Leukocyte recruitment/activation leads to Increase in RONS

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 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 the stressor ionizing radiation (IR) 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. 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.

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.