ToxSci Advance Access originally published online on March 31, 2004
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Toxicological Sciences 79, 296-303 (2004)
Toxicological Sciences vol. 79 no. 2 © Society of Toxicology; all rights reserved.
N-Acetylcysteine Prevents Lung Inflammation After Short-Term Inhalation Exposure to Concentrated Ambient Particles
Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts 02115
Received January 7, 2004; accepted February 26, 2004
Lung inflammation is a key response to increased levels of particulate air pollution (PM); however, the cellular mechanisms leading to this response are poorly understood. To determine whether oxidants are implicated in PM-dependent lung inflammation, we tested the ability of N-acetylcysteine (NAC) to prevent lung inflammation in a rat model of short-term exposure to concentrated ambient particles (CAPs). Adult Sprague-Dawley rats were exposed to either CAPs aerosols (CAPs mass concentration 1060 ± 300 µg/m3) or filtered air (Sham controls) for 5 h. NAC-treated rats received 50 mg/kg (ip) NAC 1 h prior to exposure to CAPs. Oxidative stress and recruitment of inflammatory cells into bronchoalveolar lavage were evaluated 24 h after removal of the animals from the exposure chamber. Rats breathing CAPs aerosols showed significant oxidative stress, determined by the accumulation of thiobarbituric reactive substances (TBARS, 90 ± 15 pmol/mg protein; sham control: 50 ± 5 pmol/mg protein, p < 0.02) and oxidized proteins (1.6 ± 0.4 nmol/mg protein, sham: 0.70 ± 0.02 nmol/mg protein, p < 0.01) in their lungs. CAPs-induced oxidative stress was associated with increased numbers of polymorphonuclear leukocytes in bronchoalveolar lavage (BAL) (9 ± 2%; sham: 1.6 ± 0.5%, p < 0.001) and slight lung edema (wet/dry ratio: 4.77 ± 0.03, sham: 4.69 ± 0.02). No significant change was found in BAL protein concentration, total cell count, or lactate dehydrogenase (LDH) activity. NAC pretreatment effectively prevented CAPs-induced TBARS accumulation (30 ± 10 pmol/mg protein, p < 0.006), lung edema (4.64 ± 0.08, p < 0.05), and polymorphonuclear neutrophil (PMN) influx into the lungs (2.1 ± 0.5%, p < 0.001), but did not alter the protein carbonyl content. Histological evaluation of tissue samples confirmed the BAL findings. CAPs-exposed animals showed slight bronchiolar inflammation and thickened vessels at the bronchiole, whereas NAC treated animals showed no histological alterations. Regression analyses showed strong associations between increased TBARS accumulation and the CAPs content of Al, Si, and Fe, and trends of association between carbonyl content and Cr and Na concentrations, and between BAL PMN count and Cr, Zn, and Na. These data demonstrate that oxidants are critical mediators of the inflammatory response elicited by PM inhalation.
Key Words: reactive oxygen species; oxidative stress; particulate air pollution; inflammation; CAPs.
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