Aop: 237


A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

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

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Secretion of inflammatory cytokines leading to plaque progression

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool


The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Arthur Author   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Sarah Søs Poulsen
  • Arthur Author


Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.55 Included in OECD Work Plan
This AOP was last modified on July 16, 2022 18:37

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
Lipopolysaccharride May 29, 2018 07:05
Graphene oxide nanoparticles February 15, 2017 04:41
Carbon nanotubes August 09, 2017 08:03
Insoluble nano-sized particles May 29, 2018 07:09
Virus May 29, 2018 07:10


A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

AOP Development Strategy


Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Cardiovascular disease (CVD) is the leading cause of death worldwide, being responsible for 31% of all deaths in 2012 (WHO: 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].


Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help


Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1437 Sensing of the stressor by pulmonary cells Sensing of the stressor
KE 1438 Increased production of pulmonary, pro-inflammatory cytokines Pro-inflammatory cytokines increased
KE 1439 Increased production of pulmonary SAA SAA production increased
KE 1440 Formation of HDL-SAA HDL-SAA formation
KE 1441 Increased systemic total cholesterol pool Systemic cholesterol increased
KE 1442 Foam cell formation Foam cell formation
AO 1443 Plaque progression in arteries Plaque progression

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help
Title Adjacency Evidence Quantitative Understanding
Sensing of the stressor leads to Pro-inflammatory cytokines increased adjacent Not Specified Not Specified
Pro-inflammatory cytokines increased leads to SAA production increased adjacent Not Specified Not Specified
SAA production increased leads to HDL-SAA formation adjacent Not Specified Not Specified
HDL-SAA formation leads to Systemic cholesterol increased adjacent Not Specified Not Specified
HDL-SAA formation leads to Foam cell formation adjacent Not Specified Not Specified
Foam cell formation leads to Plaque progression adjacent Not Specified Not Specified
Systemic cholesterol increased leads to Foam cell formation non-adjacent Not Specified Not Specified

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Adult Not Specified

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human Homo sapiens Not Specified NCBI
mouse Mus musculus Not Specified NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific Not Specified

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help


List of the literature that was cited for this AOP. More help

   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.