Vanadium pentoxide induces pulmonary inflammation and tumor promotion in a strain-dependent manner
© Rondini et al; licensee BioMed Central Ltd. 2010
Received: 25 November 2009
Accepted: 12 April 2010
Published: 12 April 2010
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 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.
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.
Lung cancer is the leading cause of cancer mortality in the U.S. and worldwide . Although cigarette smoke is the main risk factor for lung cancer development, approximately 10-15% of cases occur in never-smokers, implicating other important environmental, occupational, and/or genetic factors [2–4]. Epidemiology studies have suggested that long-term exposure to elevated levels of particulate air pollution increases the risk of and mortality due to lung cancer [5–8]. Particulate matter (PM) is a complex mixture of particles that vary in physiochemical properties and are further classified according to the aerodynamic size (PM2.5 = <2.5 μm; PM10 = ≤10 μm) [9, 10]. PM2.5 consists primarily of combustion products derived from automobiles and the burning of coal, fuel oil, and wood . Most adverse health effects have been attributed to this fraction, due to the ability to penetrate deep within the alveolar region of the lung . Using models developed by the World Bank, Cohen et. al.  predicted that 5% of respiratory cancer mortality worldwide is due to PM2.5.
The mechanism(s) contributing to increased lung cancer risk by PM have not been fully characterized, although it has been suggested that pulmonary inflammation mediated by particle-induced oxidative stress may play an important role [13, 14]. Generation of reactive oxygen and nitrogen species (ROS/RNS) either directly or through activation of phagocytes can cause oxidative damage to DNA leading to initiation of cancer . Additionally, ROS may potentiate tumor development by stimulating production of pro-inflammatory mediators that can promote expansion of initiated cells by influencing cell proliferation and apoptosis . Oxidative stress induced by PM is dependent on both the surface area of the particle as well as its chemical composition . Transition metals, and in particular vanadium compounds, have been implicated as the active constituents meditating oxidative lung injury in rodents exposed to residual fly oil ash (ROFA) [16–18] as well as in some studies using concentrated ambient air particles .
Vanadium pentoxide (V2O5) is the most common commercial form of vanadium . V2O5 is released into the environment during oil and coal combustion and from metallurgical works . Occupational exposure can be significant in the petrochemical, mining, and steel industries . Additionally, military personnel and the general public can be exposed to high levels of vanadium as a result of incidental or intentional burning of fuel oils, such as exposures that occurred during the Kuwait oil fires in 1991 . Adverse respiratory effects have been reported in humans, primates, and rodents exposed acutely to V2O5. Coughing, wheezing, chest pain, bronchitis, and asthma-like symptoms as well as impaired lung function occurred in humans exposed to high levels of V2O5-containing dust [22–25]. In primates, inhalation of V2O5 particles increased bronchoaveolar polymorphonuclear neutrophils (PMNs) and impaired pulmonary function , and in rodents, inhalation or intratracheal administration induced PMN influx, synthesis of pro-inflammatory mediators, as well as pulmonary fibrosis [27–30].
Occupational and ambient exposure to vanadium has been associated with an increase in biological markers for oxidative DNA damage [31, 32], however limited data are available evaluating an association between V2O5 exposure on lung cancer risk [33, 34]. In vitro studies suggest that vanadium functions as both an initiator and promoter of morphological transformation in cultured cell lines . In a National Toxicology Program (NTP) study, continuous inhalation of V2O5 (24 months inhalation; 1-4 mg/m3) resulted in a significant increase (~50%) in the incidence of alveolar/bronchiolar neoplasms in both male and female B6C3F1 mice . Although this study demonstrated the carcinogenic potential of V2O5, long-term continuous exposure was required before tumors developed and no dose response was observed, which suggests V2O5 may be promoting spontaneous tumors. In addition, different mouse strains were not assessed, which can greatly influence pulmonary responses to environmental pollutants  as well as susceptibility to carcinogenesis [37, 38].
This study was conducted to further evaluate the role of V2O5 on pulmonary neoplasia among different inbred strains of mice. Using a two-stage (initiation-promotion) model, we hypothesized that inflammation induced by sub-chronic V2O5 administration would promote tumorigenesis in susceptible strains. Three strains of mice were included in this study that display altered susceptibility to chemical carcinogenesis: A/J mice are sensitive, BALB are intermediate, whereas B6 mice are resistant to most short term chemically-induced carcinogenesis protocols (eg. not initiatable using MCA) [37–39]. These same three strains also have similar differential susceptibility in chronic pulmonary inflammation models [40–42]. Results from this study demonstrate that V2O5 functions as an in vivo lung tumor promoter in both A/J and BALB mice. Further, we demonstrate a positive relationship between tumor promotion and susceptibility to V2O5-induced inflammation, involving the induction of the chemokines KC and MCP-1, the transcription factors NFκB and c-Fos, as well as sustained activation of ERK1/2 in pulmonary tissue.
Male A/J, BALB/cJ (BALB), C57BL/6J (B6) mice were purchased from Jackson Laboratories (Bar Harbor, ME) at 5-6 weeks of age. Animals were housed in plastic, filter-capped cages containing hardwood bedding and maintained in temperature (23 ± 2°C) and humidity (40-60%) controlled rooms with a 12 hour light/dark cycle. Animals were given standard laboratory chow (Teklan foods, Indianapolis, IN) and spring water ad libitum and were assessed daily for health status. All mice were allowed one week to acclimatize prior to treatment. Animal use was conducted in AAALAC-accredited facilities and in accordance with the regulatory guidelines of the Michigan State University All University Committee on Animal Use and Care.
