title: Cigarette smoke-induced expression of heme oxygenase-1 in human lung fibroblasts is regulated by intracellular glutathione.
abstract: Fibroblasts are key structural cells that can be damaged by cigarette smoke. Cigarette smoke contains many components capable of eliciting oxidative stress, which may induce heme oxygenase (HO)-1, a cytoprotective enzyme. There are no data on HO-1 expression in primary human lung fibroblasts after cigarette smoke extract (CSE) exposure. We hypothesized that human lung fibroblasts exposed to cigarette smoke would increase HO-1 though changes in intracellular glutathione (GSH). Primary human lung fibroblasts were exposed to CSE, and changes in HO-1 expression and GSH levels were assessed. CSE induced a time- and dose-dependent increase in expression of HO-1, but not HO-2 or biliverdin reductase, in two different primary human lung fibroblast strains, a novel finding. This induction of HO-1 paralleled a decrease in intracellular GSH, and a sustained reduction in GSH resulted in a dramatic increase in HO-1. Treatment with the antioxidants N-acetyl-l-cysteine or GSH reduced the expression of HO-1 induced by CSE. We also examined the signal transduction mechanism responsible for HO-1 induction. Nuclear factor erythroid-derived 2, like 2 (Nrf2) was not involved in HO-1 induction by CSE. Activator protein-1 (AP-1) is a redox-sensitive transcription factor shown in other systems to regulate HO-1 expression. CSE exposure resulted in nuclear accumulation of c-Fos and c-Jun, two key AP-1 components. Reduction of c-Fos and c-Jun nuclear translocation by SP-600125 attenuated the CSE-induced expression of HO-1. These data support the concept that changes in the cellular redox status brought on by cigarette smoke induce HO-1 in fibroblasts. This increase in HO-1 may help protect against cigarette smoke-induced inflammation and/or cell death.
authors.affiliation: University of Rochester School of Medicine and Dentistry, Dept. of Environmental Medicine, Rochester, NY 14642, USA.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Baglole
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D050983:NF-E2 Transcription Factor / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000517:prevention & control; D012906:Smoke / Q000009:adverse effects*
chemical_list: D050983:NF-E2 Transcription Factor; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012906:Smoke; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D005978:Glutathione; D000111:Acetylcysteine