Title: Cigarette smoke-induced expression of heme oxygenase-1 in human lung fibroblasts is regulated by intracellular glutathione.
Authors: Baglole, Carolyn J; Sime, Patricia J; Phipps, Richard P
Published In Am J Physiol Lung Cell Mol Physiol, (2008 Oct)
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.
PubMed ID: 18689604
MeSH Terms: Acetylcysteine/pharmacology; Cell Death/drug effects; Fibroblasts/drug effects; Fibroblasts/pathology; Fibroblasts/physiology*; Gene Expression Regulation, Enzymologic*/drug effects; Glutathione/pharmacology*; Heme Oxygenase-1/drug effects; Heme Oxygenase-1/genetics*; Humans; Inflammation/prevention & control; Lung/drug effects; Lung/pathology; Lung/physiopathology; NF-E2 Transcription Factor/metabolism; NF-E2-Related Factor 2/metabolism; Pulmonary Disease, Chronic Obstructive/etiology; Pulmonary Disease, Chronic Obstructive/prevention & control; Smoke/adverse effects*