Preparation and Administration of Vanadium Pentoxide
The experimental designs utilized in this study are depicted in Figure 1. Protocol 1 (Fig. 1A) was conducted to investigate whether sub-chronic exposure to V2O5 would promote pulmonary carcinogenesis using a two-stage (initiation-promotion) model. Mice were injected ip. (10 μg/g body weight) with the carcinogen MCA (Sigma, St. Louis, MO) dissolved in corn oil or with corn oil alone. Beginning one week later, mice were treated with 5 weekly aspirations of either V2O5 (4 mg/kg) or PBS as described above. To assess tumor promotion, animals were sacrificed 20 weeks following MCA treatment; the lungs were perfused with saline then inflated and fixed in Tellyesniczky's fixative for 48 hrs. Tumors were enumerated using an Olympus SZX7 stereomicroscope (Olympus; Center Valley, PA) and sized with digital calipers (Mitutoyo Corporation; Japan). Using this protocol, pulmonary inflammation was additionally assessed in A/J mice 21 days following the last aspiration as described below.
To assess strain differences in inflammation, (protocol 2, Fig. 1B), mice were aspirated once per week for 4 weeks with V2O5 (4 mg/kg) or PBS. At selected time intervals (6 hr, 1, 3, 6, and 21 days) following the last dose, bronchoaveolar lavage fluid (BALF) was collected to quantify differences in cellular infiltrates and protein content, a marker of hyperpermeability, as described previously . At each time point, the right lobes were snap frozen in liquid nitrogen and stored at -80°C and the left lobe was either snap frozen and stored or inflated with and fixed overnight in 10% neutral buffered formalin for histological examination.
Because several studies demonstrated that MCA can induce p38 MAP Kinase, intracellular oxidants, as well as transcription factor activity in HepG2 cells (a hepatoma cell line) [45–47], an additional control experiment was conducted to determine whether carcinogen (MCA) administration influences pulmonary inflammation between strains. Mice were injected ip. with MCA (10 μg/g) dissolved in corn oil or oil alone, then aspirated with 4 weekly doses of PBS (Protocol 3, Fig. 1C) and sacrificed 6 hr or 1 day following the last aspiration. BALF was assessed for protein content and cellular infiltrate as described above.
Immunohistochemical Detection of PMNs
A neutrophil-specific marker (sc-59338) and ABC detection kit (sc-2019) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Left lungs were fixed in 10% NBF for 24 hrs, processed using standard histological procedures, embedded, then cut into 5 μm sections. Strain differences in pulmonary neutrophil infiltration were evaluated using peroxidase biotin-streptavidin immunohistochemistry, and bound enzyme was visualized using the chromagen 3-3'-diaminobenzidine (DAB). Tissues were then lightly counterstained in Gill's hematoxylin.
Analysis of the chemokines KC, MIP-2, and MCP-1 by ELISA
ELISA kits for keratinocyte-derived chemokine (KC, CXCL1), macrophage inflammatory protein-2 (MIP-2, CXCL2), and monocyte chemoattractant protein 1 (MCP-1, CCL2) were purchased from R&D systems (Minneapolis, MN). Protein was prepared by homogenizing lungs in ice-cold RIPA buffer (10 mM PBS, 0.5% SDS, 0.5% sodium deoxycholate) containing protease inhibitors (Sigma, St. Louis, MO). Homogenates were centrifuged at 13,000 × g for 10 min at 4°C, and protein was quantified using the DC protein assay (BioRad; Carlsbad, CA). For chemokine analysis 25-50 μg of RIPA extracted protein was used in accordance with manufacturer's instructions. Absorbance was measured at 450 nm using a VersaMax microplate reader (Molecular Devices, Sunnyvale, CA). All data are presented as pg/mg protein.
Transcription factor assay for nuclear NFκB and c-Fos activity
Nuclear protein was prepared from the left lung of mice using the TransAM nuclear extraction kit (Active Motif; Carlsbad, CA) and quantified with the DC protein assay (Biorad; Carlsbad, CA). Strain differences in binding of NFκB (p65 subunit) and AP-1 (c-Fos) were then measured from 8 μg of nuclear protein using TransAM Transcription Factor ELISA kits (Active Motif; Carlsbad, CA). Absorbance was measured at 450 nm using a VersaMax microplate reader (Molecular Devices, Sunnyvale, CA).
Immunoblotting analyses for MAPK activation
Primary antibodies specific for MAPKs were purchased from Cell Signaling (Danvers, MA) and secondary antibodies from Pierce (Thermo Fisher; Rockford, IL). Protein was prepared from right lungs as described above. Samples (100 μg protein) were resolved on 12.5% SDS polyacrylamide gels. Following transfer, PVDF membranes were blocked for 1 hr at room temperature in 5% nonfat dry milk, and then incubated with primary antibodies to detect phosphorylated ERK1/2, JNK1/2, or p38 overnight at 4°C. After washing, blots were incubated in secondary antibody linked to horseradish peroxidase for 1 hr at room temperature, and bands were detected using chemiluminescence. Images were captured using BioRad ChemiDoc illumination system (BioRad; Carlsbad, CA). Following detection, membranes were stripped in Restore stripping buffer (Thermo Fisher; Rockford, IL) then reprobed for total MAPK using procedures described above. Densitometry of bands were quantified with BioRad Quality One software and phosphorylated proteins were normalized to the respective total MAPK prior to statistical analyses.
All statistical analyses were conducted using SAS statistical software (SAS institute version 8.2, Cary, North Carolina). Time- and strain- dependent changes in BALF protein, cellularity, chemokines, nuclear transcription factor activity, protein densitometry, and tumor multiplicity/size were analyzed using an analysis of variance (ANOVA). When statistical differences were detected (P < 0.05), comparisons of means were analyzed using the least significant difference (LSD) method. All data are presented as mean ± SEM.
