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90-Day Repeated Inhalation Exposure of Surfactant Protein-C/Tumor Necrosis Factor- (SP-C/TNF-) Transgenic Mice to Air Pollutants

Safe Environments Programme, Health Canada, Ottawa, Ontario, Canada

Ian Y. R. Adamson

University of Manitoba, Winnipeg, Manitoba, Canada

J. D. Crapo
R. J. Mason

National Jewish Medical and Research Center, Denver, Colorado, USA

R. Vincent

Safe Environments Programme, Health Canada, Ottawa, Ontario, Canada

Correspondence: Address correspondence to Prem Kumarathasan, PhD, Room 338, Environmental Health Centre, 0803C Tunney’s Pasture, Ottawa, Ontario, Canada K1A 0L2. E-mail:premkumari_kumarathasan{at}hc-sc.gc.ca

Tumor necrosis factor (TNF)-, a cytokine present in inflammed lungs, is known to mediate some of the adverse effects of ozone and inhaled particles. The authors evaluated transgenic mice with constitutive pulmonary expression of TNF-under transcriptional regulation of the surfactant protein-C promoter as an animal model of biological susceptibility to air pollutants. To simulate a repeated, episodic exposure to air pollutants, wild-type and TNF mice inhaled air or a mixture of ozone (0.4 ppm) and urban particles (EHC-93, 4.8 mg/m³) for 4 h, once per week, for 12 consecutive weeks and were sacrificed 20 h after last exposure. TNF mice exhibited chronic lung inflammation with septal thickening, alveolar enlargement, and elevated protein and cellularity in bronchoalveolar lavage fluid (genotype main effect, p <.001). Repeated exposure to pollutants did not result in measurable inflammatory changes in wild-type mice and did not exacerbate the inflammation in TNF mice. The pollutants decreased recovery of alveolar macrophages in lavage fluid of both wild-type and TNF mice (exposure main effect, p < .001). Exacerbation of the rate of protein nitration reactions specifically in the lungs of TNF mice was revealed by the high ratio of 3-nitrotyrosine to _L-DOPA after exposure to the air pollutants (Genotype x Exposure factor interaction, p = .014). Serum creatine kinase-MM isoform increased in TNF mice exposed to pollutants (Genotype x Exposure factor interaction, p = .043). The marked pollutant-related nitration in the lungs of the TNF mice reveals basic differences in free radical generation and scavenging in the inflamed lungs in response to pollutants. Furthermore, elevation of circulating creatine kinase-MM isoform specifically in TNF mice exposed to pollutants suggests systemic adverse impacts from lung inflamma-tory mediators, possibly on muscles and the cardiovascular system.

Key Words: Air Pollution • Creatine Kinase • Endothelin • Oxidative Stress • Particulate Matter • Tumor Necrosis Factor-

International Journal of Toxicology, Vol. 24, No. 1, 59-67 (2005)
DOI: 10.1080/10915810590921379


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