| Sumario: | BACKGROUND: Associations between air pollution and morbidity/mortality from cardiovascular disease are recognized in epidemiologic and clinical studies, but the mechanisms by which inhaled fibers or particles mediate the exacerbation of atherosclerosis are unclear. OBJECTIVE AND METHODS: To determine whether lung inflammation after inhalation of a well-characterized pathogenic particulate, chrysotile asbestos, is directly linked to exacerbation of atherosclerosis and the mechanisms involved, we exposed apolipoprotein E--deficient (ApoE--/--) mice and ApoE--/-- mice crossed with CD4--/-- mice to ambient air, NIEHS (National Institute of Environmental Health Sciences) reference sample of chrysotile asbestos, or fine titanium dioxide (TiO2), a nonpathogenic control particle, for 3, 9, or 30 days. RESULTS: ApoE--/-- mice exposed to inhaled asbestos fibers had approximately 3-fold larger atherosclerotic lesions than did TiO2-exposed ApoE--/-- mice or asbestos-exposed ApoE--/--/CD4--/-- doubleknockout (DKO) mice. Lung inflammation and the magnitude of lung fibrosis assessed histologically were similar in asbestos-exposed ApoE--/-- and DKO mice. Monocyte chemoattractant protein-1 (MCP-1) levels were increased in bronchoalveolar lavage fluid and plasma, and plasma concentrations correlated with lesion size (p < 0.04) in asbestos-exposed ApoE--/-- mice. At 9 days, activator protein-1 (AP-1) and nuclear factor-[kappa]B (NF-[kappa]B), transcription factors linked to inflammation and found in the promoter region of the MCP-1 gene, were increased in aortas of asbestos-exposed ApoE--/-- but not DKO mice. CONCLUSION: Our findings show that the degree of lung inflammation and fibrosis does not correlate directly with cardiovascular effects of inhaled asbestos fibers and support a critical role of CD4+ T cells in linking fiber-induced pulmonary signaling to consequent activation of AP-1-- and NF-[kappa]B--regulated genes in atherogenesis.
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