Sub-chronic administration of V2O5 promotes pulmonary tumorigenesis in A/J and BALB mice
Lung tumor multiplicity and size (in parenthesis) among inbred mice following sub-chronic V2O5 exposure.a, b, c, d
Corn Oil (Control)
V 2 O 5
V 2 O 5
0.0 ± 0.0
0.50 ± 0.50
3.3 ± 0.75#
(0.72 ± 0.036)#
10 ± 1.4*#
(0.72 ± 0.032)#
0.0 ± 0.0
0.0 ± 0.0
0.78 ± 0.28
(0.49 ± 0.039)
2.2 ± 0.36*
(0.63 ± 0.068)
A/J and BALB mice are more susceptible to V2O5-induced pulmonary hyperpermeability and inflammation than B6 mice
The effects of V2O5 on BALF cellularity are depicted in Fig. 2B-2E. As shown, the extent and duration of the inflammatory response was significantly greater in A/J mice at all time points examined (P < 0.05; Fig. 2B). The most striking difference between strains was observed for PMNs, which was highest at 1 day (Fig. 2D). A/J mice exhibited a ~150-fold increase in the number of PMNs infiltrating the lung representing 36% of the total cells recovered compared to a 43-fold increase in BALB (34%) and only a 16-fold increase (~7%) in B6 mice. By 21 days, inflammation completely resolved in B6 mice, but the total number of cells, primarily macrophages and some lymphocytes, remained elevated in A/J and to a lesser degree in BALB mice (P < 0.05).
Pulmonary inflammation and hyperpermeability in A/J mice treated with either corn oil or MCA (10 μg/g) and then aspirated with 5 weekly doses of V2O5 (4 mg/kg) or PBS.a
Total Cells (×103)
129 ± 4.3
79.7 ± 8.8
73.7 ± 7.9
0.572 ± 0.12
0.422 ± 0.12
166 ± 4.0*
156 ± 17*
147 ± 18*
4.14 ± 0.65*
0.737 ± 0.23*
132 ± 15
83.1 ± 11
76.3 ± 11
0.109 ± 0.07
0.271 ± 0.073
198 ± 25*
161 ± 16*
149 ± 18*
6.01 ± 0.81*
1.47 ± 0.38*
To further confirm that strain differences in tumor promotion were not due to differences in inflammatory responses to MCA, an additional control experiment was conducted (Fig. 1C, Protocol 3). MCA or oil was administered to mice followed by 4 weekly doses of PBS and differences in BALF protein content and cellularity were measured at 6 hr and 1 day following the last aspiration (Additional file 1, Table S1). BALB mice exhibited a significant increase in protein levels compared to the other strains, similar to that observed in Fig. 2. Both BALB and A/J mice also had higher PMNs compared to B6 mice, however no additional effects of MCA on inflammatory cell types were observed within strains (Additional file 1, Table S1). Thus, these results provide further evidence that strain susceptibility to inflammation induced by V2O5 and not to MCA is more strongly associated with lung tumor promotion in our model.
Strain differences in V2O5-induced inflammatory chemokine (KC, MIP-2, MCP-1) expression
A/J mice have higher transcriptional activity of NFκB and AP-1 than B6 mice following V2O5
V2O5 activates the MAPKs ERK1/2 and p38 in pulmonary tissue
Chronic inflammation is a risk factor for several cancer types . Asthmatics and individuals with COPD are at an elevated lifetime risk for developing lung cancer . The importance of inflammation in augmenting pulmonary carcinogenesis is further supported by a wide range of pharmaceutical compounds that inhibit neoplastic development  as well as evidence from transgenic mouse models [52, 53]. Because tumor promotion involves changes in gene expression, most likely epigenetic in nature, and is the only reversible stage of carcinogenesis, studying promoters may identify additional pathways to target for preventive strategies against human lung cancer.
In the current investigation, we provide evidence that V2O5 functions as an in vivo tumor promoter among differentially susceptible inbred strains of mice. Using a two-stage model of carcinogenesis, a significant increase in tumor multiplicity was observed in both A/J (10.3 ± 0.9 tumors/mouse) and BALB (2.2 ± 0.36) mice exposed to the carcinogen MCA followed by 5 weekly aspirations of V2O5. The effect of V2O5 was limited to tumor promotion, as no significant increase in tumor numbers were observed in animals exposed to V2O5 alone. Susceptibility to promotion paralleled relative strain sensitivity to V2O5-induced inflammation: A/J mice were most sensitive and BALB were intermediate. B6 mice were found to be most resistant to V2O5-induced inflammation, however were used as a control since they are not initiated by the low dose of MCA administered in this study .
Differences between the two susceptible strains of mice (A/J and BALB) are not unusual based on past genome mapping studies demonstrating distinct genes responsible for tumorigenesis in these specific strains [54, 55]. While both strains are susceptible to lung tumor development, differences in sensitivity between these two strains has been linked to quantitative trait loci containing both tumor suppressor genes as well as inflammatory mediators, such as myeloperoxidase (Mpo), colony stimulating factor (Csf)3, CC chemokine receptor (Ccr10), and Ccl2 (Mcp-1) [54, 55]. Although MCA was used as an initiating agent in this study, additional control experiments further demonstrated that carcinogen treatment alone did not influence inflammatory indices between strains. Because significant strain responses were observed only in response to V2O5, our findings suggest that that genetic (host) factors contributing to V2O5-induced pulmonary inflammation are also strongly associated to lung tumor promotion.
Vanadium is thought to mediate pulmonary inflammation through generation of multiple reactive oxygen species (O2-, H2O2, and ·OH) in target cells [56–58]. Production of ROS is associated with phosphorylation of EGF-R and activation of MAPK signaling [57, 59–63] as well as the transcription factors NFκB [59, 63], AP-1 [59, 64], and STAT-1 . Furthermore, vanadium is known to be a phosphatase inhibitor  and likely prolongs phosphorylation and signaling along ROS-sensitive pathways. These events, in turn can influence the synthesis and release of pro-inflammatory cytokines and chemokines mediating acute lung injury [29, 65, 67, 68]. Pretreatment of human bronchial epithelial cells with metal chelators and/or free radical scavengers reduces vanadium-generated ROS, MAPK activation, as well as release of chemokines, further supporting a role for oxidative stress in vanadium-induced inflammation .
