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

Abstract

BackgroundElevated 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.ResultsA/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 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 NFκB and c-Fos binding activity, as well as sustained ERK1/2 activation in lung tissue.ConclusionsIn 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.

Quantification of Kras mutant fraction in the lung DNA of mice exposed to aerosolized particulate vanadium pentoxide by inhalation

“…In the mouse, VP induces pulmonary inflammation and promotes tumor development [3,34]. Using transgenic mice lacking cyclooxygenases and intratracheal instillation of 1 mg/ml VP in saline, Bonner et al [35] showed: (1) that VP-induced inflammation involved increased production of cyclooxygenase-2 (COX-2) and prostaglandin E 2 , as well as secretion of tumor necrosis factor-␣ (TNF-␣) into bronchoalveolar lavage fluid, and (2) that production of COX-2 and prostaglandin E 2 were necessary to resolve the inflammatory effects of VP, so that the COX-2 deficient mice developed fibrosis.…”

An antioxidant nanozyme that uncovers the cytoprotective potential of vanadia nanowires

“…These observations are in agreement with the fact that vanadium complexes can undergo redox reaction and generate ROS in cells [40][41][42] . Although V 2 O 5 is known to cause severe oxidative stress in cells 25,26 , in nano-form, it shows remarkable antioxidant GPx activity. It should be noted that complex Vc undergoes redox reactions without changing the ligand environment.…”

“…Very recently, we reported the peroxynitrite isomerase and reductase activities of graphene-hemin hybrid nanosheets 24 . During our investigations on novel materials with interesting biological activities, we observed that V 2 O 5 , largely known as an oxidant 25,26 , can exhibit antioxidant activity at nanoscale.…”

Evaluation of cII mutations in lung of male Big Blue mice exposed by inhalation to vanadium pentoxide for up to 8 weeks

“…V 2 O 5 acted as both an initiator and promoter of morphological transformation in hamster embryo cells [17], but V 2 O 5 was not an initiator in an in vivo mouse model of tumorigenicity [18], was not mutagenic in Salmonella typhimurium and did not increase the incidence of micronucleated erythrocytes in peripheral blood of mice [14]. In CD1 mice, intraperitoneal administration of V 2 O 5 induced significant DNA damage in multiple tissues, such as lung, heart, liver, bone marrow, spleen, and kidney, as measured by the alkaline comet assay 24 h following the treatment, but the increase was not concentration-dependent [19].…”