title: 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
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont 05405, USA. naomi.fukagawa@uvm.edu
authors.forename: Naomi K
authors.initials: NK
authors.lastname: Fukagawa
authors.forename: Muyao
authors.initials: M
authors.lastname: Li
authors.forename: Tara
authors.initials: T
authors.lastname: Sabo-Attwood
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Timblin
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Butnor
authors.forename: Jessica
authors.initials: J
authors.lastname: Gagne
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Taatjes
authors.forename: Sally
authors.initials: S
authors.lastname: Huber
authors.forename: Brooke T
authors.initials: BT
authors.lastname: Mossman
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D001194:Asbestos / Q000008:administration & dosage / Q000633:toxicity*; D050197:Atherosclerosis / Q000139:chemically induced* / Q000235:genetics; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D019570:Inhalation Exposure; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D001057:Apolipoproteins E; D001194:Asbestos
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