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Increased proinflammatory mediators leads to Recruitment of inflammatory cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Substance interaction with the lung resident cell membrane components leading to lung fibrosis||adjacent||High||High||Sabina Halappanavar (send email)||Under development: Not open for comment. Do not cite||EAGMST Under Review|
|Decreased fibrinolysis and activated bradykinin system leading to hyperinflammation||adjacent||Penny Nymark (send email)||Under development: Not open for comment. Do not cite|
|Frustrated phagocytosis leads to malignant mesothelioma||adjacent||High||Not Specified||Nureddin Mansour (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Pro-inflammatory mediators are the chemical and biological molecules that initiate and regulate inflammatory reactions. They are secreted following inflammation or exposure to an inflammogen. Commonly measured pro-inflammatory mediators include IL-1 family cytokines, IL-4, IL-5, IL-6, TNFa, IFNg. (https://aopwiki.org/events/1496)
Proinflammatory mediator increase is caused when there’s increased inflammation. This can be found in many ways, including bradykinin system activation or hypofibrinolysis (Koller, https://doi.org/10.1161/ATVBAHA.119.313536).With more proinflammatory mediators, this causes increased signaling from proinflammatory cytokines, which promotes leukocyte recruitment, which will differentiate into proinflammatory cells ( (Villenueve et al, https://doi.org/10.1093/toxsci/kfy047)). Increased proinflammatory mediators means this process happens more, which means increase recruitment of inflammatory cells.
Evidence Supporting this KER
Strong biological plausibility
Increased proinflammatory mediators means more proinflammatory cytokines, chemokines, vasoactive amines, and lipid mediators (Villenueve et al, https://doi.org/10.1093/toxsci/kfy047). Increased Signaling from these Cytokines and Chemokines promote leukocyte recruitment to areas of infection, including monocytes and neutrophil(Leick et al, doi: 10.1007/s00441-014-1809-9). The leukocytes will differentiate into mature proinflammatory cells, in response to mediators they encounter in the local tissue microenvironment(Villenueve et al, https://doi.org/10.1093/toxsci/kfy047). With higher levels of leukocytes from increased proinflammatory mediators, it causes an increase in proinflammatory cells (Libby, https://doi.org/10.1093/cvr/cvv188).
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Activated pro-inflammatory cells secrete pro-inflammatory mediators, and those mediators' goal is to cause signalling and response, which can lead to chronic inflammation (https://aopwiki.org/events/1497). Chronic inflammation means proinflammatory mediators increase and increased recruitment of inflammatory cells acts in a positive feedback loop, which continues a pro-inflammatory environment.
Domain of Applicability
Villeneuve D., Landesmann B., Allavena P., Ashley N., Bal-Price, A., Corsini E., Halappanavar S., Hussell T., Laskin D., Lawrence T., Nikolic-Paterson D., Pallardy M., Paini A., Pieters R., Roth R., Tschudi-Monnet F. Representing the Process of Inflammation as Key Events in Adverse Outcome Pathways. Toxicological Sciences, Volume 163, Issue 2, June 2018, Pages 346–352, https://doi.org/10.1093/toxsci/kfy047
Leick, M. Azcutia, V. Newton, G. Luscinskas, F. Leukocyte Recruitment in Inflammation: Basic Concepts and New Mechanistic Insights Based on New Models and Microscopic Imaging Technologies. Cell Tissue Res. 2014 Mar; 355(3): 647–656. doi: 10.1007/s00441-014-1809-9
Libby, P. Fanning the flames: inflammation in cardiovascular diseases. Cardiovascular Research, Volume 107, Issue 3, August, 2015. Pages 307–309, https://doi.org/10.1093/cvr/cvv188