title: Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade.
abstract: 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.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Rtuder@JHMI.EDU
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhen
authors.forename: Chung Y
authors.initials: CY
authors.lastname: Cho
authors.forename: Laima
authors.initials: L
authors.lastname: Taraseviciene-Stewart
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kasahara
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: Sonia C
authors.initials: SC
authors.lastname: Flores
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D018716:Molecular Mimicry; D018384:Oxidative Stress / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007211:Indoles; D011758:Pyrroles; C093260:benzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene; D001224:Aspartic Acid; C116890:Semaxinib; D013482:Superoxide Dismutase; D040262:Receptors, Vascular Endothelial Growth Factor