Vanadium pentoxide is a metal present in air pollution particles that causes airway fibrosis in rats and is a source of occupational asthma and bronchitis in humans. The goal of this project is to investigate signal transduction pathways activated by vanadium pentoxide and to determine how this translates into cell proliferation, apoptosis, or increased cytokine production. We have found that the epidermal growth factor receptor (EGFR) system is a major target of metal-induced oxidative stress. Over the past year we have discovered that human bronchial epithelial cells exposed to vanadium secrete mitogenic activity for human lung fibroblasts, and the majority of this mitogenic activity is due to heparin-binding epidermal growth factor (HB-EGF). Activation of the EGFR leads to downstream activation of other kinases (e.g., ERK and p38 MAPK) and transcription factors (STAT-1, NF-kB). Our goal is to determine which of these signaling pathways mediate the complex biological response to vanadium, which includes increased cytokine and growth factor production, and apoptosis. In the course of these studies, we have also identified a mechanism of cross-talk between ERK and p38 MAP kinases that is important to the regulation of lung myofibroblast proliferation. Finally, cDNA microarray experiments indicate that some genes induced or suppressed in human lung fibroblasts following vanadium treatment require generation of reactive oxygen species, whereas other genes are controlled by vanadium via oxidant-independent mechanisms. It is anticipated that these studies will allow us to better understand at the molecular level how inhaled environmental agents cause airway remodeling and disease.
