Inhaled Asbestos Exacerbates Atherosclerosis in Apolipoprotein E–Deficient Mice via CD4(+) T Cells

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 (TiO(2)), 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 TiO(2)-exposed ApoE(−/−) mice or asbestos-exposed ApoE(−/−)/CD4(−/−) double-knockout (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-κB (NF-κB), 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-κB–regulated genes in atherogenesis.