Published ahead of print on January 31, 2003, doi:10.1165/rcmb.2002-0228OC
American Journal of Respiratory Cell and Molecular Biology. Vol. 29, pp. 88-97, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2002-0228OC
Oxidative Stress and Apoptosis Interact and Cause Emphysema Due to Vascular Endothelial Growth Factor Receptor Blockade
Rubin M. Tuder,
Lijie Zhen,
Chung Y. Cho,
Laima Taraseviciene-Stewart,
Yasunori Kasahara,
Daniela Salvemini,
Norbert F. Voelkel and
Sonia C. Flores
Department of Pathology, Division of Cardiopulmonary Pathology, and Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Pulmonary and Critical Care Medicine, and Department of Medicine, COPD Center, University of Colorado School of Medicine, Denver, Colorado; Department of Respirology (B2), Chiba Medical School, Chiba, Japan; Metaphore Corporation, St. Louis, Missouri; and Webb-Waring Institute, Denver, Colorado
Address correspondence to: Rubin M. Tuder, M.D., Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 519, Baltimore, MD 21205. Email: Rtuder{at}JHMI.EDU
We have previously demonstrated that a failure of pulmonary endothelial cell survival induced by vascular endothelial growth factor (VEGF) receptor blockade results in lung alveolar septal cell apoptosis and emphysema. Because apoptosis and oxidative stress may be pathobiologically linked, we hypothesized that oxidative stress has a central role in alveolar septal cell apoptosis and emphysema induced by VEGF receptor blockade. When compared with control animals, rats treated with the VEGF receptor blocker SU5416 showed increased alveolar enlargement, alveolar septal cell apoptosis, and expression of markers of oxidative stress, all of which were prevented by the superoxide dismutase mimetic M40419. The preservation of lung structure in SU5416+M40419-treated lungs was associated with increased septal cell proliferation, and enhanced phosphorylation of the prosurvival and antiapoptotic Akt, when compared with SU5416-treated lungs. Consistent with a positive feedback interaction between oxidative stress and apoptosis, we found that apoptosis predominated in areas of oxidative stress, and that apoptosis blockade by a broad spectrum caspase inhibitor markedly reduced the expression of markers of oxidative stress induced by SU5416 treatment. Oxidative stress and apoptosis, which cause lung cellular destruction in emphysema induced by VEGF receptor blockade, may be important mediators common to human and experimental emphysema.
Abbreviations: 4 hydroxy-2-nonenal, 4-HNE • 8 hydroxy-2' deoxyguanosine, 8-HG • centrilobular alveoli, CL • control, CTL • dinitrophenyl hydrazone, DNPH • proliferating cell nuclear antigen, PCNA • peripheral alveoli, PL • terminal deoxynucleotidyl transferase-mediated dUTP end-labeling, TUNEL • vascular endothelial growth factor, VEGF • VEGF receptor 2, VEGFR2
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