Inhaled asbestos exacerbates atherosclerosis in apolipoprotein E-deficient mice via CD4+ T cells.

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 (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-kappaB (NF-kappaB), 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-kappaB-regulated genes in atherogenesis.

• Authors: Naomi K Fukagawa, Muyao Li, Tara Sabo-Attwood, Cynthia R Timblin, Kelly J Butnor, Jessica Gagne, Chad Steele, Douglas J Taatjes, Sally Huber, Brooke T Mossman
• Journal: Environmental health perspectives (Environ Health Perspect) Vol. 116 Issue 9 Pg. 1218-25 (Sep 2008) ISSN: 0091-6765 [Print] United States
• PMID: 18795166 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Apolipoproteins E
• Asbestos

Topics

• Animals
• Apolipoproteins E (genetics, physiology)
• Asbestos (administration & dosage, toxicity)
• Atherosclerosis (chemically induced, genetics)
• Blotting, Western
• CD4-Positive T-Lymphocytes (immunology)
• Electrophoretic Mobility Shift Assay
• Female
• Inhalation Exposure
• Male
• Mice
• Mice, Knockout