Vanadium pentoxide induces pulmonary inflammation and tumor promotion in a strain-dependent manner

BACKGROUND: Elevated levels of air pollution are associated with increased risk of lung cancer. Particulate matter (PM) contains transition metals that may potentiate neoplastic development through the induction of oxidative stress and inflammation, a lung cancer risk factor. Vanadium pentoxide (V(2)O(5)) is a component of PM derived from fuel combustion as well as a source of occupational exposure in humans. In the current investigation we examined the influence of genetic background on susceptibility to V(2)O(5)-induced inflammation and evaluated whether V(2)O(5 )functions as a tumor promoter using a 2-stage (initiation-promotion) model of pulmonary neoplasia in mice. RESULTS: A/J, BALB/cJ (BALB), and C57BL/6J (B6) mice were treated either with the initiator 3-methylcholanthrene (MCA; 10 μg/g; i.p.) or corn oil followed by 5 weekly aspirations of V(2)O(5 )or PBS and pulmonary tumors were enumerated 20 weeks following MCA treatment. Susceptibility to V(2)O(5)-induced pulmonary inflammation was assessed in bronchoalveolar lavage fluid (BALF), and chemokines, transcription factor activity, and MAPK signaling were quantified in lung homogenates. We found that treatment of animals with MCA followed by V(2)O(5 )promoted lung tumors in both A/J (10.3 ± 0.9 tumors/mouse) and BALB (2.2 ± 0.36) mice significantly above that observed with MCA/PBS or V(2)O(5 )alone (P < 0.05). No tumors were observed in the B6 mice in any of the experimental groups. Mice sensitive to tumor promotion by V(2)O(5 )were also found to be more susceptible to V(2)O(5)-induced pulmonary inflammation and hyperpermeability (A/J>BALB>B6). Differential strain responses in inflammation were positively associated with elevated levels of the chemokines KC and MCP-1, higher NFκB and c-Fos binding activity, as well as sustained ERK1/2 activation in lung tissue. CONCLUSIONS: In this study we demonstrate that V(2)O(5), an occupational and environmentally relevant metal oxide, functions as an in vivo lung tumor promoter among different inbred strains of mice. Further, we identified a positive relationship between tumor promotion and susceptibility to V(2)O(5)-induced pulmonary inflammation. These findings suggest that repeated exposures to V(2)O(5 )containing particles may augment lung carcinogenesis in susceptible individuals through oxidative stress mediated pathways.