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Am J Physiol Lung Cell Mol Physiol (January 10, 2003). doi:10.1152/ajplung.00189.2002
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Submitted on June 15, 2002
Accepted on January 8, 2003

Vanadium-induced HB-EGF Expression in Human Lung Fibroblasts is Oxidant-Dependent and Requires MAP Kinases

Jennifer L. Ingram1, Annette B. Rice1, Janine Santos2, Bennett Van Houten2, and James C. Bonner1*

1 Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
2 Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

* To whom correspondence should be addressed. E-mail: bonnerj{at}niehs.nih.gov.

Vanadium pentoxide (V2O5) is a transition metal derived from the burning of petrochemicals that causes airway fibrosis and remodeling. Vanadium compounds activate many intracellular signaling pathways via the generation of hydrogen peroxide (H2O2), or other reactive oxygen species (ROS). In this study, we investigated the regulation of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in human lung fibroblasts after V2O5 treatment. V2O5-induced HB-EGF mRNA expression was abolished by N-acetyl-L-cysteine (NAC), suggesting an oxidant-mediated effect. Exogenous H2O2 above 10 µM mimicked the effect of V2O5 in up-regulating HB-EGF expression. Fibroblasts spontaneously released low levels of H2O2 (1-2 µM) and the addition of V2O5 depleted the endogenous H2O2 pool within minutes. V2O5 caused a subsequent increase of H2O2 into the culture medium at 12 hrs. However, the burst of V2O5-induced H2O2 occurred after V2O5-induced HB-EGF mRNA expression at 3 hrs, indicating that the V2O5-stimulated H2O2 burst did not mediate HB-EGF expression. Either V2O5 or H2O2 activated ERK-1/2 and p38 MAP kinase. Inhibitors of ERK-1/2 (PD98059) or p38 MAP kinase (SB203580) significantly reduced either V2O5- or H2O2-induced HB-EGF expression. These data indicate that vanadium up-regulates HB-EGF via ERK and p38 MAP kinases. The induction of HB-EGF is not related to a burst of H2O2 in V2O5 treated cells, yet the action of V2O5 in up-regulating HB-EGF is oxidant-dependent and could be due to the reaction of V2O5 with endogenous H2O2.




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