Biological Effects of Vanadium in the Lung - ACS Symposium Series

Chapter 17

Biological Effects of Vanadium in the Lung

Downloaded by TUFTS UNIV on November 23, 2015 | http://pubs.acs.org Publication Date: August 30, 2007 | doi: 10.1021/bk-2007-0974.ch017

Andrew J . Ghio and James M . Samet Human Studies Facility, National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Chapel Hill, NC 27599-7315

Exposures of the lung to vanadium can affect a biological response in cells and an injury in tissues. Investigation supports the postulate that vanadium either produces an oxidative stress or disrupts phosphotyrosine metabolism resulting in cell changes in signaling, transcription factor activation, and induction of mediator expression. These culminate in inflammatory and fibrotic lung injuries.

While vanadium is an essential trace element for humans and certain animals, it occurs rarely in living systems (/). Certain plants can have higher levels of vanadium (e.g. sugar beets, vines, and beech and oak trees) but the greatest concentrations are found in lower marine animals (e.g. tunicates) (/). Since oil is derived from fossilized marine organisms, vanadium can be found in this fuel at high concentrations and, subsequently, in its fly ash. Higher contents of the metal occur in the heavy oils which are left (i.e. the residual) after the more volatile fractions such as petrol, paraffin, and diesel oil have been distilled, hence the term "residual oil" fly ash (7). Fugitive fly ash from the combustion of oil and residual fuel oil contributed 76,000 and 49,000 tons, respectively, to the national ambient particle burden in 1992. This is a major source of vanadium since, in the general atmosphere, concentrations of vanadium in the atmosphere are usually quite low. In a rural setting, vanadium in ambient air can vary between 25 to 75 ng/m (2). In other environments where combustion of oil products is frequent, levels of vanadium can be significantly greater than this ranging up to 300 ng/m (3). 3

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© 2007 American Chemical Society

In Vanadium: The Versatile Metal; Kustin, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

241 Specific occupational environments can similarly expose individuals to vanadium. Among these are included the worksites of steel workers and boilermakers.

Lung Injury after Exposure to Vanadium Compounds The first report of a toxic human exposure to vanadium was in 1911 (4). "Vanadiumism" was defined to be a chronic intoxication with the principal evidence of injury observed in the lungs, kidneys, and gastrointestinal tract (5). Such significant exposures occurred during the mining, separation, and use of V 0 in the steel and chemical industries. Vanadium exposure was mostly via inhalation, and excretion followed via the urine with a smaller amount in the feces. Vanadium dust caused symptoms of respiratory tract irritation with conjunctivitis, sneezing, rhinorrhea, sore throat, and chest tightness (4-6). The cough was prominent and characteristically dry and paroxysmal (4). Examination of vanadium-exposed individuals revealed a greenish discoloration of the tongue, wheezing, rhonchi, and rales (5,6). A n increase in the inflammatory cells in nasal smears and biopsies from the nasal mucosa accompanied symptoms of respiratory tract irritation. There could be concurrent changes in pulmonary function indices associated with vanadium exposure (5,6). Vanadium workers were observed to be more susceptible to tuberculosis and could rapidly succumb to this disease (4). At high exposure levels, the lungs became highly congested and show a marked destruction of the alveolar epithelium (4). At high vanadium exposures, hemorrhages were frequent and severe, even causing death (5,6). Workers who died from vanadium exposure showed congested lungs with destruction of the alveolar epithelium (5,6).


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Human lung injury after exposure to oil fly ash has been reported predominantly after occupational exposures of workers engaged in the maintenance of oil-fired boilers in power generating stations (7-13). Vanadium is accepted as that component of oil fly ash responsible for toxicity of this dust. The clinical presentation of these workers has been termed "boilermakers' bronchitis" or "vanadium bronchitis". Individuals exposed to high concentrations of oil fly ash provide a history of eye irritation, sore throat, hoarseness, cough, dyspnea, wheezing, and, infrequently, symptoms consistent with pneumonitis. Physical examination can demonstrate rhinitis, conjunctivitis, and wheezing. Within 24 hours of exposure, dose-dependent losses in pulmonary function have been observed, including diminished forced vital capacity, forced expiratory volume in one second, and forced expiratory flows (12,13). Bronchoscopic examination shows a bronchitis with erythema and discharge in oil fly ash exposed individuals. Symptoms and signs subside, and pulmonary function decrements can resolve, within a few days or weeks of cessation of the exposure (//).