In our study, differential strain induction of chemokines and upstream signaling molecules in response to V2O5 correlated to the extent and duration of inflammatory cells recovered in pulmonary tissue. MIP-2 and KC are principle neutrophil chemoattractants in rodent models, homologous to IL-8 in humans , whereas MCP-1 induces monocyte and lymphocyte chemotaxis and migration . We observed moderate, although significant induction of MIP-2 in all strains at 6 hr following vanadium exposure, which likely involved initial PMN influx. However, strain differences in the peak PMN response were more closely associated with pulmonary levels of KC. MCP-1 was highly induced in A/J and BALB mice and expression coincided with the influx of both monocytes and lymphocytes into pulmonary tissue. The transcription factors NFκB and c-Fos as well as the MAPK pERK1/2 were also found to be differentially regulated in the sensitive (A/J) and resistant (B6) mice and corresponded to both altered chemokine induction and BALF cellularity.
The microenvironment is becoming increasingly recognized as actively contributing to the tumorigenic process. Evidence suggests that PMNs and macrophages appear to be involved in tumor development through multiple mechanisms, including more direct, such as induction of DNA damage and regulation of cell cycle , as well as indirect mechanisms, such as promotion of angiogenesis by cytokines and chemokines and suppression of adaptive immune responses [71, 72]. Local production of cytokines and chemokines may also stimulate expansion of initiated cells by influencing cell proliferation and apoptotic pathways . Several signaling molecules altered by V2O5 in this study have been implicated in lung cancer development. For example, IL-8 has been reported to serve as an autocrine growth factor in lung cancer cell lines [73, 74] and both IL-8 and MCP-1 are elevated in bronchiolar epithelium from patients with COPD [75, 76] and non-small cell lung cancer (NSCLC) . In mouse models, neutralization of CXCR2, the principle receptor for KC and MIP-2 reduces PMN infiltration  as well as tumor growth and angiogenesis, suggesting a role in tumor progression [53, 79, 80]. Constitutive activation of pERK1/2 [81, 82] and the transcription factors NFκB  and c-Fos  have well known effects on cell cycle regulation. Additional evidence for ERK1/2 in pulmonary tumorigenesis was recently demonstrated in transgenic mice overexpressing mutant B-raf and K-ras. Pharmacological inhibition of pERK1/2 resulted in tumor regression by inhibiting cell proliferation and restoring apoptosis . Constitutive activation of ERK1/2 was also observed in V2O5-induced mouse carcinomas from the NTP study containing both K-ras mutations and loss of heterozygosity , which supports findings in this model and suggests involvement of ERK1/2 as one pathway driving tumor promotion by V2O5.
Our study provides evidence that V2O5 functions as an in vivo tumor promoter and suggests that susceptibility to V2O5-induced inflammation and tumor promotion is influenced by genetic background. Tumor promotion in our model was associated with a robust inflammatory response involving induction of multiple chemokines, the transcription factors NFκB and c-Fos, as well as sustained activation of ERK1/2 in susceptible mice. These findings suggest that activation of oxidative stress-mediated signaling events may be one mechanism contributing to increased lung cancer risk by PM. A limitation in the current study was that the dose of V2O5 utilized was significantly higher than either occupational or ambient exposure levels, and was not meant to be directly used for risk assessment. It should be noted, however, that in the NTP study, a significant increase in pulmonary tumors was also reported after 2 years in B6C3F1 mice, a resistant strain, at more relevant occupational levels of V2O5. Although we found that V2O5 alone did not initiate tumorigenesis, our findings highlight that repeated exposures to inflammatory stimuli augments pulmonary carcinogenesis in susceptible strains. Additional studies examining genetic differences in antioxidant enzyme levels and adenoma susceptibility genes potentially contributing to tumor promotion by V2O5 as well as to other PM constituents warrant further investigation.
Analysis of variance
Bronchoalveolar lavage fluid
chronic obstructive pulmonary disease
Enzyme-linked immunosorbent assay
Extracellular-signal related kinase
Mitogen-activated protein kinase
Monocyte chemoattractant protein-1
Macrophage inflammatory protein-2
non small cell lung cancer
Nuclear factor-kappa B
c-Jun N-terminal kinase
Phosphate buffered saline
Reactive nitrogen species
Reactive oxygen species
Residual oil fly ash
Tris buffered saline
Tris buffered saline with Tween-20
The authors would like to thank the Department of Pathobiology and Diagnostic Investigation and the Center for Integrative Toxicology at Michigan State University for funding this project.
