Phagocyte-Generated Superoxide Reduces Fe3+ to Displace It from the Surface of Asbestos

doi:10.1006/abbi.1994.1493

Archives of Biochemistry and Biophysics

Volume 315, Issue 2, December 1994, Pages 219-225

https://doi.org/10.1006/abbi.1994.1493 Get rights and content

Abstract

Injury after exposure to mineral oxide dusts is considered to be mediated by free radical generation. In vitro production of hydroxyl radical by a fibrous silicate increases with the [Fe³⁺] complexed to the dust surface. The study hypothesis tested was that extracellular fluids and phagocytic cells can decrease concentrations of iron complexed to the surface of a fibrous silicate by employing host chelators and reductants. Such a depletion of surface [Fe³⁺] would predict decrements in both oxidant generation and the resultant injury after inhalation and instillation of these mineral oxides. Crocidolite (2.0 mg) which was exposed to either 5.0 ml rat plasma or 10.0 ml rat lavage fluid for 1 h had diminished surface [Fe³⁺]. Similarly, incubations of crocidolite (2.0 mg) with either 10.0 ml rat alveolar macrophages (1.0 × 10⁶ cells/ml) or 10.0 ml rat neutrophils (1.0 × 10⁷ cells/ml) decreased concentrations of surface iron. In vivo exposures of asbestos contained in chambers allowing or precluding inflammatory cell entry revealed that the influx of phagocytes was associated with greater decreases in surface [Fe³⁺]. The body chelators transferrin and lactoferrin were unable to extract the metal from fiber surface in vitro. However, superoxide generated by phagocytes did displace the iron from the crocidolite surface. We conclude that extracellular fluids and phagocytic cells have a capacity to diminish [Fe³⁺] complexed to the surface of asbestos and therefore decrease the potential for oxidative stress and injury to a living system after exposure to these dusts. Rather than a direct reaction with a chelator either resident in lining fluid or released by phagocytes, this effect is likely the result of Fe³⁺ reduction by reducing agents in the fluids and by superoxide generated by phagocytic cells.

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Cited by (23)

