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International Journal of Radiation Biology

ISSN: 0955-3002 (Print) 1362-3095 (Online) Journal homepage: http://www.tandfonline.com/loi/irab20

Mechanisms of inflammatory responses to radiation and normal tissues toxicity; clinical implications Masoud Najafi, Elahe Motevaseli, Alireza Shirazi, Ghazale Graily, Abolhasan Rezaeyan, Farzad Norouzi, Saeed Rezapoor & Hamid Abdollahi To cite this article: Masoud Najafi, Elahe Motevaseli, Alireza Shirazi, Ghazale Graily, Abolhasan Rezaeyan, Farzad Norouzi, Saeed Rezapoor & Hamid Abdollahi (2018): Mechanisms of inflammatory responses to radiation and normal tissues toxicity; clinical implications, International Journal of Radiation Biology To link to this article: https://doi.org/10.1080/09553002.2018.1440092

Accepted author version posted online: 05 Mar 2018.

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Mechanisms of inflammatory responses to radiation and normal tissues toxicity; clinical implications Masoud Najafi1, Elahe Motevaseli2*, Alireza Shirazi3*, Ghazale Graily3, Abolhasan Rezaeyan4,

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Farzad Norouzi5, Saeed Rezapoor5, Hamid Abdollahi4

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1 Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah

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University of Medical Science, Kermanshah, Iran

University of Medical Sciences, Tehran, Iran

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2 Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran

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3 Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran

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University of Medical Sciences, Tehran, Iran

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4 Department of Medical Physics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

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5 Science and Research Branch, Azad University, Tehran, Iran

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6 Department of Radiology, Faculty of Paramedical Sciences, Tehran University of Medical Sciences, Tehran, Iran Corresponding author: E. Motevaseli, [email protected], Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

Co-Corresponding author: A. Shirazi, [email protected], Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

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Abstract

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Purpose: Cancer treatment is one of the most challenging diseases in the present era. Among a

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few modalities for cancer therapy, radiotherapy plays a pivotal role in more than half of all

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treatments alone or combined with other cancer treatment modalities. Management of normal

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tissue toxicity induced by radiation is one of the most important limiting factors for an appropriate radiation treatment course. The evaluation of mechanisms of normal tissue toxicity

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has shown that immune responses especially inflammatory responses play a key role in both early and late side effects of exposure to ionizing radiation (IR). DNA damage and cell death, as

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well as damage to some organelles such as mitochondria initiate several signaling pathways that

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result in the response of immune cells. Massive cell damage which is a common phenomenon following exposure to a high dose of IR cause secretion of a lot of inflammatory mediators

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including cytokines and chemokines. These mediators initiate different changes in normal tissues

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that may continue for a long time after irradiation. In this study, we reviewed the mechanisms of inflammatory responses to IR that are involved in normal tissue toxicity and considered as the most important limiting factors in radiotherapy. Also, we introduced some agents that have been proposed for management of these responses. Conclusion: The early inflammation during the radiation treatment is often a limiting factor in radiotherapy. In addition to the limiting factors, chronic inflammatory responses may increase

the risk of second primary cancers through continuous free radical production, attenuation of tumor suppressor genes and activation of oncogenes. Moreover, these effects may influence nonirradiated tissues through a mechanism named bystander effect. Keywords: Radiation; Inflammation, Normal Tissue, Clinical Implications, Immune System

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Introduction

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The knowledge of the responses of the immune system to cell death, DNA damage and DNA

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damage responses following ionizing radiation (IR) exposure are essential to understanding the

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underlying normal tissue complications. IR induces single strand and double strand DNA breaks

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(DSBs). Most single strand breaks can be repaired, while DSBs result in cell death. Exposure to high doses of IR produces massive DNA damage in cells. Accumulation of unrepaired DNA

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damage can result in the induction of deletion, mutations, chromosome aberrations or cell death. For a typical radiation dose of 2 Gy of gamma or x-ray, about 3000 DNA breaks are produced

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per cell exposed. There are two main types of IR induced DNA lesions including direct damages due to direct interaction with radiation and indirect damages due to interaction with IR induced

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reactive oxygen species (ROS) produced by chemical changes (Lomax et al. 2013). In addition to ROS production by IR, there are several inflammatory signaling pathways

