaction. Changes in TRAIL receptor, Bax, Bcl-x_L, and p53 protein levels after in vitro H₂O₂ and/or TNF stimulation of A549 cells were also assessed by Western blot.

Measurements and Main Results: The p53 protein levels, the Bax/Bcl-x_L ratio, and TRAIL receptors 1, 2, and 3 protein levels were significantly higher in subjects with emphysema. Moreover, they were also increased after H₂O₂ and TNF treatments of A549 cells.

Conclusions: These findings suggest that oxidative stress and proinflammatory cytokines may be involved in the elevation of p53 levels, the Bax/Bcl-x_L ratio, and TRAIL receptor levels, new mechanisms that may be implicated in the increased alveolar cell apoptosis that occurs in emphysema.

Key Words: chronic obstructive pulmonary disease • cell death • oxidative stress • inflammation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Little is known of the mechanisms involved in increased alveolar cell apoptosis in emphysema. What This Study Adds to the Field p53 and the TRAIL apoptotic system are mechanisms that may be responsible for the increased alveolar cell apoptosis in emphysema.