242


Mechanism of Lung Injury Following Exposure to Vanadium Compounds The mechanism of biological effect and injury after exposure to vanadium has been postulated to be mediated by metal-catalyzed oxidant generation, metal ion dysregulation of phosphotyrosine metabolism, or possibly elements of both (Figure 1). These events are then proposed to result in phosphorylationdependent cell signaling, an activation of specific transcription factors, an increased expression of pro-inflammatory proteins whose genes have binding sites for these transcription factors in their promoter regions, and inflammatory and fibrotic injuries to the lung. Vanadium generates oxygen-based free radicals to present an oxidative stress to the cell (14) comparable to acellular systems (15). This production of oxidants can be inhibited by either the metal chelator deferoxamine or the antioxidants N-acetylcysteine and dimethylthiourea (DMTU). In vivo oxidative stress in the lungs of animals instilled with both vanadium and oil fly ash has been verified by electron spin resonance (Figure 2) (16).

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Figure 1. Proposed mechanism for the biological effect of vanadium on respiratory cells.


243

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Figure 2. Electron spin resonance in the lipid soluble fraction of rat lung following intratracheal exposure to vanadium, nickel, and iron compounds in concentrations equivalent to that found in an oil fly ash (previously published, 16). Vanadium is that metal associated with the greatest signal reflecting a significant in vivo oxidative stress. Vanadium in oil fly ash accounts for the oxidative stress presented both in vitro and in vivo by this specific particle.

Soluble vanadium salts are also known inducers of protein phosphorylation and, as such, they have been used as an experimental stimulus for many years. As a result, there are numerous studies showing the effects of vanadium on a broad array of signal transduction processes. In addition, the use of oil fly ash as a model particle has produced a substantial literature that is relevant to these specific effects of vanadium exposure (17). The relationship between oxidative stress and protein phosphorylation is only now beginning to be understood. The pivotal initiating event of vanadium on signaling is believed to be the inhibition of protein tyrosine phosphatases (18). Inhibition of protein tyrosine phosphatases by vanadium leads to unopposed kinase activity and a net accumulation of tyrosine phosphoproteins, which would be expected to result in a simultaneous activation of multiple signaling cascades in the cell (19). Multiple mechanisms have been proposed for the inhibitory effect of vanadium on protein tyrosine phosphatases. The vanadate ion has been proposed as a phosphate analog that acts as a competitive (and, therefore, reversible) inhibitor of protein tyrosine phosphatases (18). Vanadyl


244 and vanadate species occur in equilibrium in solution and solutions of either form appear equally potent in inducing phosphotyrosine accumulation in respiratory epithelial cells (18,19). Oxidized forms of vanadium such as pervanadate, produced by the reaction of vanadate with H 0 , act as potent irreversible inhibitors of protein tyrosine phosphatases by oxidizing the catalytic cysteine in the active site (20-22). A third potential mechanism of vanadium-induced inhibition of protein tyrosine phosphatase activity is catalyzed formation of reactive oxidant species through redox cycling. H 0 is a direct inhibitor of protein tyrosine phosphatase activity that functions by oxidizing the reactive cysteine to form the sulfenyl derivative of the cysteinyl thiol (23). Oxidation of protein tyrosine phosphatases is now recognized as an essential event in physiological signaling (23-30). Activation of kinases involved in cell signaling by vanadium ions has been shown in a human airway epithelial cell line (31,32) (Figure 3). Similarly, it has been reported that vanadium pentoxide ( V 0 ) induces kinase activation in human lung fibroblasts and rat lung myofibroblasts (33,34). Separate studies have reported that exposure to vanadium ions increases the activation of a transcription factor and protein kinase C dependent signaling. Vanadium induced transcriptional activity in mouse epidermal cells through a protein kinase C-dependent process, and this effect was inhibited by superoxide dismutase, catalase and N-acetyl cysteine (35). Another report using the same cells confirmed vanadate-induced activation of protein kinase C (36). Also, it was demonstrated that vanadate induces transactivation of the tumor suppressor protein p53 in cells that could be blocked by pre-treatment with the antioxidants N-acetyl cysteine, catalase and deferoxamine, and enhanced by superoxide dismutase, implicating H 0 as the reactive oxygen species involved (37). In a subsequent study, the same authors described activation of another transcription factor in vanadate exposed fibroblasts and epidermal cells (38). Again, N-acetyl cysteine, catalase and deferoxamine blocked transcription factor activation but superoxide dismutase synergized its activation by vanadate. As previously noted, incubation of respiratory epithelial cells with oil fly ash is associated with the initiation of phosphorylation-dependent signaling reactions that may be modulated by specific redox changes (19). Redox active vanadium compounds can reproduce these events while catalytically active iron and nickel compounds have no effect (Figure 4) (19). One transcription factor that is known to be associated with oxidant responses is nuclear factor kappa B (NFkB). N F k B is normally sequestered in the cytoplasm as an inactive multiunit complex bound by an inhibitory protein (IKB). In the nucleus, N F K B binds to promoter and enhancer regions of a multitude of genes involved in the inflammatory response, including cytokines, chemokines, and growth factors. It is postulated that these genes then function to initiate, amplify, and coordinate the inflammatory response. O i l fly ash induces phosphorylation and degradation of I K B , with a resulting translocation of the active dimer into the nucleus in respiratory epithelial cells (39). O i l fly ash-induced activation of N F K B is 2