- Ferlay J, Bray F, Pisani P, Parkin DM: GLOBOCAN 2002: Cancer incidence, mortality, and prevalence worldwide. Lyon, France: IARC Press; 2004.Google Scholar
- Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer statistics, 2007. CA Cancer J Clin 2007, 57: 43–66. 10.3322/canjclin.57.1.43View ArticlePubMedGoogle Scholar
- Thun MJ, Henley SJ, Burns D, Jemal A, Shanks TG, Calle EE: Lung cancer death rates in lifelong nonsmokers. J Natl Cancer Inst 2006, 98: 691–699.View ArticlePubMedGoogle Scholar
- Siemiatycki J, Richardson L, Straif K, Latreille B, Lakhani R, Campbell S, Rousseau MC, Boffetta P: Listing occupational carcinogens. Environ Health Perspect 2004, 112: 1447–1459.PubMed CentralView ArticlePubMedGoogle Scholar
- Barbone F, Bovenzi M, Cavallieri F, Stanta G: Air-Pollution and Lung-Cancer in Trieste, Italy. American Journal of Epidemiology 1995, 141: 1161–1169.PubMedGoogle Scholar
- Dockery DW, Pope CA III, Xu X, Spengler JD, Ware JH, Fay ME, Ferris BG Jr, Speizer FE: An association between air pollution and mortality in six U.S. cities. N Engl J Med 1993, 329: 1753–1759. 10.1056/NEJM199312093292401View ArticlePubMedGoogle Scholar
- Pope CA, Burnett RT, Thun MJ, Calle EE, Krewski D, Ito K, Thurston GD: Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution. Jama 2002, 287: 1132–1141. 10.1001/jama.287.9.1132PubMed CentralView ArticlePubMedGoogle Scholar
- Pope CA, Namboodiri MM, Dockery DW, Evans JS, Speizer FE, Heath CW: Particulate air pollution as a predictor of mortality in a prospective study of U.S. adults. Am J Respir Crit Care Med 1995, 151: 669–674.View ArticlePubMedGoogle Scholar
- U.S.EPA: Air Quality Criteria for Particulate Matter (Final Report, Oct 2004). Washington, DC, USA: U.S. Environmental Protection Agency; 2004.Google Scholar
- WHO: Health Aspects of Air Pollution with Particulate Matter, Ozone and Nitrogen Dioxide. Bonn, Germany: World Health Organization (WHO); 2003.Google Scholar
- Lippmann M, Yeates DB, Albert RE: Deposition, retention, and clearance of inhaled particles. Br J Ind Med 1980, 37: 337–362.PubMed CentralPubMedGoogle Scholar
- Cohen AJ, Ross Anderson H, Ostro B, Pandey KD, Krzyzanowski M, Kunzli N, Gutschmidt K, Pope A, Romieu I, Samet JM, Smith K: The global burden of disease due to outdoor air pollution. J Toxicol Environ Health A 2005, 68: 1301–1307. 10.1080/15287390590936166View ArticlePubMedGoogle Scholar
- Galaris D, Evangelou A: The role of oxidative stress in mechanisms of metal-induced carcinogenesis. Crit Rev Oncol Hematol 2002, 42: 93–103. 10.1016/S1040-8428(01)00212-8View ArticlePubMedGoogle Scholar
- Knaapen AM, Borm PJ, Albrecht C, Schins RP: Inhaled particles and lung cancer. Part A: Mechanisms. Int J Cancer 2004, 109: 799–809. 10.1002/ijc.11708View ArticlePubMedGoogle Scholar
- Bonner JC: Lung fibrotic responses to particle exposure. Toxicol Pathol 2007, 35: 148–153. 10.1080/01926230601060009View ArticlePubMedGoogle Scholar
- Costa DL, Dreher KL: Bioavailable transition metals in particulate matter mediate cardiopulmonary injury in healthy and compromised animal models. Environ Health Perspect 1997, 105(Suppl 5):1053–1060. 10.2307/3433509PubMed CentralView ArticlePubMedGoogle Scholar
- Dreher KL, Jaskot RH, Lehmann JR, Richards JH, McGee JK, Ghio AJ, Costa DL: Soluble transition metals mediate residual oil fly ash induced acute lung injury. J Toxicol Environ Health 1997, 50: 285–305. 10.1080/009841097160492View ArticlePubMedGoogle Scholar
- Kadiiska MB, Mason RP, Dreher KL, Costa DL, Ghio AJ: In vivo evidence of free radical formation in the rat lung after exposure to an emission source air pollution particle. Chemical Research in Toxicology 1997, 10: 1104–1108. 10.1021/tx970049rView ArticlePubMedGoogle Scholar
- Saldiva PH, Clarke RW, Coull BA, Stearns RC, Lawrence J, Murthy GG, Diaz E, Koutrakis P, Suh H, Tsuda A, Godleski JJ: Lung inflammation induced by concentrated ambient air particles is related to particle composition. Am J Respir Crit Care Med 2002, 165: 1610–1617. 10.1164/rccm.2106102View ArticlePubMedGoogle Scholar
- IARC: Cobalt in Hard Metals and Cobalt Sulfate, Gallium Arsenide, Indium Phosphide and Vanadium Pentoxide. Lyon, France: International Agency for Research on Cancer (IARC); 2006.Google Scholar
- Sadiq M, Mian AA: Nickel and Vanadium in Air Particulates at Dhahran (Saudi-Arabia) During and after the Kuwait Oil Fires. Atmospheric Environment 1994, 28: 2249–2253. 10.1016/1352-2310(94)90364-6View ArticleGoogle Scholar
- Hauser R, Eisen EA, Pothier L, Christiani DC: A prospective study of lung function among boilermaker construction workers exposed to combustion particulates. Am J Ind Med 2001, 39: 454–462. 10.1002/ajim.1039View ArticlePubMedGoogle Scholar
- Hauser R, Eisen EA, Pothier L, Lewis D, Bledsoe T, Christiani DC: Spirometric abnormalities associated with chronic bronchitis, asthma, and airway hyperresponsiveness among boilermaker construction workers. Chest 2002, 121: 2052–2060. 10.1378/chest.121.6.2052View ArticlePubMedGoogle Scholar
