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

Our plain-English summary of Inhaled asbestos exacerbates atherosclerosis in apolipoprotein E-deficient mice via CD4+ T cells, by N.K. Fukagawa, M. Li, T. Sabo-Attwood, et al (Environmental Health Perspectives, 2008).

The study

• Authors: N.K. Fukagawa, M. Li, T. Sabo-Attwood, C.R. Timblin, K.J. Butnor, J. Gagne, C. Steele, D.J. Taatjes, S. Huber, B.T. Mossman
• Journal: Environmental Health Perspectives
• Published: 2008;116(9):1218-25
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

In this mouse experiment, the authors tested whether inhaled chrysotile asbestos worsens atherosclerosis (fatty buildup in arteries) and whether CD4+ T cells, a type of immune cell, are involved. Female mice prone to atherosclerosis (ApoE-deficient), and similar mice also lacking CD4+ T cells, breathed clean air or chrysotile asbestos at about 5 mg per cubic meter of air for 6 hours a day, 5 days a week, for 3, 9 or 30 days. Some ApoE-deficient mice breathed titanium dioxide, a comparison dust. Lesion size did not differ after 3 or 9 days. After 30 days, lesions in asbestos-exposed ApoE-deficient mice were about three times larger than in clean-air or titanium dioxide groups, or in asbestos-exposed mice lacking CD4+ T cells. Lung inflammation and fibrosis were similar in both asbestos-exposed strains. Blood levels of the signaling protein MCP-1 rose in asbestos-exposed ApoE-deficient mice and correlated with lesion size. The authors concluded the effect appeared to depend on CD4+ T cells, not on the degree of lung inflammation or fibrosis. They noted the asbestos concentrations used were high.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (inhalation study in genetically modified mice)
• Who was studied: Female atherosclerosis-prone apolipoprotein E-deficient (ApoE-deficient) mice and ApoE-deficient mice also lacking CD4 (double-knockout, DKO) mice, 4 to 6 weeks old at the start of exposure, bred and studied at the University of Vermont. Three separate inhalation experiments used 6 to 10 mice per group per time point per experiment.
• Exposure: Whole-body inhalation of NIEHS reference chrysotile asbestos at approximately 5 mg per cubic meter of air (range 4.7 to 5.7), 6 hours a day, 5 days a week, for 3, 9 or 30 days. Controls breathed clean air. In some experiments ApoE-deficient mice breathed fine titanium dioxide (about 28 mg per cubic meter) as a nonpathogenic control particle.
• Main results:
  • No detectable differences in atherosclerotic lesion size were seen after 3- or 9-day asbestos exposures.
  • After 30 days, lesions in asbestos-exposed ApoE-deficient mice were approximately three times larger than in clean-air or titanium dioxide-exposed ApoE-deficient mice, or in asbestos-exposed DKO mice (p less than 0.001). Group sizes were 11 clean-air, 11 asbestos and 6 titanium dioxide ApoE-deficient mice, and 8 clean-air and 8 asbestos DKO mice.
  • Lung inflammation and fibrosis scores did not differ between asbestos-exposed ApoE-deficient and DKO mice at any time point.
  • In fiber analyses of aortas from two control and two asbestos-exposed mice, the only fibers seen were one or two small fibers in a clean-air control, which the authors attributed to contamination. The authors took this to suggest the aortic effects were not due to fibers moving directly to the aorta.
  • At 30 days, plasma MCP-1 was significantly higher in asbestos-exposed than clean-air ApoE-deficient mice (p less than 0.04). In asbestos-exposed ApoE-deficient mice, plasma MCP-1 correlated with lesion size (p less than 0.04).
  • After 9 days of asbestos exposure, the inflammation-linked transcription factors AP-1 and NF-kappaB were significantly activated in aortas of ApoE-deficient mice. No AP-1 or NF-kappaB DNA binding was seen in aortas of DKO mice exposed to clean air or asbestos.
• The authors' conclusion: The authors concluded that inhaled chrysotile asbestos was associated with worsened atherosclerotic lesions in ApoE-deficient mice. They concluded this effect appeared to depend on CD4+ T cells and to be dissociated from the magnitude of lung inflammation or fibrosis.
• Limitations the authors state:
  • The airborne asbestos concentrations used were high, like those encountered episodically during the World Trade Center disaster, and much higher than typical ambient levels.
  • Lesions were larger than those reported in the literature for ApoE-deficient mice of similar age, for reasons the authors called unclear.
  • Only the aortic sinus was examined. Longer exposures or en face analysis might have given different results.
  • The authors did not stain lesions for the presence of CD4+ T cells.
  • The source of the elevated cytokines remains unknown.

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Chrysotile, Fibrosis, Bronchoalveolar Lavage (BAL).

Related studies

• Asbestos-induced peribronchiolar cell proliferation and cytokine production are attenuated in lungs of protein kinase C-delta knockout mice — A. Shukla, K.M. Lounsbury, et al. (2007)
• TNF-alpha receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers — J.Y. Liu, D.M. Brass, et al. (1998)
• Local effector failure in mesothelioma is not mediated by CD4+ CD25+ T-regulator cells — C. Jackaman, S. Cornwall, et al. (2009)
• Susceptibility of p53-deficient mice to induction of mesothelioma by crocidolite asbestos fibers — J.M. Marsella, B.L. Liu, et al. (1997)
• WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer — L.M. Krug, T. Dao, et al. (2010)
• Decreased CXCR3 expression in CD4+ T cells exposed to asbestos or derived from asbestos-exposed patients — M. Maeda, Y. Nishimura, et al. (2011)

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