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
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.
Fukagawa
Naomi K
NK
Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont 05405, USA. naomi.fukagawa@uvm.edu
Li
Muyao
M
Sabo-Attwood
Tara
T
Timblin
Cynthia R
CR
Butnor
Kelly J
KJ
Gagne
Jessica
J
Steele
Chad
C
Taatjes
Douglas J
DJ
Huber
Sally
S
Mossman
Brooke T
BT
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
D001057:Apolipoproteins E; D001194:Asbestos
MMWR Morb Mortal Wkly Rep. 2003 Feb 21;52(7):131-6
12617538
JAMA. 2005 Dec 21;294(23):3003-10
16414948
Science. 1990 Jan 19;247(4940):294-301
2153315
Am J Pathol. 2007 Jan;170(1):140-51
17200189
Science. 2005 May 6;308(5723):804-6
15879201
Arterioscler Thromb Vasc Biol. 2001 Dec;21(12):1876-90
11742859
Histochem Cell Biol. 2002 Jul;118(1):59-68
12122448
Br J Ind Med. 1993 Dec;50(12):1073-81
8280638
Am J Pathol. 2004 Dec;165(6):2013-8
15579444
JAMA. 2006 Mar 8;295(10):1127-34
16522832
Am J Pathol. 1996 Aug;149(2):359-66
8701976
Atherosclerosis. 1987 Dec;68(3):231-40
3426656
J Immunol. 2007 Feb 1;178(3):1800-8
17237430
J Leukoc Biol. 2005 Sep;78(3):656-64
15961574
J Clin Invest. 1997 Jun 1;99(11):2752-61
9169506
Am J Pathol. 2005 Nov;167(5):1243-56
16251409
Am J Pathol. 2003 Sep;163(3):1117-25
12937153
J Clin Invest. 1995 Mar;95(3):1370-6
7883984
JAMA. 2002 Mar 6;287(9):1132-41
11879110
Am J Pathol. 2000 Dec;157(6):1819-24
11106554
Br J Ind Med. 1993 Sep;50(9):785-90
8398871
Am J Pathol. 1997 Aug;151(2):389-401
9250152
J Air Waste Manag Assoc. 2006 Jun;56(6):709-42
16805397
Toxicol Appl Pharmacol. 1996 Mar;137(1):67-74
8607143
Nucleic Acids Res. 1989 Aug 11;17(15):6419
2771659
Inhal Toxicol. 2000 Jan;12 Suppl 3:307-16
26368630
Am J Ind Med. 1983;4(3):421-33
6846339
Scand J Work Environ Health. 2001 Dec;27(6):420-1
11800330
Environ Health Perspect. 2005 Aug;113(8):934-46
16079061
J Immunol. 1998 May 1;160(9):4606-14
9574568
Angiology. 2004 May-Jun;55(3):289-94
15156262
N Engl J Med. 1989 Jun 29;320(26):1721-30
2659987
Occup Environ Med. 1997 Jul;54(7):466-9
9282121
Circulation. 2004 Jun 1;109(21):2655-71
15173049
Histochem Cell Biol. 2000 Mar;113(3):161-73
10817670
Arch Pathol Lab Med. 1982 Oct 8;106(11):544-96
6897166
Environ Health Perspect. 2002 Aug;110(8):A440-1
12153769
Eur J Immunol. 1997 May;27(5):1091-7
9174597
J Clin Invest. 1999 Mar;103(6):773-8
10079097
Am J Respir Crit Care Med. 2005 Sep 1;172(5):530-51
15879415