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Bradykinin, activated leads to Hyperinflammation
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Decreased fibrinolysis and activated bradykinin system leading to hyperinflammation||non-adjacent||Penny Nymark (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
Bradykinin (BK) plays an important role in the kinin-kallikrein system (KKS) as a regulator of blood pressure and can induce vasodilation, increase blood flow, as well as hypotension. BK is also an important part of the inflammatory process after injury, inducing pain stimulation, and increased vascular permeability (Maas, 10.1007/s12016-016-8540-0). The bradykinin system gets activated through various methods, including nanoparticles and SARS-COV-2 via the contact activation system (Maas, 10.1007/s12016-016-8540-0).
Activation of the bradykinin system increases production of bradykinin. Bradykinin increases vascular permeability and activates endothelial cells(Garvin 2020 doi: 10.7554/eLife.59177). Vascular permeability is present in covid-19 patients with severe vascular damage and neutrophil infiltration (Carvalho 2021 doi: 10.1038/s41577-021-00522-1). Endothelial cell activation by bradykinin causes loss of anti-inflammatory properties and recruitment of proinflammatory mediators such as an increase in IL6, CXCL10, TNF as well as hyperactivation of CD4+ and CD8+, and increased numbers of monocytes, including plasmablast-like neutrophils and eosinophils, all hallmarks of a hyperinflammatory state (Bernard 2020 doi: 10.3390/v13010029). IL-6, activated by bradykinin’s activation of the endothelium, also exacerbates hyperinflammation.
Evidence Collection Strategy
Evidence Supporting this KER
Activation of the bradykinin system increases production of bradykinin. Bradykinin increases vascular permeability by DABK binding to B1 receptor, leading to leaky blood vessels (Garvin 2020 doi: 10.7554/eLife.59177), activated RAS and BK which leads to increased permeability of endothelium, (Bernard 2020 doi: 10.3390/v13010029) and bradykinin binding to bradykinin receptor 2 leading to endothelium dysfunction (Zwaveling 2020 doi: 10.1016/j.jaci.2020.08.038). Patients suffering from severe COVID-19 have had evidence of vascular damage, neutrophil infiltration and neutrophil extracellular traps inside micro-vessels (Carvalho 2021 doi: 10.1038/s41577-021-00522-1).
RAAS dysfunction and bradykinin system activation causes Endothelial dysfunction, leading to immunothrombosis and induction of a pro-thrombotic state, causing hyperinflammation and increased platelets (Bernard 2020 doi: 10.3390/v13010029). The endothelial dysfunction also causes loss of anti-inflammatory properties and recruitment of proinflammatory mediators such as an increase in IL6, CXCL10, TNF, hyperactivation of CD4+ and CD8+, and increased numbers of monocytes, including plasmablast-like neutrophils and eosinophils, all hallmarks of a hyperinflammatory state (Ekdahl 2019 doi: 10.1080/14686996.2019.1625721). Bradykinin also activates pathways to proinflammatory cytokine production for cytokines such as IL6, and IL6 exacerbates hyperinflammation (Bernard 2020 doi: 10.3390/v13010029). Finally, bradykinin activation is activated by nanomaterials and specifically coagulation factor XII (F12), and due to the bradykinin system being activated via the contact system, the coagulation cascade is activated as well, leading to increased production of fibrinogen and fibrin, leading to more production of D-dimers, a biomarker for hyperinflammation (Maas, 10.1007/s12016-016-8540-0).
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
1. Bernard, I. Limonta, D. Mahal, L. Hobman, T. Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19. Viruses 2021, 13(1), 29; https://doi.org/10.3390/v13010029
2. Carvalho, T. Krammer, F. Iwasaki, A. The first 12 months of COVID-19: a timeline of immunological insights. Nature Reviews Immunology. volume 21, pages 245–256 (2021). doi: 10.1038/s41577-021-00522-1
3. Ekdahl, K. Fromell, K. Mohlin, C. Teramura, Y. Nilsson, B. A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity. Science and Technology of Advanced Materials. Volume 20, 2019- Issue 1. Page 688-698. doi: 10.1080/14686996.2019.1625721
4. Garvin et al. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. eLife 2020;9:e59177 DOI: 10.7554/eLife.59177
5. Hofman, Z., de Maat, S., Hack, C.E. et al. Bradykinin: Inflammatory Product of the Coagulation System. Clinic Rev Allerg Immunol 51, 152–161 (2016). https://doi.org/10.1007/s12016-016-8540-0
6. McCarthy, C. Wilczynski, S. Wencesiaum C. Webb, R .A new storm on the horizon in COVID-19: Bradykinin-induced vascular complications. Vascular Pharmacology, 137. https://doi.org/10.1016/j.vph.2020.106826
7. Welsh, L. Vascular permeability—the essentials. Upsala Journal of Medical Sciences. Volume 120, 2015-Issue 3. Pages 135-143. https://doi.org/10.3109/03009734.2015.1064501
8. Zwaveling, S. Wijk, R. Karim, F. Pulmonary edema in COVID-19: Explained by bradykinin? Allergy Clin Immunol. 2020 Dec; 146(6): 1454–1455. DOI:10.1016/j.jaci.2020.08.038