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Development of a Hub Adverse Outcome Pathway for Hyperinflammation
Citation:
Mei, Liang Merlin, M. Mei, M. Martens, D. Jacobson, J. Waspe, S. Halappanavar, P. Nymark, AND H. Mortensen. Development of a Hub Adverse Outcome Pathway for Hyperinflammation. Society of Advancement of Adverse Outcome Pathways (AAOP), RTP, NC, February 15 - 22, 2022.
Impact/Purpose:
Fibrinolysis, decreased/Bradykinin, activated leading to increased hyperinflammation, describes Key Events (KE) associated with immune response, leading to the uncontrolled inflammatory response referred to as hyperinflammation.
Description:
AOP392 –Fibrinolysis, decreased/Bradykinin, activated leading to increased hyperinflammation, describes Key Events (KE) associated with immune response, leading to the uncontrolled inflammatory response referred to as hyperinflammation. The aim of this work is to understand the complex inflammatory processes induced by various stressors, including SARS-CoV-2 and nanoparticles. AOP392 is considered a “hub” AOP and connects with many upstream and downstream KEs. For example, hyperinflammation may cause loss of alveolar capillary membrane integrity, thus connecting AOP392 to AOP173 (lung fibrosis). AOP392 has two molecular initiating events (MIEs), hypo-fibrinolysis (KE1866) and bradykinin activation (KE1867). Upon MIE activation, inflammatory processes are triggered, which include increased pro-inflammatory mediator secretion (KE1496) and increased recruitment of pro-inflammatory cells (KE1497). Pro-inflammatory monocytes and macrophages further exacerbate the inflammatory process, leading to a persistent pro-inflammatory feedback loop and the hyperinflammation adverse outcome (KE1868), which is defined by multiple changes including high serum levels of C-reactive protein (CRP) and neutrophil. AOP392 is currently being developed based on evidence in literature of SARS-CoV-2 and nanoparticle stressor activation. AOP392 has the potential to provide better understanding of the dysfunctional inflammation process that is central to many AOPs. Additionally, AOP392 serves as a case study for improved FAIRness (Findability, Accessibility, Interoperability, and Reuse) of the AOP-Wiki, through extensive ontology annotations and external database linkage. This abstract does not reflect EPA policy.