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Bradykinin, activated leads to Increased proinflammatory mediators
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||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 Do not cite||Under Development|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, induces pain stimulation, and increases 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, Ekdahl doi: 10.1080/14686996.2019.1625721). Activation of the bradykinin system leads to increase of proinflammatory mediators due to increased production of proinflammatory mediator bradykinin(https://doi.org/10.1161/01.CIR.95.5.1115) as well as upregulating bradykinin receptor 1 (BDKRB1) and 2(BDKRB2), leading to induction of proinflammatory mediators such as IL-2, IL-6 and IL-8 (https://doi.org/10.1165/rcmb.2002-0040OC) and the activation of the NFKb pathway leading to production of proinflammatory mediators TNF and IL1(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC507648/).
Evidence Collection Strategy
Evidence Supporting this KER
Bradykinin (BK) system activation causes increased production of bradykinin. Bradykinin has been established as a potent proinflammatory mediator due to bradykinin’s role in inflammation. BK acts as a vasodilator, increases vascular permeability, and stimulates prostaglandin synthesis(https://www.ncbi.nlm.nih.gov/books/NBK537187/).
Bradykinin can also induce proinflammatory cytokine production such as TNF, IL2, IL6, and IL8 through stimulation of ERK1/2 and p38 MAPK pathways, causing inflammation and leading to an increase in proinflammatory mediators (https://www.frontiersin.org/articles/10.3389/fphar.2020.01278/full).
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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
Curran, C. Rivera, D. Kopp, J. Covid-19 usurps host regulatory networks. Frontiers. Pharmacol., 14 August 2020 | https://doi.org/10.3389/fphar.2020.01278
Hayashi R, et al. Bradykinin stimulates IL-6 and IL-8 production by human lung fibroblasts through ERK- and p38 MAPK-dependent mechanisms. Eur Respir J. 2000 Sep;16(3):452-8. doi: 10.1034/j.1399-3003.2000.016003452.
Hornig B., Kohler C., and Drexler H.. Role of Bradykinin in Mediating Vascular Effects of Angiotensin-Converting Enzyme Inhibitors in Humans. Circulation. 4 Mar 1997. Circulation. 1997;95:1115–1118. https://doi.org/10.1161/01.CIR.95.5.111
Huang, C. Tliba, O. Panettieri, R., Amrani, Y. Bradykinin Induces Interleukin-6 Production in Human Airway Smooth Muscle Cells. American Journal of Respiratory Cell and Molecular Biology. 2002. Vol 28, issue 3; doi:https://doi.org/10.1165/rcmb.2002-0040OC
Garvin, M. 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
Golias Ch, Charalabopoulos A, Stagikas D, Charalabopoulos K, Batistatou A. The kinin system--bradykinin: biological effects and clinical implications. Multiple role of the kinin system--bradykinin. Hippokratia. 2007;11(3):124-128.
Pan ZK, Zuraw BL, Lung CC, Prossnitz ER, Browning DD, Ye RD. Bradykinin stimulates NF-kappaB activation and interleukin 1beta gene expression in cultured human fibroblasts. J Clin Invest. 1996;98(9):2042-2049. doi:10.1172/JCI119009
Pirahanchi Y, Sharma S. Physiology, Bradykinin. [Updated 2020 Aug 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537187/