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Naomi K. Fukagawa,¹ Muyao Li,¹ Tara Sabo-Attwood,² Cynthia R. Timblin,¹ Kelly J. Butnor,³ Jessica Gagne,^1* Chad Steele,⁴ Douglas J. Taatjes,³ Sally Huber,³ and Brooke T. Mossman³

¹Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA; ²Department of Environmental Health Sciences, University of South Carolina, Columbia, South Carolina, USA; ³Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont, USA; ⁴Department of Medicine, University of Alabama, Birmingham, Alabama, USA

Abstract
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^–/– 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.

Key words: AP-1, atherosclerosis, CD4⁺ T-cells, chrysotile asbestos, fibrosis, inflammation, knockout mice, lung, MCP-1, NF-κB. Environ Health Perspect 116:1218–1225 (2008) . doi:10.1289/ehp.11172 available via http://dx.doi.org/ [Online 21 May 2008]

Address correspondence to N.K. Fukagawa, Department of Medicine, 89 Beaumont Ave., Given Bldg., Room C207, Burlington, VT 05405 USA. Telephone: (802) 656-4403. Fax: (802) 656-2636. E-mail: naomi.fukagawa@uvm.edu

*Current address: Waters, Inc., Woburn, MA.

We thank T. Barrett, J. Levis, E. Parker, J. Robbins, D. Sartini, M. von Turkovich, and M. Wadsworth, for expert technical assistance.

This work was supported by grants from the National Institute on Aging (K01-AG00947 and R01-AG21106) ; the National Heart, Lung, and Blood Institute (P01-HL067004) ; and the National Institute of Environmental Health Sciences (T32 ES0071) .

The authors declare they have no competing financial interests.

Received 13 December 2007 ; accepted 21 May 2008.