Apoptosis and Bax Expression Are Increased by Coal Dust in the Polycyclic Aromatic Hydrocarbon-Exposed Lung

By Ghanem, Mohamed M.; Battelli, Lori A. et al. | Environmental Health Perspectives, September 2006 | Go to article overview
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Apoptosis and Bax Expression Are Increased by Coal Dust in the Polycyclic Aromatic Hydrocarbon-Exposed Lung


Ghanem, Mohamed M., Battelli, Lori A., Mercer, Robert R., Scabilloni, James F., Kashon, Michael L., Ma, Jane Y. C., Nath, Joginder, Hubbs, Ann F., Environmental Health Perspectives


BACKGROUND: Miners inhaling respirable coal dust (CD) frequently develop coal workers' pneumoconiosis, a dust-associated pneumoconiosis characterized by lung inflammation and variable fibrosis. Many coal miners are also exposed to polycyclic aromatic hydrocarbon (PAH) components of diesel engine exhaust and cigarette smoke, which may contribute to lung disease in these workers. Recently, apoptosis was reported to play a critical role in the development of another pneumoconiosis of miners, silicosis. In addition, CD was reported to suppress cytochrome P450 1A1 (CYP1A1) induction by PAHs.

METHODS: We investigated the hypothesis that apoptosis plays a critical role in lung injury and down-regulation of CYP1A1 induction in mixed exposures to CD and PAHs. We exposed rats intratracheally to 0.0, 2.5, 10.0, 20.0, or 40.0 mg/rat CD and, 11 days later, to intraperitoneal [beta]-naphthoflavone (BNF), a PAH. In another group of rats exposed to CD and BNF, caspase activity was inhibited by injection of the pan-caspase inhibitor Q-VD-OPH [quinoline-Val-Asp (OMe)-C[H.sub.2]-OPH].

RESULTS: In rats exposed to BNF, CD exposure increased alveolar expression of the proapoptotic mediator Bax but decreased CYP1A1 induction relative to BNF exposure alone. Pan-caspase inhibition decreased CD-associated Bax expression and apoptosis but did not restore CYP1A1 activity. Further, CD-induced lung inflammation and alveolar epithelial cell hypertrophy and hyperplasia were not suppressed by caspase inhibition.

CONCLUSIONS: Combined BNF and CD exposure increased Bax expression and apoptosis in the lung, but Bax and apoptosis were not the major determinants of early lung injury in this model.

KEY WORDS: apoptosis, Bax, caspase, coal dust, CYP1A1, CYP2B1, modifiers, polycyclic aromatic hydrocarbons, pneumoconiosis, xenobiotic metabolism. Environ Health Perspect 114:1367-1373 (2006). doi:10.1289/ehp.8906 available via http://dx.doi.org/[Online 18 May 2006]

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Coal miners are commonly exposed to coal dust (CD) and polycyclic aromatic hydrocarbons (PAHs). The CD originates within the mine, whereas the PAHs are components of occupational and avocational exposures such as diesel engine exhaust and cigarette smoke. The CD exposure can cause coal workers' pneumoconiosis, a disease of coal miners characterized by the aggregation of dust-laden macrophages near the respiratory bronchioles to form structures known as macules. Inflammation is a consistent feature of the pulmonary response to respirable CD (Ghanem et al. 2004; Rom et al. 1987). Although chronic inflammation is increasingly believed to play a role in carcinogenesis in many tissues (Marx 2004), the role of particle-induced inflammation in pulmonary carcinogenesis, the influence of particle-induced inflammation on the metabolism of PAHs and other known carcinogens, and the histopathologic alterations produced by combined exposure to CD and PAHs remain incompletely investigated.

PAHs are metabolized to reactive intermediates by cytochrome P450 1 (CYP1) gene products. Recently, our laboratory has demonstrated that respirable CD inhibits PAH-induced CYP1A1 activity in the lung of rats. The down-regulation of CYP1A1 induction was associated with inflammation (Ghanem et al. 2004). This information suggests that CD may modify the metabolism of PAHs in the lung. However, molecular changes that are associated with CD exposure and resulting pulmonary inflammation and down-regulation of CYP1A1 induction have not yet been identified. In an experimental model of another pneumoconiosis, silicosis, caspase inhibition with resulting apoptosis down-regulation reduces silica-induced inflammation (Borges et al. 2002). Caspases play an important role in both the intrinsic and extrinsic apoptotic pathways (Droin and Green 2004), making their inhibition an elegant tool for investigating the overall role of caspase-dependent apoptosis in the pneumoconioses (Borges et al.

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Apoptosis and Bax Expression Are Increased by Coal Dust in the Polycyclic Aromatic Hydrocarbon-Exposed Lung
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