DNA damage in lung epithelial cells isolated from rats exposed to quartz: role of surface reactivity and neutrophilic inflammation

Knaapen, Ad M.; Albrecht, Catrin; Becker, A.; Höhr, Doris; Winzer, Astrid; Haenen, Guido R.M.M.; Borm, Paul J. A.; Schins, Roel P.F.

doi:10.1093/carcin/23.7.1111

Cited by 94 publications

(77 citation statements)

References 68 publications

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“…Similar findings were reported by Knaapen et al (2002) in rats and by Schins et al (2002) using A549 culture cells. These studies indicated that DNA strand breakage occurred more readily with exposure to crystallite silica; that is, such exposure leads to the production of more urinary 8-OHdG.…”

Section: Possible Mechanismssupporting

confidence: 91%

An engineering intervention resulting in improvement in lung function and change in urinary 8-hydroxydeoxyguanosine among foundry workers in Taiwan

Lin

Liou

Chang

et al. 2010

Int Arch Occup Environ Health

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Section: Possible Mechanismssupporting

confidence: 91%

An engineering intervention resulting in improvement in lung function and change in urinary 8-hydroxydeoxyguanosine among foundry workers in Taiwan

Lin

Liou

Chang

et al. 2010

Int Arch Occup Environ Health

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“…We specifically applied type II cells, since this is the cell type from which (rat) lung tumours are most probably derived after chronic particle exposure (33). Although our findings may very well have implications for other organs where neutrophil influx is accompanied by an accumulation of nitrite, we specifically focused on the lung epithelium because of several reasons: (i) neutrophils are recognized as crucial effector cells in the pathogenicity of pulmonary inflammation (34,35), (ii) we and others showed that DNA strand breakage and mutagenicity in pulmonary epithelium of (particle-treated) rats was closely related to neutrophil influx (6,15,36), (iii) pulmonary inflammation is characterized by the release of the MPO substrate H 2 O 2 (37) and (iv) mainly by the presence of alveolar macrophages, the lung contains a potent source of nitrite (19,21,22). We demonstrated that nitrite significantly enhances neutrophil-induced DNA strand breakage in co-cultured epithelial cells.…”

Section: Discussionmentioning

confidence: 98%

Nitrite enhances neutrophil-induced DNA strand breakage in pulmonary epithelial cells by inhibition of myeloperoxidase

Knaapen¹,

Schins²,

Borm³

et al. 2005

Carcinogenesis

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Chronic inhalation of environmental particles is associated with pulmonary carcinogenesis. Although the mechanism has not yet been fully elucidated, influx of inflammatory cells, including neutrophils, is suggested to play a major role in this process. Typically, in the particle-exposed lung, influx of neutrophils is accompanied by an accumulation of nitrite. Previous studies indicated that nitrite may affect the toxicity of neutrophils, involving an interaction with neutrophil-derived myeloperoxidase (MPO). To evaluate the possible consequences of this interaction for inflammation-mediated genotoxicity, we investigated the effect of nitrite on neutrophil-induced DNA damage in pulmonary target cells. Therefore, activated neutrophils were co-cultured with alveolar type II epithelial cells (RLE), and DNA strand breakage was evaluated using single-cell gel electrophoresis (comet assay). In this system, addition of nitrite caused an increase in neutrophil-induced DNA strand breakage in RLE cells, which was associated with an inhibition of MPO activity. Similar results were obtained by co-culturing RLE cells with neutrophils in the presence of the specific MPO inhibitor 4-aminobenzoic acid hydrazide (4-ABAH). To further investigate the mechanism underlying these observations, in vitro experiments were performed using mixtures of nitrite, MPO and its substrate H 2 O 2 . DNA strand breakage by reagent H 2 O 2 was inhibited when it was allowed to react with MPO before addition to the RLE cells. However, when MPO and H 2 O 2 were pre-mixed in the presence of nitrite or 4-ABAH, the inhibitory effect of MPO on resultant DNA damage was reversed. Further studies using catalase indicated that DNA strand breakage by the pre-mixtures of MPO, H 2 O 2 and nitrite was H 2 O 2 -specific, suggesting that nitrite prevents consumption of H 2 O 2 by MPO. Collectively, our results show that nitrite enhances neutrophilinduced DNA strand breakage in pulmonary epithelial cells. This effect is probably due to an inhibition of MPO activity, which increases the availability of its DNA strand breaking substrate H 2 O 2 .

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“…In silicosis, lung neutrophils have an important role in the development of cellular and DNA injury (41,42), and several studies proposed that radicals and enzymes produced by neutrophils lead to lung destruction and cancer (43,44). Activated macrophages and epithelial cells release proinflammatory mediators that induce neutrophil differentiation from the hematopoietic progenitors, their recruitment, and activation inside the inflamed lung tissue (45).…”

Section: Discussionmentioning

confidence: 99%

IL-17A–Producing γδ T and Th17 Lymphocytes Mediate Lung Inflammation but Not Fibrosis in Experimental Silicosis

Re¹,

Dumoutier

Couillin

et al. 2010

The Journal of Immunology

131

107

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IL-17–producing T lymphocytes play a crucial role in inflammation, but their possible implication in fibrosis remains to be explored. In this study, we examined the involvement of these cells in a mouse model of lung inflammation and fibrosis induced by silica particles. Upregulation of IL-17A was associated with the development of experimental silicosis, but this response was markedly reduced in athymic, γδ T cell-deficient or CD4+ T cell-depleted mice. In addition, γδ T lymphocytes and CD4+ T cells, but not macrophages, neutrophils, NK cells or CD8 T cells, purified from the lungs of silicotic mice markedly expressed IL-17A. Depletion of alveolar macrophages or neutralization of IL-23 reduced upregulation of IL-17A in the lung of silicotic mice. IL-17R–deficient animals (IL-17R−/−) or IL-17A Ab neutralization, but not IL-22−/− mice, developed reduced neutrophil influx and injury during the early lung response to silica. However, chronic inflammation, fibrosis, and TGF-β expression induced by silica were not attenuated in the absence of IL-17R or -22 or after IL-17A Ab blockade. In conclusion, a rapid lung recruitment of IL-17A–producing T cells, mediated by macrophage-derived IL-23, is associated with experimental silicosis in mice. Although the acute alveolitis induced by silica is IL-17A dependent, this cytokine appears dispensable for the development of the late inflammatory and fibrotic lung responses to silica.

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DNA damage in lung epithelial cells isolated from rats exposed to quartz: role of surface reactivity and neutrophilic inflammation

Cited by 94 publications

References 68 publications

An engineering intervention resulting in improvement in lung function and change in urinary 8-hydroxydeoxyguanosine among foundry workers in Taiwan

An engineering intervention resulting in improvement in lung function and change in urinary 8-hydroxydeoxyguanosine among foundry workers in Taiwan

Nitrite enhances neutrophil-induced DNA strand breakage in pulmonary epithelial cells by inhibition of myeloperoxidase

IL-17A–Producing γδ T and Th17 Lymphocytes Mediate Lung Inflammation but Not Fibrosis in Experimental Silicosis

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