Alveolar macrophage cytokine response to air pollution particles: oxidant mechanisms.
Alveolar macrophages (AMs) primed with LPS and treated with concentrated ambient air particles (CAPs) showed enhanced release of tumor necrosis factor (TNF) and provide an in vitro model for the amplified effects of air pollution particles seen in people with preexisting lung disease. To investigate the mechanism(s) by which CAPs mediate TNF release in primed rat AMs, we first tested the effect of a panel of antioxidants. N-Acetyl-l-cysteine (20 mM), dimethyl thiourea (20 mM) and catalase (5 microM) significantly inhibited TNF release by primed AMs incubated with CAPs. Conversely, when LPS-primed AMs were treated with CAPs in the presence of exogenous oxidants (H(2)O(2) generated by glucose oxidase, 10 microM/h), TNF release and cell toxicity was significantly increased. The soluble fraction of CAPs suspensions caused most of the increased bioactivity in the presence of exogenous H(2)O(2). The metal chelator deferoxamine (DFO) strongly inhibited the interaction of the soluble fraction with H(2)O(2) but had no effect on the bioactivity of the insoluble CAPs fraction. We conclude that CAPs can mediate their effects in primed AMs by acting on oxidant-sensitive cytokine release in at least two distinct ways. In the primed cell, insoluble components of PM mediate enhanced TNF production that is H(2)O(2)-dependent (catalase-sensitive) yet independent of iron (DFO-insensitive). In the presence of exogenous H(2)O(2) released by AMs, PMNs, or other lung cells within an inflamed alveolar milieu, soluble iron released from air particles can also mediate cytokine release and cell toxicity.
Imrich
Amy
A
Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, USA.
Ning
YaoYu
Y
Lawrence
Joy
J
Coull
Brent
B
Gitin
Elena
E
Knutson
Mitchell
M
Kobzik
Lester
L
D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D004338:Drug Combinations; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010316:Particle Size; D052638:Particulate Matter / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000393:Air Pollutants; D000975:Antioxidants; D004338:Drug Combinations; D008070:Lipopolysaccharides; D052638:Particulate Matter; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D002374:Catalase; D003676:Deferoxamine