API

Relationship: 1903

Title

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Increased pro-inflammatory mediators leads to Increase in RONS

Upstream event

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Increased pro-inflammatory mediators

Downstream event

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Increase in RONS

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Increased DNA damage leading to increased risk of breast cancer adjacent High Not Specified
Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer adjacent High Not Specified

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Pro-inflammatory mediators increase reactive oxygen and nitrogen species (RONS).

Evidence Supporting this KER

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Biological Plausibility is High. Inflammation is commonly understood to generate RONS via inflammatory signaling and activated immune cells.

Empirical Support is High. Signals arising from inflammation can be both pro- and anti-inflammatory, and both can have effects on RONS and downstream key events. Multiple inflammation-related factors increase RONS or oxidative damage, and ionizing radiation increases both inflammation-related signaling and RONS or oxidative damage over the same time points. Interventions to reduce inflammation also reduce RONS. The dose-dependence response to stressors is generally consistent between the two key events, although this is based on a small number of studies with some conflicting evidence.

Biological Plausibility

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Biological Plausibility is High. Inflammation is commonly understood to generate RONS via inflammatory signaling and activated immune cells (Zhao and Robbins 2009; Ratikan, Micewicz et al. 2015; Blaser, Dostert et al. 2016). Inflammation-related signals contributing to RONS include the cytokines TNF-a, IL1, and INF and the JNK/MAPK pathway (Bubici, Papa et al. 2006; Yang, Elner et al. 2007; Blaser, Dostert et al. 2016), as well as neutrophil and macrophage immune cells (Jackson, Gajewski et al. 1989; Stevens, Bucurenci et al. 1992; Fan, Li et al. 2007; Lorimore, Chrystal et al. 2008; Rastogi, Boylan et al. 2013; Weigert, von Knethen et al. 2018).

Empirical Evidence

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High. Signals arising from inflammation can be both pro- and anti-inflammatory, and both can have effects on RONS and downstream key events. Multiple inflammation-related factors increase RONS or oxidative damage, and ionizing radiation increases both inflammation-related signaling and RONS or oxidative damage over the same time points. Interventions to reduce inflammation also reduce RONS. The dose-dependence response to stressors is generally consistent between the two key events, although this is based on a small number of studies with some conflicting evidence.

Multiple inflammation-related factors increase RONS or oxidative damage including neutrophils (Jackson, Gajewski et al. 1989; Stevens, Bucurenci et al. 1992), macrophages (Rastogi, Boylan et al. 2013), TNF-a (Fehsel, Kolb-Bachofen et al. 1991; Yan, Wang et al. 2006; Natarajan, Gibbons et al. 2007; Zhang, Zhu et al. 2017), and TGF-β (Shao, Folkard et al. 2008; Dickey, Baird et al. 2009; Dickey, Baird et al. 2012). Inflammation-related factors TGF-β, TNF-a, COX2, and NO are also implicated in the generation of RONS in bystander cells after IR (Shao, Folkard et al. 2008; Zhou, Ivanov et al. 2008; Wang, Wu et al. 2015).

IR increases both inflammation-related signaling and RONS or oxidative damage. This relationship has been shown in lung, liver, cardiac, and mammary tissue in animals (Azimzadeh, Scherthan et al. 2011; Chai, Lam et al. 2013; Azimzadeh, Sievert et al. 2015; Wang, Wu et al. 2015) and fibroblasts, keratinocytes, and glioblastoma cells in vitro (Narayanan, LaRue et al. 1999; Shao, Folkard et al. 2008; Zhou, Ivanov et al. 2008; Zhang, Zhu et al. 2017). Changes occur within 30 minutes (Narayanan, LaRue et al. 1999), and both responses are detectable hours (Shao, Folkard et al. 2008; Zhou, Ivanov et al. 2008; Azimzadeh, Scherthan et al. 2011; Wang, Wu et al. 2015; Zhang, Zhu et al. 2017), days (Shibata, Takaishi et al. 2010; Ameziane-El-Hassani, Talbot et al. 2015), or months (Azimzadeh, Sievert et al. 2015) after IR. When multiple time points are measured in the same study, inflammation and RONS follow the same time course after the radiation stimulus (Ha, Chung et al. 2010; Azimzadeh, Scherthan et al. 2011; Ameziane-El-Hassani, Talbot et al. 2015; Azimzadeh, Sievert et al. 2015; Zhang, Zhu et al. 2017).