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Figure 3. MAP kinase signaling following exposure of respiratory epithelial cells to equivalent concentrations of several metals (previously published, 31). Vanadium exposure is associated with significant elevations in the phosphorylation of the three MAP kinases assayed (ERK, JNK, and P38).

Ct As Cr Cu V

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Figure 4. Transcription factor activation following exposure of respiratory epithelial cells to equivalent concentrations of several different metals (previously published, 31). Vanadium exposure is associated with significant activation of the transcription factors assayed (ATF-2 and c-jun).



246 blocked by metal chelators and free radical scavengers, suggesting that this activation is dependent on the generation of oxidants (39). Effects of oil fly ash on the translocation of NFkB and phosphorylation of several transcription factors have been demonstrated in the rat lung (17). Respiratory epithelial cells exposed to either oil fry ash or vanadium, but not iron or nickel, showed increased mRNA and protein expression of numerous cytokines, including IL-6, IL-8, and TNF (40). In addition, prostaglandin H synthase 2 expression is induced, and there is concomitant enhanced secretion of prostaglandins Ez and F ^fromnormal human airway epithelial cells exposed to oil fry ash (41). As with N F K B activation, deferoxamine and an antioxidant diminishes the release of inflammatory mediators induced by oilflyash in these cells. mRNA and protein expression of mediators of inflammation and fibrosis are also elevated in tissues following instillation of oil fly ash and vanadium (42). Finally, exposure to oil fly ash and vanadium results in a dose-dependent influx of inflammatory cells (Figure 5) (43). Almost always, this is neutrophilic but occasional eosinophilic infiltration into the lower respiratory tract has been noted (43). The peak of this influx occurs 18 to 24 hours following exposure. Detachment of ciliated and mucus cellsfromthe epithelial lining of the terminal bronchioles and hemorrhage can also be observed at 24 hours following oil fly ash and vanadium exposure. While incursion of inflammatory cells appears to best correlate with vanadium exposure, injury assessed as protein concentrations in the lavage fluid correlated best with the nickel content in oil fly ash (44). The cellular influx persists 96 hours later and resolution occurs slowly. Pulmonary inflammatory injury induced by oil fly ash is reproducible by instillation of a mixture of soluble forms of vanadium, nickel, and iron in the proportions found in a saline leachate (45). Pretreatment with DMTU significantly decreased the number of neutrophils present in bronchoalveolar lavage fluid, further supporting metal-catalyzed oxidative stress as a factor determining inflammatory injury after oil fly ash instillation in animals (46).

Figure 5. Airways in an animal model following exposure to saline (left) and oil fly ash (right). Twenty four hours after exposure of a Sprague Dawley rat to oil fly ash (intratracheal), there is hyperplasia of the airway epithelial cells, perivascular edema, inflammatory influx, and cell debris in the airway.


247 Finally, animals exposed to vanadium-containing compounds demonstrate neutrophilic inflammatory injury of the bronchi and the distal lung accompanied by a significant air-flow limitation, confirming that it is a significant determinant of injury presented by oil fly ash in the respiratory system (47).

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Biological Effects of Vanadium in the Lung - ACS Symposium Series

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