- Irsigler GB, Visser PJ, Spangenberg PA: Asthma and chemical bronchitis in vanadium plant workers. Am J Ind Med 1999, 35: 366–374. 10.1002/(SICI)1097-0274(199904)35:4<366::AID-AJIM7>3.0.CO;2-NView ArticlePubMedGoogle Scholar
- Hauser R, Elreedy S, Hoppin JA, Christiani DC: Upper airway response in workers exposed to fuel oil ash: nasal lavage analysis. Occup Environ Med 1995, 52: 353–358. 10.1136/oem.52.5.353PubMed CentralView ArticlePubMedGoogle Scholar
- Knecht EA, Moorman WJ, Clark JC, Lynch DW, Lewis TR: Pulmonary effects of acute vanadium pentoxide inhalation in monkeys. Am Rev Respir Dis 1985, 132: 1181–1185.PubMedGoogle Scholar
- Bonner JC, Rice AB, Ingram JL, Moomaw CR, Nyska A, Bradbury A, Sessoms AR, Chulada PC, Morgan DL, Zeldin DC, Langenbach R: Susceptibility of cyclooxygenase-2-deficient mice to pulmonary fibrogenesis. Am J Pathol 2002, 161: 459–470.PubMed CentralView ArticlePubMedGoogle Scholar
- Bonner JC, Rice AB, Moomaw CR, Morgan DL: Airway fibrosis in rats induced by vanadium pentoxide. Am J Physiol Lung Cell Mol Physiol 2000, 278: L209–216.PubMedGoogle Scholar
- Pierce LM, Alessandrini F, Godleski JJ, Paulauskis JD: Vanadium-induced chemokine mRNA expression and pulmonary inflammation. Toxicol Appl Pharmacol 1996, 138: 1–11. 10.1006/taap.1996.9999View ArticlePubMedGoogle Scholar
- Ress NB, Chou BJ, Renne RA, Dill JA, Miller RA, Roycroft JH, Hailey JR, Haseman JK, Bucher JR: Carcinogenicity of inhaled vanadium pentoxide in F344/N rats and B6C3F1 mice. Toxicol Sci 2003, 74: 287–296. 10.1093/toxsci/kfg136View ArticlePubMedGoogle Scholar
- Ehrlich VA, Nersesyan AK, Hoelzi C, Ferk F, Bichler J, Valic E, Schaffer A, Schulte-Hermann R, Fenech M, Wagner KH, Knasmuller S: Inhalative Exposure to Vanadium Pentoxide Causes DNA Damage in Workers: Results of a Multiple End Point Study. Environmental Health Perspectives 2008, 116: 1689–1693. 10.1289/ehp.11438PubMed CentralView ArticlePubMedGoogle Scholar
- Sorensen M, Schins RP, Hertel O, Loft S: Transition metals in personal samples of PM2.5 and oxidative stress in human volunteers. Cancer Epidemiol Biomarkers Prev 2005, 14: 1340–1343. 10.1158/1055-9965.EPI-04-0899View ArticlePubMedGoogle Scholar
- Hickey RJ, Schoff EP, Clelland RC: Relationship between air pollution and certain chronic disease death rates. Multivariate statistical studies. Arch Environ Health 1967, 15: 728–738.View ArticlePubMedGoogle Scholar
- Boice JD, Mumma MT, Blot WJ: Cancer and noncancer mortality in populations living near uranium and vanadium mining and milling operations in Montrose County, Colorado, 1950–2000. Radiation Research 2007, 167: 711–726. 10.1667/RR0839.1View ArticlePubMedGoogle Scholar
- Rivedal E, Roseng LE, Sanner T: Vanadium compounds promote the induction of morphological transformation of hamster embryo cells with no effect on gap junctional cell communication. Cell Biol Toxicol 1990, 6: 303–314. 10.1007/BF02443805View ArticlePubMedGoogle Scholar
- Bauer AK, Malkinson AM, Kleeberger SR: Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities. Am J Physiol Lung Cell Mol Physiol 2004, 287: L685–703. 10.1152/ajplung.00223.2003View ArticlePubMedGoogle Scholar
- Bauer AK, Dwyer-Nield LD, Keil K, Koski K, Malkinson AM: Butylated hydroxytoluene (BHT) induction of pulmonary inflammation: a role in tumor promotion. Exp Lung Res 2001, 27: 197–216. 10.1080/019021401300053948View ArticlePubMedGoogle Scholar
- Malkinson AM, Radcliffe RA, Bauer AK: Quantitative trait locus mapping of susceptibilities to butylated hydroxytoluene-induced lung tumor promotion and pulmonary inflammation in CXB mice. Carcinogenesis 2002, 23: 411–417. 10.1093/carcin/23.3.411View ArticlePubMedGoogle Scholar
- Miller YE, Dwyer-Nield LD, Keith RL, Le M, Franklin WA, Malkinson AM: Induction of a high incidence of lung tumors in C57BL/6 mice with multiple ethyl carbamate injections. Cancer Lett 2003, 198: 139–144. 10.1016/S0304-3835(03)00309-4View ArticlePubMedGoogle Scholar
- Ewart SL, Kuperman D, Schadt E, Tankersley C, Grupe A, Shubitowski DM, Peltz G, Wills-Karp M: Quantitative trait loci controlling allergen-induced airway hyperresponsiveness in inbred mice. Am J Respir Cell Mol Biol 2000, 23: 537–545.View ArticlePubMedGoogle Scholar
- Lewkowich IP, Lajoie S, Clark JR, Herman NS, Sproles AA, Wills-Karp M: Allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives airway hyperresponsiveness in asthma-susceptible mice. PLoS One 2008, 3: e3879. 10.1371/journal.pone.0003879PubMed CentralView ArticlePubMedGoogle Scholar
- Bauer AK, Dwyer-Nield LD, Hankin JA, Murphy RC, Malkinson AM: The lung tumor promoter, butylated hydroxytoluene (BHT), causes chronic inflammation in promotion-sensitive BALB/cByJ mice but not in promotion-resistant CXB4 mice. Toxicology 2001, 169: 1–15. 10.1016/S0300-483X(01)00475-9View ArticlePubMedGoogle Scholar
- Foster WM, Walters DM, Longphre M, Macri K, Miller LM: Methodology for the measurement of mucociliary function in the mouse by scintigraphy. J Appl Physiol 2001, 90: 1111–1117.PubMedGoogle Scholar
