Department of Pathobiology and Diagnostic Investigation and Center for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824, USA.
Part Fibre Toxicol. 2010 Apr 12;7:9. doi: 10.1186/1743-8977-7-9.
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 (V2O5) 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 V2O5-induced inflammation and evaluated whether V2O5 functions as a tumor promoter using a 2-stage (initiation-promotion) model of pulmonary neoplasia in mice.
A/J, BALB/cJ (BALB), and C57BL/6J (B6) mice were treated either with the initiator 3-methylcholanthrene (MCA; 10 microg/g; i.p.) or corn oil followed by 5 weekly aspirations of V2O5 or PBS and pulmonary tumors were enumerated 20 weeks following MCA treatment. Susceptibility to V2O5-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 V2O5 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 V2O5 alone (P < 0.05). No tumors were observed in the B6 mice in any of the experimental groups. Mice sensitive to tumor promotion by V2O5 were also found to be more susceptible to V2O5-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 NFkappaB and c-Fos binding activity, as well as sustained ERK1/2 activation in lung tissue.
In this study we demonstrate that V2O5, 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 V2O5-induced pulmonary inflammation. These findings suggest that repeated exposures to V2O5 containing particles may augment lung carcinogenesis in susceptible individuals through oxidative stress mediated pathways.
空气污染水平升高与肺癌风险增加有关。颗粒物（PM）含有过渡金属，可能通过诱导氧化应激和炎症（肺癌的一个风险因素）促进肿瘤的发展。五氧化二钒（V2O5）是燃料燃烧产生的 PM 的组成部分，也是人类职业暴露的来源。在目前的研究中，我们研究了遗传背景对 V2O5 诱导的炎症易感性的影响，并使用小鼠肺肿瘤发生的 2 阶段（起始-促进）模型评估了 V2O5 是否作为肿瘤促进剂发挥作用。
A/J、BALB/cJ（BALB）和 C57BL/6J（B6）小鼠分别用启动子 3-甲基胆蒽（MCA；10μg/g；ip）或玉米油处理，然后每周 5 次吸入 V2O5 或 PBS，并在 MCA 处理后 20 周计数肺肿瘤。通过支气管肺泡灌洗（BALF）评估 V2O5 诱导的肺部炎症的易感性，并在肺匀浆中定量测定趋化因子、转录因子活性和 MAPK 信号。我们发现，MCA 后用 V2O5 处理动物可显著促进 A/J（10.3 +/- 0.9 个肿瘤/只）和 BALB（2.2 +/- 0.36 个肿瘤/只）小鼠的肺肿瘤形成，高于 MCA/PBS 或 V2O5 单独处理的肿瘤形成（P < 0.05）。在任何实验组中，B6 小鼠均未观察到肿瘤。V2O5 诱导的肺部炎症和通透性增加（A/J>BALB>B6），易感性增加，V2O5 诱导的肺部炎症和通透性增加（A/J>BALB>B6），易感性增加。炎症的差异应变与趋化因子 KC 和 MCP-1 的水平升高、NFkappaB 和 c-Fos 结合活性升高以及肺组织中 ERK1/2 的持续激活呈正相关。
在这项研究中，我们证明 V2O5，一种职业和环境相关的金属氧化物，作为不同近交系小鼠体内的肺肿瘤促进剂。此外，我们发现肿瘤促进作用与 V2O5 诱导的肺部炎症易感性之间存在正相关关系。这些发现表明，反复暴露于含 V2O5 的颗粒可能通过氧化应激介导的途径增加易感个体的肺癌发生。