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This paper summarizes recent insights into causal biological mechanisms underlying the carcinogenicity of asbestos. It addresses their implications for the shapes of exposure-response curves and considers recent epidemiologic trends in malignant mesotheliomas (MMs) and lung fiber burden studies. Since the commercial amphiboles crocidolite and amosite pose the highest risk of MMs and contain high levels of iron, endogenous and exogenous pathways of iron injury and repair are discussed. Some practical implications of recent developments are that: (1) Asbestos-cancer exposure-response relationships should be expected to have non-zero background rates; (2) Evidence from inflammation biology and other sources suggests that there are exposure concentration thresholds below which exposures do not increase inflammasome-mediated inflammation or resulting inflammation-mediated cancer risks above background risk rates; and (3) The size of the suggested exposure concentration threshold depends on both the detailed time patterns of exposure on a time scale of hours to days and also on the composition of asbestos fibers in terms of their physiochemical properties. These conclusions are supported by complementary strands of evidence including biomathematical modeling, cell biology and biochemistry of asbestos-cell interactions in vitro and in vivo, lung fiber burden analyses and epidemiology showing trends in human exposures and MM rates.
Iron and redox cycling. Do's and don'ts
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Thermodynamically, this is possible, because E°(O2/O2•−), being −0.18 V (1 M O2 reference state) [34], is well below 0 V. One such case has been documented involving phagocytes that produce high concentrations of superoxide [78]. But there is a kinetics concern: the steady-state concentration of O2•– in most tissues is so low that the reduction of iron complexes by this radical would have to be diffusion-controlled in order to compete with the diffusion-controlled reactions of O2•– with superoxide dismutase [79,80] and with NO• [37].
A major form of toxicity arises from the ability of iron to redox cycle, that is, to accept an electron from a reducing compound and to pass it on to H₂O₂ (the Fenton reaction). In order to do so, iron must be suitably complexed to avoid formation of Fe₂O₃. The ligands determine the electrode potential; this information should be known before experiments are carried out. Only one-electron transfer reactions are likely to be significant; thus two-electron potentials should not be used to determine whether an iron(III) complex can be reduced or oxidized. Ascorbate is the relevant reducing agent in blood serum, which means that iron toxicity in this compartment arises from the ascorbate-driven Fenton reaction. In the cytosol, an iron(II)-glutathione complex is likely to be the low-molecular weight iron complex involved in toxicity. When physiologically relevant concentrations are used the window of redox opportunity ranges from +0.1 V to +0.9 V. The electrode potential for non-transferrin-bound iron in the form of iron citrate is close to 0 V and the reduction of iron(III) citrate by ascorbate is slow. The clinically utilised chelators desferrioxamine, deferiprone and deferasirox in each case render iron complexes with large negative electrode potentials, thus being effective in preventing iron redox cycling and the associated toxicity resulting from such activity. There is still uncertainty about the product of the Fenton reaction, HO^• or FeO²⁺.
Iron from a geochemical viewpoint. Understanding toxicity/pathogenicity mechanisms in iron-bearing minerals with a special attention to mineral fibers
2019, Free Radical Biology and Medicine
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Ghio et al. [100] noted that the amount of H2O2 consumed by asbestos, following incubation in saline solution containing H2O2, parallels the amounts of iron released and explained this behavior with the reduction of Fe3+ and the higher instability of Fe2+ compared to Fe3+ [101]. Likewise, exposures of asbestos to phagocytic cells was associated with a decrease in the surface Fe3+, probably as a consequence of Fe3+ reduction by superoxide [102]. More recently, formation of iron oxy-hydroxides aggregates and Fe-rich amorphous nanoparticles on the surface of tremolite [103] and crocidolite [104] was observed after incubation in an oxidative medium buffered at pH 7.
Iron and its role as soul of life on Earth is addressed in this review as iron is one of the most abundant elements of our universe, forms the core of our planet and that of telluric (i.e., Earth-like) planets, is a major element of the Earth's crust and is hosted in an endless number of mineral phases, both crystalline and amorphous. To study iron at an atomic level inside the bulk of mineral phases or at its surface, where it is more reactive, both spectroscopy and diffraction experimental methods can be used, taking advantage of nearly the whole spectrum of electromagnetic waves. These methods can be successfully combined to microscopy to simultaneously provide chemical (e.g. iron mapping) and morphological information on mineral particles, and shed light on the interaction of mineral surfaces with organic matter. This review describes the crystal chemistry of iron-bearing minerals of importance for the environment and human health, with special attention to iron in toxic minerals, and the experimental methods used for their study. Special attention is devoted to the Fenton-like chain reaction involving Fe²⁺ in the formation of highly reactive hydroxyl radicals. The final part of this review deals with release and adsorption of iron in biological fluids, coordinative and oxidative state of iron and in vitro reactivity. To disclose the very mechanisms of carcinogenesis induced by iron-bearing toxic mineral particles, crystal chemistry and surface chemistry are fundamental for a multidisciplinary approach which should involve geo-bio-scientists, toxicologists and medical doctors.
Multi-walled carbon nanotube induced frustrated phagocytosis, cytotoxicity and pro-inflammatory conditions in macrophages are length dependent and greater than that of asbestos
