Inhaled underground subway dusts may stimulate multiple pathways of cell death signals and disrupt immune balance

Abstract

In this study, we aimed to identify a toxic mechanism and the potential health effects of ambient dusts in an underground subway station. At 24 h exposure to human bronchial epithelial (BEAS-2B) cells (0, 2.5, 10, and 40 mu g/mL), dusts located within autophagosome-like vacuoles, whereas a series of autophagic processes appeared to be blocked. The volume, potential and activity of mitochondria decreased in consistent with a condensed configuration, and the percentage of late apoptotic cells increased accompanying S phase arrest. While production of reactive oxygen species, expression of ferritin (heavy chain) protein, secretion of IL-6, IL-8 and matrix metalloproteinases, and the released LDH level notably increased in dust-treated cells (40 mu g/mL), intracellular calcium level decreased. At day 14 after a single instillation to mice (0, 12.5, 50, and 200 mu g/head), the total number of cells increased in the lungs of dust-treated mice with no significant change in cell composition. The pulmonary levels of TGF-beta, GM-CSF, IL-12 and IL-13 clearly increased following exposure to dusts, whereas that of CXCL-1 was dose-dependently inhibited. Additionally, the population of cytotoxic T cells in T lymphocytes in the spleen increased relative to that of helper T cells, and the levels of IgA and IgM in the bloodstream were significantly reduced in the dust-treated mice. Subsequently, to improve the possibility of extrapolating our findings to humans, we repeatedly instilled dusts (1 time/week, 4 weeks, 0.25 and 1.0 mg/head) to monkeys. The total number of cells, the relative portion of neutrophils, the level of TNF-a significantly increased in the lungs of dust-treated monkeys, and the expression of cytochrome C was enhanced in the lung tissues. Meanwhile, the pulmonary level of MIP-alpha was clearly reduced, and the expression of caveolin-1 was inhibited in the lung tissues. More importantly, inflammatory lesions, such as granuloma, were seen in both mice and monkeys instilled with dusts. Taken together, we conclude that dusts may impair the hosts immune function against foreign bodies by inhibiting the capacity for production of antibodies. In addition, iron metabolism may be closely associated with dust-induced cell death and inflammatory response.