A variety of man-made particles are sources of environmental fibroproliferative lung diseases. A key feature of these diseases is fibroblast hyperplasia. We have investigated the mechanisms through which a fibrogenic metal, vanadium pentoxide, causes lung fibrosis. Our recent experiments have demonstrated that vanadium injury in rats causes airway remodeling associated with peribronchiolar fibrosis, mucous cell metaplasia and smooth muscle cell thickening, which is consistent with the pathology of asthma. In vivo experiments in rats have shown that vanadium causes induction of the platelet-derived growth factor receptor (PDGF-Ra). In vitro experiments have elucidated the mechanisms that mediate PDGF-Ra induction. A required signaling intermediate is p38 MAP kinase, which stabilizes the PDGF-Ra mRNA and thereby up-regulates the expression of this receptor. We have also observed that mitogen-activated protein (MAP) kinases are activated in vivo following vanadium-induced lung injury. In vitro, we have investigated the mechanism of vanadium-induced MAP kinase activation and discovered that vanadium acts via an oxidant-mediated mechanism to cause phosphorylation of the epidermal growth factor receptor (EGF-R), which then triggers downstream activation of molecules such as Raf-1, MEK-1 and MAP kinase. A potentially important observation regards the formation of nitrotyrosine in lung cells in vivo following vanadium exposure as observed by immunohistochemistry. This suggests a role for peroxynitrite in vanadium-induced lung fibrosis. In vitro, nitrotyrosine formation is associated with MAP kinase activation and activation of receptor tyrosine kinases, including PDGF-R and EGF-R. The consequence of MAP kinase activation and phosphorylation of growth factor receptor tyrosine kinases by metals such as vanadium and oxidants such as peroxynitrite remains to be elucidated, but it is postulated that these environmental agents cause dysregulation of proteins involved in proliferative signaling. Finally, we have shown that tyrosine kinase inhibitors administered in vivo block the progression of lung fibrosis induced by vanadium pentoxide. It is anticipated that these studies will lead to therapeutic intervention of environmentally-induced, inflammatory lung diseases.
