title: Vanadium-induced HB-EGF expression in human lung fibroblasts is oxidant dependent and requires MAP kinases.
abstract: Vanadium pentoxide (V(2)O(5)) 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 (H(2)O(2)) or other reactive oxygen species. In this study, we investigated the regulation of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in human lung fibroblasts after V(2)O(5) treatment. V(2)O(5)-induced HB-EGF mRNA expression was abolished by N-acetyl-l-cysteine, suggesting an oxidant-mediated effect. Exogenous H(2)O(2) (>10 microM) mimicked the effect of V(2)O(5) in upregulating HB-EGF expression. Fibroblasts spontaneously released low levels of H(2)O(2) (1-2 microM), and the addition of V(2)O(5) depleted the endogenous H(2)O(2) pool within minutes. V(2)O(5) caused a subsequent increase of H(2)O(2) into the culture medium at 12 h. However, the burst of V(2)O(5)-induced H(2)O(2) occurred after V(2)O(5)-induced HB-EGF mRNA expression at 3 h, indicating that the V(2)O(5)-stimulated H(2)O(2) burst did not mediate HB-EGF expression. Either V(2)O(5) or H(2)O(2) activated ERK-1/2 and p38 MAP kinase. Inhibitors of the ERK-1/2 pathway (PD-98059) or p38 MAP kinase (SB-203580) significantly reduced either V(2)O(5)- or H(2)O(2)-induced HB-EGF expression. These data indicate that vanadium upregulates HB-EGF via ERK and p38 MAP kinases. The induction of HB-EGF is not related to a burst of H(2)O(2) in V(2)O(5) treated cells, yet the action of V(2)O(5) in upregulating HB-EGF is oxidant dependent and could be due to the reaction of V(2)O(5) with endogenous H(2)O(2).
authors.affiliation: Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ingram
authors.forename: Annette B
authors.initials: AB
authors.lastname: Rice
authors.forename: Janine
authors.initials: J
authors.lastname: Santos
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.forename: James C
authors.initials: JC
authors.lastname: Bonner
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000166:cytology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017968:Vanadium Compounds / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D017968:Vanadium Compounds; D004815:Epidermal Growth Factor; D006861:Hydrogen Peroxide; C066075:vanadium pentoxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases