Cigarette smoke-induced expression of heme oxygenase-1 in human lung fibroblasts is regulated by intracellular glutathione.
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.
Baglole
Carolyn J
CJ
University of Rochester School of Medicine and Dentistry, Dept. of Environmental Medicine, Rochester, NY 14642, USA.
Sime
Patricia J
PJ
Phipps
Richard P
RP
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*
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