A relatively small number of studies in a variety of cell types have examined both inflammatory markers and RONS across multiple doses following application of stressors. Three of these report dose-dependent increases in both intracellular RONS and inflammatory markers; one in which the key events are evaluated 1-24 hours after H2O2 application (Nakao, Kurokawa et al. 2008), and two others evaluating them 24 hours or 8-16 weeks after IR (Ha, Chung et al. 2010; Azimzadeh, Sievert et al. 2015). A fourth study reports a dose-dependent reduction in inflammation in response to treatment with antioxidants (Nakahira, Kim et al. 2006). In three other studies, some or all markers of inflammation increase at lower doses but decrease at higher doses (Saltman, Kraus et al. 2010; Black, Gordon et al. 2011; Zhang, Zhu et al. 2017). In two of these studies, RONS does not consistently increase with dose (Saltman, Kraus et al. 2010; Zhang, Zhu et al. 2017), however, this finding is consistent with findings from other studies about lack of dose-dependence of ROS measured at intermediate time points after IR. Similarly, 30 minutes after low dose IR IL8 is dose dependent while ROS is not (Narayanan, LaRue et al. 1999). The mixed inflammatory response at higher doses suggests that additional factors such as negative and positive feedback and crosstalk between pathways are also involved in the relationship between RONS and IR.

Reducing inflammation-related signals can reduce RONS. Inhibiting TGF-β, TNF-a, and IL13 reduces IR-induced RONS in glioblastoma cells, keratinocytes, and thyrocytes (Shao, Folkard et al. 2008; Ameziane-El-Hassani, Talbot et al. 2015; Zhang, Zhu et al. 2017), and inflammatory signal CCL2 is required for oxidative damage at a distance from tumors (Redon, Dickey et al. 2010).

In addition, COX2 inhibitors reduce oxidative and other DNA damage in lung, liver, fibroblasts, and bone marrow (Mukherjee, Coates et al. 2012; Chai, Lam et al. 2013) (Rastogi, Coates et al. 2012; Hosseinimehr, Nobakht et al. 2015) and mutations in lung fibroblasts (Zhou, Ivanov et al. 2005). However, multiple non-steroidal anti-inflammatory agents (NSAIDS) also have direct antioxidant activity (Asanuma, Nishibayashi-Asanuma et al. 2001), so the reduction of RONS with NSAIDS may reflect a direct action on RONS rather than the effect of decreased inflammation.

Uncertainties and Inconsistencies

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Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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RONS activates or is essential to many inflammatory pathways including TGF-β  (Barcellos-Hoff and Dix 1996; Jobling, Mott et al. 2006), TNF (Blaser, Dostert et al. 2016), Toll-like receptor (TLR) (Park, Jung et al. 2004; Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006; Miller, Goodson et al. 2017; Cavaillon 2018), and NF-kB signaling (Gloire, Legrand-Poels et al. 2006; Morgan and Liu 2011). These interactions principally involve ROS, but RNS can indirectly activate TLRs and possibly NF-kB.

Domain of Applicability

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References

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Ameziane-El-Hassani, R., M. Talbot, et al. (2015). "NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation." Proceedings of the National Academy of Sciences of the United States of America 112(16): 5051-5056.

Asanuma, M., S. Nishibayashi-Asanuma, et al. (2001). "Neuroprotective effects of non-steroidal anti-inflammatory drugs by direct scavenging of nitric oxide radicals." J Neurochem 76(6): 1895-1904.

Azimzadeh, O., H. Scherthan, et al. (2011). "Rapid proteomic remodeling of cardiac tissue caused by total body ionizing radiation." Proteomics 11(16): 3299-3311.

Azimzadeh, O., W. Sievert, et al. (2015). "Integrative proteomics and targeted transcriptomics analyses in cardiac endothelial cells unravel mechanisms of long-term radiation-induced vascular dysfunction." J Proteome Res 14(2): 1203-1219.

Black, A. T., M. K. Gordon, et al. (2011). "UVB light regulates expression of antioxidants and inflammatory mediators in human corneal epithelial cells." Biochem Pharmacol 81(7): 873-880.

Blaser, H., C. Dostert, et al. (2016). "TNF and ROS Crosstalk in Inflammation." Trends in cell biology 26(4): 249-261.

Bubici, C., S. Papa, et al. (2006). "Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance." Oncogene 25(51): 6731-6748.

Chai, Y., R. K. Lam, et al. (2013). "Radiation-induced non-targeted response in vivo: role of the TGFbeta-TGFBR1-COX-2 signalling pathway." Br J Cancer 108(5): 1106-1112.

Dickey, J. S., B. J. Baird, et al. (2012). "Susceptibility to bystander DNA damage is influenced by replication and transcriptional activity." Nucleic acids research 40(20): 10274-10286.