- Cho HY, Jedlicka AE, Reddy SP, Kensler TW, Yamamoto M, Zhang LY, Kleeberger SR: Role of NRF2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol 2002, 26: 175–182.View ArticlePubMedGoogle Scholar
- Ainbinder E, Bergelson S, Pinkus R, Daniel V: Regulatory mechanisms involved in activator-protein-1 (AP-1)-mediated activation of glutathione-S-transferase gene expression by chemical agents. Eur J Biochem 1997, 243: 49–57. 10.1111/j.1432-1033.1997.0049a.xView ArticlePubMedGoogle Scholar
- Bergelson S, Pinkus R, Daniel V: Intracellular glutathione levels regulate Fos/Jun induction and activation of glutathione S-transferase gene expression. Cancer Res 1994, 54: 36–40.PubMedGoogle Scholar
- Kwon YW, Ueda S, Ueno M, Yodoi J, Masutani H: Mechanism of p53-dependent apoptosis induced by 3-methylcholanthrene: involvement of p53 phosphorylation and p38 MAPK. J Biol Chem 2002, 277: 1837–1844. 10.1074/jbc.M105033200View ArticlePubMedGoogle Scholar
- Bauer AK, Dixon D, DeGraff LM, Cho HY, Walker CR, Malkinson AM, Kleeberger SR: Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis. J Natl Cancer Inst 2005, 97: 1778–1781.View ArticlePubMedGoogle Scholar
- Coussens LM, Werb Z: Inflammation and cancer. Nature 2002, 420: 860–867. 10.1038/nature01322PubMed CentralView ArticlePubMedGoogle Scholar
- Engels EA: Inflammation in the development of lung cancer: epidemiological evidence. Expert Rev Anticancer Ther 2008, 8: 605–615. 10.1586/14737188.8.131.525View ArticlePubMedGoogle Scholar
- Bauer AK, Rondini EA: Review paper: the role of inflammation in mouse pulmonary neoplasia. Vet Pathol 2009, 46: 369–390. 10.1354/vp.08-VP-0217-B-REVView ArticlePubMedGoogle Scholar
- Ji H, Houghton AM, Mariani TJ, Perera S, Kim CB, Padera R, Tonon G, McNamara K, Marconcini LA, Hezel A, et al.: K-ras activation generates an inflammatory response in lung tumors. Oncogene 2006, 25: 2105–2112. 10.1038/sj.onc.1209237View ArticlePubMedGoogle Scholar
- Wislez M, Fujimoto N, Izzo JG, Hanna AE, Cody DD, Langley RR, Tang H, Burdick MD, Sato M, Minna JD, et al.: High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic kras. Cancer Res 2006, 66: 4198–4207. 10.1158/0008-5472.CAN-05-3842View ArticlePubMedGoogle Scholar
- Festing MF, Lin L, Devereux TR, Gao F, Yang A, Anna CH, White CM, Malkinson AM, You M: At least four loci and gender are associated with susceptibility to the chemical induction of lung adenomas in A/J × BALB/c mice. Genomics 1998, 53: 129–136. 10.1006/geno.1998.5450View ArticlePubMedGoogle Scholar
- Obata M, Nishimori H, Ogawa K, Lee GH: Identification of the Par2 (Pulmonary adenoma resistance) locus on mouse chromosome 18, a major genetic determinant for lung carcinogen resistance in BALB/cByJ mice. Oncogene 1996, 13: 1599–1604.PubMedGoogle Scholar
- Wang L, Medan D, Mercer R, Overmiller D, Leornard S, Castranova V, Shi X, Ding M, Huang C, Rojanasakul Y: Vanadium-induced apoptosis and pulmonary inflammation in mice: Role of reactive oxygen species. J Cell Physiol 2003, 195: 99–107. 10.1002/jcp.10232View ArticlePubMedGoogle Scholar
- Wang YZ, Ingram JL, Walters DM, Rice AB, Santos JH, Van Houten B, Bonner JC: Vanadium-induced STAT-1 activation in lung myofibroblasts requires H2O2and P38 MAP kinase. Free Radic Biol Med 2003, 35: 845–855. 10.1016/S0891-5849(03)00399-XView ArticlePubMedGoogle Scholar
- Grabowski GM, Paulauskis JD, Godleski JJ: Mediating phosphorylation events in the vanadium-induced respiratory burst of alveolar macrophages. Toxicol Appl Pharmacol 1999, 156: 170–178. 10.1006/taap.1999.8642View ArticlePubMedGoogle Scholar
- Huang C, Chen N, Ma WY, Dong Z: Vanadium induces AP-1- and NFkappB-dependent transcription activity. Int J Oncol 1998, 13: 711–715.PubMedGoogle Scholar
- Ingram JL, Rice AB, Santos J, Van Houten B, Bonner JC: Vanadium-induced HB-EGF expression in human lung fibroblasts is oxidant dependent and requires MAP kinases. Am J Physiol Lung Cell Mol Physiol 2003, 284: L774–782.View ArticlePubMedGoogle Scholar
- Wang YZ, Bonner JC: Mechanism of extracellular signal-regulated kinase (ERK)-1 and ERK-2 activation by vanadium pentoxide in rat pulmonary myofibroblasts. Am J Respir Cell Mol Biol 2000, 22: 590–596.View ArticlePubMedGoogle Scholar
- Samet JM, Graves LM, Quay J, Dailey LA, Devlin RB, Ghio AJ, Wu W, Bromberg PA, Reed W: Activation of MAPKs in human bronchial epithelial cells exposed to metals. Am J Physiol 1998, 275: L551–558.PubMedGoogle Scholar
- Chen F, Demers LM, Vallyathan V, Ding M, Lu Y, Castranova V, Shi X: Vanadate induction of NF-kappaB involves IkappaB kinase beta and SAPK/ERK kinase 1 in macrophages. J Biol Chem 1999, 274: 20307–20312. 10.1074/jbc.274.29.20307View ArticlePubMedGoogle Scholar
- Ding M, Li JJ, Leonard SS, Ye JP, Shi X, Colburn NH, Castranova V, Vallyathan V: Vanadate-induced activation of activator protein-1: role of reactive oxygen species. Carcinogenesis 1999, 20: 663–668. 10.1093/carcin/20.4.663View ArticlePubMedGoogle Scholar
