Cigarette smoke-induced expression of heme oxygenase-1 in human lung fibroblasts is regulated by intracellular glutathione

Abstract

Baglole CJ, Sime PJ, Phipps RP. Cigarette smoke-induced expression of heme oxygenase-1 in human lung fibroblasts is regulated by intracellular glutathione. Am J Physiol Lung Cell Mol Physiol 295: L624 -L636, 2008. First published August 8, 2008 doi:10.1152/ajplung.90215.2008.-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. oxidative stress; activator protein-1; biliverdin reductase; chronic obstructive pulmonary disease; nuclear factor erythroid-derived 2, like 2 HEME OXYGENASE (HO) enzymes catalyze the rate-limiting step in the oxidative degradation of heme to form equimolar amounts of ferrous iron, carbon monoxide (CO), and biliverdin (60, 69). Biliverdin is subsequently converted to bilirubin by biliverdin reductase (BVR). Two isozymes of HO have been well-characterized: an inducible form, HO-1, and the constitutive form, HO-2. Under basal condition, HO-1 occurs at low to undetectable levels in most tissues, but its expression is rapidly increased in response to a variety of environmental stimuli, particularly those that produce oxidative stress and generate reactive oxygen species (49, 60).Cigarette smoke contains many compounds capable of eliciting oxidative stress, yielding an estimated 10 17 oxidant molecules per puff (14). Oxidative stress caused by cigarette smoke leads to bronchial and alveolar inflammation and lung cell death...

Inhibition of Transglutaminase 2, a Novel Target for Pulmonary Fibrosis, by Two Small Electrophilic Molecules

“…We have previously shown that CDDO potently up-regulates expression of oxidative stressresponse proteins in a glutathionedependent manner and that NAC inhibits this up-regulation (29,41). Here, we show that NAC blocks up-regulation of HO-1 but does not inhibit the ability of CDDO to reduce TG2 expression ( Figure 5C).…”

Hypoxia-Mediated Expression of 5-Lipoxygenase–Activating Protein Involves HIF-1α and NF-κB and MicroRNAs 135a and 199a-5p

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The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

“…Chiba et al (43) have reported that AhR activation in airway epithelial cells induces mucin secretion through production of ROS, suggesting that antioxidant treatments may be appropriate for patients with respiratory symptoms related to dioxin exposure. On the contrary, Baglole et al (44) have shown that AhR activation by cigarette smoke extracts has a protective effect on airway inflammation by inducing the production of the cytoprotective enzyme heme-oxygenase-1 by lung fibroblasts. The discrepancy between these results may be ascribed to the model (human versus mouse cell lines), the mechanism (structural damage versus inflammation), and AhR agonists adopted.…”