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It is worth noting that O2− levels found here may be an underestimation for SFA, LFA, CNTA and CNTC. O2− has the ability to reduce Fe3+ (Ghio et al., 1994), creating O2, it is plausible that the Fe3+ easily accessible on these particles may be used in this reaction and therefore no longer detectible in our assay, which marks a possible limitation of this assay. To further explore the implications of MWCNT interactions and frustrated phagocytosis, phagocytic impairment was addressed.
The potential toxicity of carbon nanotubes (CNTs) has been compared to pathogenic fibres such as asbestos. It is important to test this hypothesis to ascertain safe methods for CNT production, handling and disposal. In this study aspects reported to contribute to CNT toxicity were assessed: length, aspect ratio, iron content and crystallinity; with responses compared to industrially produced MWCNTs and toxicologically relevant materials such as asbestos. The impacts of these particles on a range of macrophage models in vitro were assessed due to the key role of macrophages in particle clearance and particle/fibre-induced disease.
Industrially produced and long MWCNTs were cytotoxic to cells, and were potent in inducing pro-inflammatory and pro-fibrotic immune responses. Short CNTs did not induce any cytotoxicity. Frustrated phagocytosis was most evident in response to long CNTs, as was respiratory burst and reduction in phagocytic ability. Short CNTs, metal content and crystallinity had less or no influence on these endpoints, suggesting that many responses were fibre-length dependent.
This study demonstrates that CNTs are potentially pathogenic, as they were routinely found to induce detrimental responses in macrophages greater than those induced by asbestos at the same mass-based dose.
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We report on a deposition of oxalate crystals on ferruginous bodies after occupational exposure to asbestos demonstrated in 3 patients. We investigated the mechanism and possible significance of this deposition by testing the hypothesis that oxalate generated through nonenzymatic oxidation of ascorbate by asbestos-associated iron accounts for the deposition of the crystal on a ferruginous body. Crocidolite asbestos (1000 μg/mL) was incubated with 500 μmol H₂O₂ and 500 μmol ascorbate for 24 hours at 22°C. The dependence of oxalate generation on iron-catalyzed oxidant production was tested with the both the metal chelator deferoxamine and the radical scavenger dimethylthiourea. Incubation of crocidolite, H₂O₂, and ascorbate in vitro generated approximately 42 nmol of oxalate in 24 hours. Oxalate generation was diminished significantly by the inclusion of either deferoxamine or dimethylthiourea in the reaction mixture. Incubation of asbestos bodies and uncoated fibers isolated from human lung with 500 μmol H₂O₂ and 500 μmol ascorbate for 24 hours at 22°C resulted in the generation of numerous oxalate crystals. We conclude that iron-catalyzed production of oxalate from ascorbate can account for the deposition of this crystal on ferruginous bodies.
Influence of cigarette smoking on crocidolite-induced ferritin release by human alveolar macrophages
2000, Journal of Laboratory and Clinical Medicine
Citation Excerpt :
Cells regulate intracellular iron concentrations by controlling iron uptake, primarily via expression of cell receptors for transferrin, and by synthesizing apoferritin for iron storage.21 Our findings in the current study extend the prior observations of Ghio et al8,9 that exposure to silica induces ferritin synthesis in AMs and is consistent with prior studies demonstrating that macrophages acquire iron from crocidolite. As noted in the prior study with silica, we found that crocidolite-induced ferritin synthesis in AMs was iron-dependent, because it was completely inhibited by the iron chelator deferoxamine.9
Alveolar macrophages (AMs) mobilize iron from the surface of iron-containing minerals such as asbestos and synthesize ferritin for intracellular iron storage or secretion. Although the synthesis of iron-free ferritin (apoferritin) provides antioxidant protection, the secretion of iron-containing ferritin by AMs could increase the availability of catalytic iron in the lungs. Cigarette smoking may promote the secretion of ferritin by AMs after iron acquisition from mineral sources, because smokers' AMs are iron loaded. The first objective of this study was to determine whether ferritin secretion/release by AMs after in vitro exposure to crocidolite asbestos is enhanced by cigarette smoking. The second objective was to assess whether exogenous ferritin-bound iron could enhance the toxicity of crocidolite to lung cells in vitro. AMs recovered from nonsmokers (n = 8) or smokers (n = 8) were exposed to crocidolite or titanium dioxide (TiO₂)(1 × 10⁶ AMs, 50 to 200 μg/mL) for up to 18 hours. AMs exposed to crocidolite but not TiO₂ showed increased cell content of iron and ferritin and increased cell supernatant ferritin concentrations. Increases in iron and ferritin content were similar for AMs recovered from smokers and those recovered from nonsmokers; however, increases in supernatant ferritin were >7-fold greater for smokers' AMs than for nonsmokers' AMs (P < .001). Exposure of A549 cells, a lung cancer-derived cell line, to crocidolite (50 to 200 μg/mL, 18 hours) caused dose-dependent cell death as indicated by lactate dehydrogenase release. The addition of ferritin (≥ 500 mg/mL) but not apoferritin to culture media enhanced crocidolite-induced LDH release (P < .01). These findings suggest that cigarette smoking and crocidolite exposure have synergistic effects that promote ferritin release by AMs, which could catalyze oxidative injury to other alveolar cells. (J Lab Clin Med 2000;136:449-56)

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Regular ArticlePhagocyte-Generated Superoxide Reduces Fe3+ to Displace It from the Surface of Asbestos

Abstract

Regular Article
Phagocyte-Generated Superoxide Reduces Fe³⁺ to Displace It from the Surface of Asbestos