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activated after radiation exposure which amplify ROS and nitric oxide (NO) production. Inflammatory cytokines and growth factors produced by irradiated cells provoke several signaling cascades that stimulate ROS and NO producing enzymes such as NADPH Oxidase, inducible nitric oxide synthetize (iNOS), and cyclooxygenase-2 (COX-2). These enzymes produce ROS and NO which amplify IR induced DNA damage and cell death (Bours et al. 2000). Moreover, increased superoxide anions production by the electron transfer chains of

mitochondria can amplify intracellular oxidative stress (Zorov et al. 2006). Potent evidences have proposed that during chronic inflammation, free radicals serve as intracellular signals that potentiate the inflammatory response (Filippin et al. 2008). A ROS induced ROS phenomenon after exposure to radiation may continue for a long time leading to appearance of pathological changes in normal tissues (Zorov et al. 2014). Continued ROS formation after exposure to IR

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may be the origin of radiosensitivity of some cells such as T lymphocytes (Ogawa et al. 2003).

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DNA damage and cell death are the main mechanisms involved in triggering of inflammatory responses following exposure to IR. In response to IR, there are tissue-specific responses to

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DNA damage (Park et al. 2014) and inflammation (Chai Y., Calaf G. M., et al. 2013).

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Accordingly, we have described the exact mechanisms in each organ and then proposed possible

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mitigation strategies.

Although the immunologic basis of IR induced normal tissue toxicity is widely studied and

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taught, there is no comprehensive review in this field. In this present work, we reviewed

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literatures on the underlying mechanisms in which inflammatory responses are involved in

implications.

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radiation induced normal tissue toxicity in different organs and summarize some of the clinical

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Radiation cause induced DNA damage and immunologic or anti-immunologic cell death Exposure of cells to radiation leads to oxidative DNA damage, mutation, and several types of cell death. (Rock et al. 2011, Muralidharan and Mandrekar 2013). Mitotic catastrophe, apoptosis, necrosis, necroptosis (secondary necrosis), autophagy, and senescence are various types of cell death induced by IR (Golden and Apetoh 2015b). From immunologic point of view, IR induced cell death can be categorized to immunologic and anti-immunologic cell death. Necrosis and

necroptosis are immunogenic, while apoptosis is anti-immunogenic cell death (Park et al. 2014). Inflammatory or anti-inflammatory responses to IR result in release of different soluble mediators as well as changes in immune cell surface receptors which have been reported to play critical roles in IR induced normal tissues toxicities. For example, some studies have indicated that high levels of some immune factors such as TGF-β have been detected in serum level of the

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Chernobyl accident survivors of cancer patients undergoing RT (Marozik et al. 2007, Emerit et

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al. 1995, Ballardin et al. 2002).

As an interesting issue, secreted products from apoptotic cells determine whether the apoptosis is

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immunogenic or not. In this light, when cells are exposed to radiation, several pathways can be

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activated which would lead to cellular stress, production of different species of free radical, DNA damage and finally immunogenic apoptosis (necroptosis) (Opferman 2008). Whilst in another

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way, normal apoptosis state is mostly non-immunogenic. In regard to necrosis, it is an inherently

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immunogenic and pathological cell death associated with several inflammatory responses (Green

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et al. 2009). The balance between apoptosis and necrosis play a key role in the immune responses to early and late effects consequences (Golden and Apetoh 2015a).

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In regard to cell types, it is widely observed that apoptosis is the most common form of cell

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death in some radiosensitive organs such as bone marrow and peripheral lymphocytes. Studies on acute radiation exposure have shown that depletion of bone marrow stem cells, granulocytes and natural killer (NK) cells are more obvious followed by pelvic and chest bone irradiation, where the bone marrow cells are producing new marrow cells (Iyer and Jhingran 2006) (MacVittie et al. 2015). Also, some studies have identified that the occurrence of apoptosis compared to necrosis is very obvious after exposure radiation doses lower than 1 Gy (Kaur and Asea 2012).

p53 has a crucial role in radiation-induced apoptosis. Apoptosis or programmed cell death dependent on p53 occurs within a few hours after irradiation (Lee et al. 2013). The extrinsic apoptosis pathways stimulated by binding of the cell death surface receptor FAS by FAS ligand. The interaction of FAS by its ligand results in apoptotic cell death, mediated by caspase cascade activation (Watters 1999). The evidence has been shown that intrinsic or extrinsic apoptosis can

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be independently regulated within the same cell type and the decision of life or death was controlled by the cell (Hotchkiss et al. 2000, Nowsheen and Yang 2012). The mitochondrial

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cells such as lymphocytes (Enoch and Norbury 1995).