Dickey, J. S., B. J. Baird, et al. (2009). "Intercellular communication of cellular stress monitored by gamma-H2AX induction." Carcinogenesis 30(10): 1686-1695.

Fan, J., Y. Li, et al. (2007). "Hemorrhagic shock induces NAD(P)H oxidase activation in neutrophils: role of HMGB1-TLR4 signaling." J Immunol 178(10): 6573-6580.

Fehsel, K., V. Kolb-Bachofen, et al. (1991). "Analysis of TNF alpha-induced DNA strand breaks at the single cell level." Am J Pathol 139(2): 251-254.

Ha, Y. M., S. W. Chung, et al. (2010). "Molecular activation of NF-kappaB, pro-inflammatory mediators, and signal pathways in gamma-irradiated mice." Biotechnol Lett 32(3): 373-378.

Hosseinimehr, S. J., R. Nobakht, et al. (2015). "Radioprotective effect of mefenamic acid against radiation-induced genotoxicity in human lymphocytes." Radiat Oncol J 33(3): 256-260.

Jackson, J. H., E. Gajewski, et al. (1989). "Damage to the bases in DNA induced by stimulated human neutrophils." J Clin Invest 84(5): 1644-1649.

Lorimore, S. A., J. A. Chrystal, et al. (2008). "Chromosomal instability in unirradiated hemaopoietic cells induced by macrophages exposed in vivo to ionizing radiation." Cancer Res 68(19): 8122-8126.

Mukherjee, D., P. J. Coates, et al. (2012). "The in vivo expression of radiation-induced chromosomal instability has an inflammatory mechanism." Radiation research 177(1): 18-24.

Nakahira, K., H. P. Kim, et al. (2006). "Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts." J Exp Med 203(10): 2377-2389.

Nakao, N., T. Kurokawa, et al. (2008). "Hydrogen peroxide induces the production of tumor necrosis factor-alpha in RAW 264.7 macrophage cells via activation of p38 and stress-activated protein kinase." Innate Immun 14(3): 190-196.

Narayanan, P. K., K. E. LaRue, et al. (1999). "Alpha particles induce the production of interleukin-8 by human cells." Radiation research 152(1): 57-63.

Natarajan, M., C. F. Gibbons, et al. (2007). "Oxidative stress signalling: a potential mediator of tumour necrosis factor alpha-induced genomic instability in primary vascular endothelial cells." Br J Radiol 80 Spec No 1: S13-22.

Rastogi, S., M. Boylan, et al. (2013). "Interactions of apoptotic cells with macrophages in radiation-induced bystander signaling." Radiation research 179(2): 135-145.

Rastogi, S., P. J. Coates, et al. (2012). "Bystander-type effects mediated by long-lived inflammatory signaling in irradiated bone marrow." Radiation research 177(3): 244-250.

Ratikan, J. A., E. D. Micewicz, et al. (2015). "Radiation takes its Toll." Cancer Lett 368(2): 238-245.

Redon, C. E., J. S. Dickey, et al. (2010). "Tumors induce complex DNA damage in distant proliferative tissues in vivo." Proceedings of the National Academy of Sciences of the United States of America 107(42): 17992-17997.

Saltman, B., D. H. Kraus, et al. (2010). "In vivo and in vitro models of ionizing radiation to the vocal folds." Head Neck 32(5): 572-577.

Shao, C., M. Folkard, et al. (2008). "Role of TGF-beta1 and nitric oxide in the bystander response of irradiated glioma cells." Oncogene 27(4): 434-440.

Shibata, W., S. Takaishi, et al. (2010). "Conditional deletion of IkappaB-kinase-beta accelerates helicobacter-dependent gastric apoptosis, proliferation, and preneoplasia." Gastroenterology 138(3): 1022-1034 e1021-1010.

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Wang, T. J., C. C. Wu, et al. (2015). "Induction of Non-Targeted Stress Responses in Mammary Tissues by Heavy Ions." PLoS One 10(8): e0136307.

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Yang, D., S. G. Elner, et al. (2007). "Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells." Exp Eye Res 85(4): 462-472.

Zhang, Q., L. Zhu, et al. (2017). "Ionizing radiation promotes CCL27 secretion from keratinocytes through the cross talk between TNF-alpha and ROS." J Biochem Mol Toxicol 31(3).

Zhao, W. and M. E. Robbins (2009). "Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications." Curr Med Chem 16(2): 130-143.

Zhou, H., V. N. Ivanov, et al. (2005). "Mechanism of radiation-induced bystander effect: role of the cyclooxygenase-2 signaling pathway." Proceedings of the National Academy of Sciences of the United States of America 102(41): 14641-14646.

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