Aop: 237

AOP Title


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

Short name:


Secretion of inflammatory cytokines leading to plaque progression

Graphical Representation


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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


Sarah Søs Poulsen   (email point of contact)



  • Sarah Søs Poulsen



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 Do not cite Under Development 1.55 Included in OECD Work Plan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 October 13, 2020 05:16


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



Background (optional)


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


Events: Molecular Initiating Events (MIE)


Key Events (KE)


Adverse Outcomes (AO)


Sequence Type Event ID Title Short name
1 MIE 1437 Sensing of the stressor by pulmonary cells Sensing of the stressor
2 KE 1438 Increased production of pulmonary, pro-inflammatory cytokines Pro-inflammatory cytokines increased
3 KE 1439 Increased production of pulmonary SAA SAA production increased
4 KE 1440 Formation of HDL-SAA HDL-SAA formation
5 KE 1441 Increased systemic total cholesterol pool Systemic cholesterol increased
6 KE 1442 Foam cell formation Foam cell formation
7 AO 1443 Plaque progression in arteries Plaque progression

Relationships Between Two Key Events
(Including MIEs and AOs)


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





Name Evidence Term
Lipopolysaccharride Not Specified
Graphene oxide nanoparticles Not Specified
Carbon nanotubes Not Specified
Insoluble nano-sized particles Not Specified
Virus Not Specified

Life Stage Applicability


Life stage Evidence
Adult Not Specified

Taxonomic Applicability


Term Scientific Term Evidence Link
human Homo sapiens Not Specified NCBI
mouse Mus musculus Not Specified NCBI

Sex Applicability


Sex Evidence
Unspecific Not Specified

Overall Assessment of the AOP


Domain of Applicability


Essentiality of the Key Events


Evidence Assessment


Quantitative Understanding


Considerations for Potential Applications of the AOP (optional)




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