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apoptosis pathway is considered as a reason for high intrinsic radiosensitivity of some immune

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Necrosis has been investigated using different radiation doses, but it is very important after exposure to higher doses of radiation. The most common reason for necrosis in normal cells after

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irradiation is damages to vessels and hypoxia situation. Vascular damages due to high doses of

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radiation is a mechanism for nutrition deprivation and hypoxia that amplify radiation induced

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necrosis (Greene-Schloesser et al. 2012). Evidences have shown that combined chemotherapy and radiation therapy increases the incidence of necrosis to manifold that is seen with

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radiotherapy alone (Miyaguchi et al. 1997, Keime-Guibert et al. 1998).

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Why IR induced DNA damage and cell death trigger inflammation? Immunogenic VS. tolerogenic cell death Cells dying by normal apoptosis are phagocytosed by macrophages and don’t trigger inflammatory responses. Also, some mechanisms involved in the process of apoptosis cause tolerogenic and anti-inflammatory responses. Interactions of macrophages with apoptotic cells can stimulate macrophages to generate anti-inflammatory cytokines such as IL-10, TGF-β,

platelet-activating factor and prostaglandin E2 (PGE2) which result in suppression of the inflammatory responses. An increased level of TGF-β inhibits the production of proinflammatory cytokines such as IL-1 and TNF-α by activated macrophages. Thus, these changes lead to a loss of immune responses (Chung et al. 2006). In contrast, in some stress conditions like exposure to IR, a higher number of cells may undergo

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apoptosis, which can overwhelm the phagocytic system. This may result in release of danger

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signals from damaged membranes, and organelles such as mitochondria (Rock and Kono 2008; Silva 2010). This may result in release of danger signals from destroying membrane, and

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organelles such as mitochondria. Danger signals as so called ‘damage-associated molecular

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patterns (DAMPs)’ are endogenous molecular structures within the cells which are hidden from the immune system. These molecular structures such as uric acid, adenosine triphosphate (ATP),

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heat shock proteins (HSPs), and high-mobility group box 1 (HMGB1) are liberated after tissue

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damage like after exposure to radiation (Klune et al. 2008; Krysko et al. 2012; Chacon et al.

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2016). Danger signals released during necrosis, as well as secondary necrosis that occurs following apoptosis trigger pro-inflammatory cytokines production and immune-stimulatory

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Oxidized DNA

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response (Poon et al. 2014).

In addition to dying cells, evidences have shown that the DNA damage after irradiation can stimulate the inflammatory responses. The extensive DNA damage results in the release of triggering signals. DAMPs such as HMGB1 and oxidized DNA are considered as a link between DNA damage and immune responses (Gehrke et al. 2013). DNA damage after exposure to radiation can lead to the formation of cell free oxidized DNA. (Veiko 2013).

In addition to nuclear DNA, mitochondrial DNA (mtDNA) has a role in immune system activation. Mitochondrial apoptosis can result in the release of oxidized mtDNA into the cytosol and bound it to NLRP3 inflammasome in the cytosol, which causes activation of the NLRP3 inflammasome (Allam et al. 2014). Also, a part of increased levels of some inflammatory cytokines after exposure to radiation may activate apoptosome and inflammasome during

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apoptosis (Hogquist et al. 1991; Shimada et al. 2012; Chai J and Shi 2014; Ha et al. 2014). The

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inflammasome promotes the maturation and secretion of the inflammatory cytokines IL-1β and

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IL-18 (Pétrilli et al. 2007).

