API

Aop: 237

AOP Title

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Secretion of inflammatory cytokines after cellular sensing of the stressor leading to plaque progression

Short name:

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Secretion of inflammatory cytokines leading to plaque progression

Authors

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Sarah Søs Poulsen, The National Research Centre for the Working Environment
Ulla Vogel, The National Research Centre for the Working Environment
Håkan Wallin, Statens Arbeidsmiljøinstitutt
Sabina Halappanavar, Health Canada
Carole Yauk, Health Canada

Point of Contact

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Sarah Søs Poulsen

Contributors

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  • Sarah Søs Poulsen

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on June 29, 2017 01:51

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Revision dates for related pages

Page Revision Date/Time
Sensing of the stressor by pulmonary cells June 29, 2017 02:24
Increased production of pulmonary, pro-inflammatory cytokines June 29, 2017 02:25
Increased production of pulmonary SAA June 29, 2017 02:27
Formation of HDL-SAA June 29, 2017 02:28
Increased systemic total cholesterol pool June 29, 2017 02:32
Foam cell formation June 29, 2017 02:32
Plaque progression in arteries June 29, 2017 02:33
Sensing of the stressor leads to Pro-inflammatory cytokines increased June 29, 2017 02:36
Pro-inflammatory cytokines increased leads to SAA production increased June 29, 2017 02:37
SAA production increased leads to HDL-SAA formation June 29, 2017 02:37
HDL-SAA formation leads to Systemic cholesterol increased June 29, 2017 02:38
Systemic cholesterol increased leads to Foam cell formation June 29, 2017 02:38
HDL-SAA formation leads to Foam cell formation June 29, 2017 02:38
Foam cell formation leads to Plaque progression June 29, 2017 02:39

Abstract

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Background (optional)

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Cardiovascular disease (CVD) is the leading cause of death worldwide, being responsible for 31% of all deaths in 2012 (WHO: http://www.who.int). The term CVD covers all diseases of the cardiovascular system, including atherosclerosis, which is manifested as increased plaque deposition or build-up in the arteries. Atherosclerosis is normally asymptotic disease and is initiated by a biological, chemical or physical insult to the artery walls. This leads to the expression of cell adhesion molecules (selectins, VCAM-1 and ICAM-1) on the endothelial lining of the arteries, which facilitates the activation, recruitment, and migration of monocytes through the endothelial monolayer [1;2]. Inside the intima layer, the monocytes differentiate into macrophages and internalize fatty deposits (mainly oxidized low-density lipoprotein). This results in them transforming into foam cells, which is a major component of the atherosclerotic fatty streaks. The fatty streaks reduce the elasticity of the artery walls and the foam cells promote a pro-inflammatory environment by secretion of cytokines and ROS. In addition, foam cells also induce the recruitment of smooth muscle cells to the intima. Added together, these changes lead to the formation of plaques on the artery walls. A fibrous cap of collagen and vascular smooth muscle cells protects the necrotic core and stabilizes the plaque [3;4]. However, blood clots can be formed if the plaque ruptures. These may travel with the bloodstream and obstruct the blood flow of smaller vessels, eg. the coronary arteries, which ultimately can lead to myocardial infarction.


Inhalation of particulate matter, chemicals and pathogens have been related to increased pulmonary inflammation. Whereas a normal immune reaction is crucial for effective elimination of incoming threats, chronic and unresolved inflammation has been linked to both adverse pulmonary and adverse systemic effects in humans. In concordance with this, various retrospective and prospective epidemiological studies have linked pulmonary exposure to respirable air particulates with increased the risk of developing CVD [5-8]. Inhalation of particles has been proposed to affect the cardiovascular system in several different ways, including through disruption of vasomotor function and through acceleration of plaque progression in atherosclerosis [9;10]. We recently showed that a sustained pulmonary inflammatory response occurs concurrently with a persistent acute phase response (APR) in the lungs and in the plasma after exposure to particulate matter in mice [11-13]. Both responses were dose-dependent [14] and the most differentially expressed genes were the serum amyloid A (Saa) isoforms, with Saa3 showing the greatest fold changes [11;13-15]. The SAAs are characterized as APR proteins. Similar to the APR protein C-reactive protein (CRP), elevated plasma levels of SAA protein are a risk factor for CVD in human [16-19]. However, in contrast to CRP, increased plasma protein levels of SAA is still related to CVD after Mendelian randomization, suggesting a causal relationship [20;21]. Indeed, studies in rodents have shown that increased levels of SAA increase plaque progression in ApoE−/− mice [22;23].


Summary of the AOP

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Stressors

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Molecular Initiating Event

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Title Short name
Sensing of the stressor by pulmonary cells Sensing of the stressor

Key Events

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Title Short name
Increased production of pulmonary, pro-inflammatory cytokines Pro-inflammatory cytokines increased
Increased production of pulmonary SAA SAA production increased
Formation of HDL-SAA HDL-SAA formation
Increased systemic total cholesterol pool Systemic cholesterol increased
Foam cell formation Foam cell formation

Adverse Outcome

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Title Short name
Plaque progression in arteries Plaque progression

Relationships Between Two Key Events (Including MIEs and AOs)

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Title Directness Evidence Quantitative Understanding
Sensing of the stressor leads to Pro-inflammatory cytokines increased Directly leads to Not Specified Not Specified
Pro-inflammatory cytokines increased leads to SAA production increased Directly leads to Not Specified Not Specified
SAA production increased leads to HDL-SAA formation Directly leads to Not Specified Not Specified
HDL-SAA formation leads to Systemic cholesterol increased Directly leads to Not Specified Not Specified
Systemic cholesterol increased leads to Foam cell formation Indirectly leads to Not Specified Not Specified
HDL-SAA formation leads to Foam cell formation Directly leads to Not Specified Not Specified
Foam cell formation leads to Plaque progression Directly leads to Not Specified Not Specified

Network View

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Life Stage Applicability

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Sex Applicability

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Graphical Representation

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Click to download graphical representation template

Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Weight of Evidence Summary

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Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

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References

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   1.   Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006; 6(7):508-519.

