title: Molecular regulation of cigarette smoke induced-oxidative stress in human retinal pigment epithelial cells: implications for age-related macular degeneration.
abstract: Cigarette smoke is the most important environmental risk factor for developing age-related macular degeneration (AMD). Damage to the retinal pigment epithelium (RPE) caused by cigarette smoke may underlie the etiology of AMD. This study investigated the molecular and cellular effects of cigarette smoke exposure on human RPE cells. ARPE-19 or primary human RPE cells were exposed to cigarette smoke extract (CSE) or hydroquinone (HQ), a component of cigarette smoke. The effect of this exposure on key aspects of RPE vitality including viability, cell size, mitochondrial membrane potential (DeltaPsi(m)), superoxide production, 4-hydroxy-2-nonenal (4-HNE), vascular endothelial growth factor (VEGF), and heme oxygenase-1 (HO-1) expression was determined. Exposure of RPE cells to CSE or HQ caused oxidative damage and apoptosis, characterized by a reduction in cell size and nuclear condensation. Evidence of oxidative damage also included increased lipid peroxidation (4-HNE) and mitochondrial superoxide production, as well as a decrease in intracellular glutathione (GSH). Exogenous administration of antioxidants (GSH and N-acetyl-cysteine) prevented oxidative damage to the RPE cells caused by CSE. Cigarette smoke also induced expression of VEGF, HO-1, and the transcription factor nuclear factor erythroid-derived 2, like 2 (NRF2). However, NRF2 was only modestly involved in CSE-induced HO-1 expression, as shown by the NRF2 small interfering RNA studies. These new findings demonstrate that cigarette smoke is a potent inducer of oxidative damage and cell death in human RPE cells. These data support the hypothesis that cigarette smoke contributes to AMD pathogenesis by causing oxidative damage and cell death to RPE cells.
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
authors.forename: Kurt M
authors.initials: KM
authors.lastname: Bertram
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Baglole
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.forename: Richard T
authors.initials: RT
authors.lastname: Libby
mesh_terms: D000375:Aging / Q000187:drug effects*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity; D008268:Macular Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009153:Mutagens / Q000633:toxicity; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D034741:RNA, Small Interfering; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D013481:Superoxides / Q000378:metabolism; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
chemical_list: D000975:Antioxidants; D006873:Hydroquinones; D009153:Mutagens; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D014028:Tobacco Smoke Pollution; D042461:Vascular Endothelial Growth Factor A; D013481:Superoxides; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C031927:hydroquinone