- Antao-Menezes A, Turpin EA, Bost PC, Ryman-Rasmussen JP, Bonner JC: STAT-1 signaling in human lung fibroblasts is induced by vanadium pentoxide through an IFN-beta autocrine loop. J Immunol 2008, 180: 4200–4207.View ArticlePubMedGoogle Scholar
- Samet JM, Silbajoris R, Wu W, Graves LM: Tyrosine phosphatases as targets in metal-induced signaling in human airway epithelial cells. Am J Respir Cell Mol Biol 1999, 21: 357–364.View ArticlePubMedGoogle Scholar
- Carter JD, Ghio AJ, Samet JM, Devlin RB: Cytokine production by human airway epithelial cells after exposure to an air pollution particle is metal-dependent. Toxicol Appl Pharmacol 1997, 146: 180–188. 10.1006/taap.1997.8254View ArticlePubMedGoogle Scholar
- Chong IW, Shi MM, Love JA, Christiani DC, Paulauskis JD: Regulation of chemokine mRNA expression in a rat model of vanadium-induced pulmonary inflammation. Inflammation 2000, 24: 505–517. 10.1023/A:1007021322323View ArticlePubMedGoogle Scholar
- Huang S, Paulauskis JD, Kobzik L: Rat KC cDNA cloning and mRNA expression in lung macrophages and fibroblasts. Biochem Biophys Res Commun 1992, 184: 922–929. 10.1016/0006-291X(92)90679-FView ArticlePubMedGoogle Scholar
- Matsushima K, Larsen CG, DuBois GC, Oppenheim JJ: Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line. J Exp Med 1989, 169: 1485–1490. 10.1084/jem.169.4.1485View ArticlePubMedGoogle Scholar
- Gungor N, Pennings JL, Knaapen AM, Chiu RK, Peluso M, Godschalk RW, van Schooten FJ: Transcriptional profiling of the acute pulmonary inflammatory response induced by LPS: role of neutrophils. Respir Res 2010, 11: 24. 10.1186/1465-9921-11-24PubMed CentralView ArticlePubMedGoogle Scholar
- de Visser KE, Eichten A, Coussens LM: Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 2006, 6: 24–37. 10.1038/nrc1782View ArticlePubMedGoogle Scholar
- Zhu YM, Webster SJ, Flower D, Woll PJ: Interleukin-8/CXCL8 is a growth factor for human lung cancer cells. Br J Cancer 2004, 91: 1970–1976. 10.1038/sj.bjc.6602227PubMed CentralView ArticlePubMedGoogle Scholar
- Luppi F, Longo AM, de Boer WI, Rabe KF, Hiemstra PS: Interleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptor transactivation. Lung Cancer 2007, 56: 25–33. 10.1016/j.lungcan.2006.11.014View ArticlePubMedGoogle Scholar
- de Boer WI, Sont JK, van Schadewijk A, Stolk J, van Krieken JH, Hiemstra PS: Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD. J Pathol 2000, 190: 619–626. 10.1002/(SICI)1096-9896(200004)190:5<619::AID-PATH555>3.0.CO;2-6View ArticlePubMedGoogle Scholar
- Tomaki M, Sugiura H, Koarai A, Komaki Y, Akita T, Matsumoto T, Nakanishi A, Ogawa H, Hattori T, Ichinose M: Decreased expression of antioxidant enzymes and increased expression of chemokines in COPD lung. Pulm Pharmacol Ther 2007, 20: 596–605. 10.1016/j.pupt.2006.06.006View ArticlePubMedGoogle Scholar
- Arenberg DA, Keane MP, DiGiovine B, Kunkel SL, Strom SR, Burdick MD, Iannettoni MD, Strieter RM: Macrophage infiltration in human non-small-cell lung cancer: the role of CC chemokines. Cancer Immunol Immunother 2000, 49: 63–70. 10.1007/s002620050603View ArticlePubMedGoogle Scholar
- Chapman RW, Minnicozzi M, Celly CS, Phillips JE, Kung TT, Hipkin RW, Fan X, Rindgen D, Deno G, Bond R, et al.: A novel, orally active CXCR1/2 receptor antagonist, Sch52 inhibits neutrophil recruitment, mucus production, and goblet cell hyperplasia in animal models of pulmonary inflammation. J Pharmacol Exp Ther 2007, 322: 486–493. 10.1124/jpet.106.119040View ArticlePubMedGoogle Scholar
- Keane MP, Belperio JA, Xue YY, Burdick MD, Strieter RM: Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer. J Immunol 2004, 172: 2853–2860.View ArticlePubMedGoogle Scholar
- Sparmann A, Bar-Sagi D: Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 2004, 6: 447–458. 10.1016/j.ccr.2004.09.028View ArticlePubMedGoogle Scholar
- Ji H, Wang Z, Perera SA, Li D, Liang MC, Zaghlul S, McNamara K, Chen L, Albert M, Sun Y, et al.: Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models. Cancer Res 2007, 67: 4933–4939. 10.1158/0008-5472.CAN-06-4592View ArticlePubMedGoogle Scholar
- Roberts PJ, Der CJ: Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 2007, 26: 3291–3310. 10.1038/sj.onc.1210422View ArticlePubMedGoogle Scholar
- Stathopoulos GT, Sherrill TP, Cheng DS, Scoggins RM, Han W, Polosukhin VV, Connelly L, Yull FE, Fingleton B, Blackwell TS: Epithelial NF-kappaB activation promotes urethane-induced lung carcinogenesis. Proc Natl Acad Sci USA 2007, 104: 18514–18519. 10.1073/pnas.0705316104PubMed CentralView ArticlePubMedGoogle Scholar
- Angel P, Karin M: The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1991, 1072: 129–157.PubMedGoogle Scholar
- Devereux TR, Holliday W, Anna C, Ress N, Roycroft J, Sills RC: Map kinase activation correlates with K-ras mutation and loss of heterozygosity on chromosome 6 in alveolar bronchiolar carcinomas from B6C3F1 mice exposed to vanadium pentoxide for 2 years. Carcinogenesis 2002, 23: 1737–1743. 10.1093/carcin/23.10.1737View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.