   2.   Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest. 2001; 107(10):1255-1262.

   3.   Libby P. Inflammation in atherosclerosis. Nature. 2002; 420(6917):868-874.

   4.   Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol. 2005; 25(10):2054-2061.

   5.   Clancy L, Goodman P, Sinclair H, Dockery DW. Effect of air-pollution control on death rates in Dublin, Ireland: an intervention study. Lancet. 2002; 360(9341):1210-1214.

   6.   Dockery DW, Pope CA, III, Xu X, Spengler JD, Ware JH, Fay ME et al. An association between air pollution and mortality in six U.S. cities. N Engl J Med. 1993; 329(24):1753-1759.

   7.   Pope CA, III, Thun MJ, Namboodiri MM, Dockery DW, Evans JS, Speizer FE et al. Particulate air pollution as a predictor of mortality in a prospective study of U.S. adults. Am J Respir Crit Care Med. 1995; 151(3 Pt 1):669-674.

   8.   Pope CA, III, Burnett RT, Thurston GD, Thun MJ, Calle EE, Krewski D et al. Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation. 2004; 109(1):71-77.

   9.   Cao Y, Jacobsen NR, Danielsen PH, Lenz AG, Stoeger T, Loft S et al. Vascular effects of multiwalled carbon nanotubes in dyslipidemic ApoE-/- mice and cultured endothelial cells. Toxicol Sci. 2014; 138(1):104-116.

10.   Moller P, Christophersen DV, Jacobsen NR, Skovmand A, Gouveia AC, Andersen MH et al. Atherosclerosis and vasomotor dysfunction in arteries of animals after exposure to combustion-derived particulate matter or nanomaterials. Crit Rev Toxicol. 2016; 46(5):437-476.

11.   Bourdon JA, Halappanavar S, Saber AT, Jacobsen NR, Williams A, Wallin H et al. Hepatic and pulmonary toxicogenomic profiles in mice intratracheally instilled with carbon black nanoparticles reveal pulmonary inflammation, acute phase response, and alterations in lipid homeostasis. Toxicol Sci. 2012; 127(2):474-484.

12.   Poulsen SS, Saber AT, Mortensen A, Szarek J, Wu D, Williams A et al. Changes in cholesterol homeostasis and acute phase response link pulmonary exposure to multi-walled carbon nanotubes to risk of cardiovascular disease. Toxicol Appl Pharmacol. 2015; 283(3):210-222.

13.   Poulsen SS, Saber AT, Williams A, Andersen O, Kobler C, Atluri R et al. MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs. Toxicol Appl Pharmacol. 2015; 284(1):16-32.

14.   Saber AT, Jacobsen NR, Jackson P, Poulsen SS, Kyjovska ZO, Halappanavar S et al. Particle-induced pulmonary acute phase response may be the causal link between particle inhalation and cardiovascular disease. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2014; 6(6):517-531.

15.   Husain M, Saber AT, Guo C, Jacobsen NR, Jensen KA, Yauk CL et al. Pulmonary instillation of low doses of titanium dioxide nanoparticles in mice leads to particle retention and gene expression changes in the absence of inflammation. Toxicol Appl Pharmacol. 2013; 269(3):250-262.

16.   Johnson BD, Kip KE, Marroquin OC, Ridker PM, Kelsey SF, Shaw LJ et al. Serum amyloid A as a predictor of coronary artery disease and cardiovascular outcome in women: the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation. 2004; 109(6):726-732.

17.   Lowe GD. The relationship between infection, inflammation, and cardiovascular disease: an overview. Ann Periodontol. 2001; 6(1):1-8.

18.   Mezaki T, Matsubara T, Hori T, Higuchi K, Nakamura A, Nakagawa I et al. Plasma levels of soluble thrombomodulin, C-reactive protein, and serum amyloid A protein in the atherosclerotic coronary circulation. Jpn Heart J. 2003; 44(5):601-612.

19.   Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342(12):836-843.

20.   Elliott P, Chambers JC, Zhang W, Clarke R, Hopewell JC, Peden JF et al. Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA. 2009; 302(1):37-48.

21.   Pai JK, Mukamal KJ, Rexrode KM, Rimm EB. C-reactive protein (CRP) gene polymorphisms, CRP levels, and risk of incident coronary heart disease in two nested case-control studies. PLoS One. 2008; 3(1):e1395.

22.   Christophersen DV, Moller P, Thomsen MB, Lykkesfeldt J, Loft S, Wallin H et al. Accelerated atheroslerosis and pulmonary inflammation caused by repeated i.t. instillations with recombinant Serum Amyloid A.  2017.

23.   Dong Z, Wu T, Qin W, An C, Wang Z, Zhang M et al. Serum amyloid A directly accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Mol Med. 2011; 17(11-12):1357-1364.