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The oxidized DNA originated from both DNA and mtDNA has been implicated in the secretion

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of pro-inflammatory cytokines through NLRP3 inflammasome activation (Haneklaus et al. 2013; Abderrazak et al. 2015). On the other hand, generation of ROS via IR itself, stimulates

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inflammasome activation (Martinon 2010; Sorbara and Girardin 2011; Zhou R et al. 2011). Stoecklein et al. showed that IR induces a dose-dependent augmentation in inflammasome

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activation in immune cells, such as macrophages, T and B lymphocytes, dendritic cells and NK cells. They have hypothesized that the inflammasome contributes to both acute and chronic

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immune responses due to radiation exposure (Stoecklein et al. 2015).

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Toll-like receptors (TLRs)

The release of intracellular contents like DAMPs can engage in the immune system through some ligands causing inflammation. The pattern recognition receptors (PRRs) that are expressed by Dendritic cells (DCs) recognize some of these DAMPs that stimulate antigen uptake. PRRs including Toll-like receptors (TLRs) identify danger signals, cytokines and chemokines released by the inflammatory cells. DAMPs recognized by TLRs activate the inflammation cascades and transcription of NF-κB and activator proteins (AP-1). Danger signals derived from necrotic cells

compared to apoptosis, have more potent effects on DCs maturation. In addition, secondary necrosis after apoptosis post-irradiation were more effective for DC maturation compared to physiological apoptosis (Piccinini and Midwood 2010; Karki and Igwe 2013). Increased HMGB1, HSPs and oxidized DNA following irradiation usually through TLR2, TLR4, TLR5 and TLR9 can increase expression of NF-κB and pro-inflammatory cytokines (Lyudmila

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G. Burdelya 2008; Piccinini and Midwood 2010). TLRs are the key link between tissue injury

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and cell death, and immune system responses to IR.

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NF-κB plays a central role in response to danger signals released from necrotic or necroptotic cells. The recognition of DAMPs with TLRs induces NF-κB signaling through the mitogen

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activated protein kinases (MAPKs), DNA-dependent protein kinases (DNA-PKs) and

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phosphoinositide 3-kinase (PI3K) pathways (Hellweg 2015). NF-κB controls the expression of many growth factors, apoptosis inhibitors and molecules needed for inflammation, including pro-

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inflammatory cytokines and chemokines, iNOS, COX-2 and vascular adhesion molecules needed

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for leukocyte recruitment. The cytokines and chemokines generated in irradiated tissues depends on tissue type, because the resident immune cells type and numbers are varying between

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different tissues. Therefore, immunomodulatory changes that lead to normal tissue damages and

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carcinogenesis can vary among different tissue types (Pos et al. 2005; Aggarwal et al. 2006).

Fig 1: Mechanisms of inflammation activation following exposure to IR Role of inflammatory responses to IR in carcinogenesis Epidemiological studies have proposed that 25% of all cases of cancer is related to chronic inflammation (Okada 2014). Inflammatory responses to IR can result in DNA damage and

inhibition of DNA repair pathways, damages to non-irradiated tissues through non-targeted effect, increased carcinogenesis risk and some non-cancerous diseases like heart diseases, diabetes, dermatitis and digestive disorders (Kusunoki and Hayashi 2008). In this section, we describe some possible carcinogenic effect of IR through stimulation of inflammation.

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Activation of Inflammation mediators

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Inflammatory responses induced by IR are mediated by several mediators such as NF-κB, iNOS,

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COX-2, EGFR, MCP-1, and cytokines such as IL-1, IL-2, IL-6, TNF-α and IFN-γ. An elevated

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level of inflammatory cytokines in normal tissues is reported in cancer patients undergoing radiotherapy and chemotherapy (Wang XS et al. 2010; Siva et al. 2014). Macrophages and

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monocytes are the most important immune cells in the initiation and maintenance of

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inflammation by secreting pro-inflammatory cytokines. Acute inflammation usually occurs due to massive cell death in rapidly dividing cells. This response is the initial response of the body to

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a high dose radiation and was initiated by release of chemokines and then the increased

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movement of leukocytes from the blood into the irradiated tissues. In this situation, the resident macrophages, neutrophils, lymphocytes and DCs are increased in irradiated tissues during a few

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hours after exposure. Depending on location, acute inflammation can cause temporary erythema,

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ulceration, edema and in the lung, pneumonitis (Sprung et al. 2015). High dose radiobiology studies have shown that these doses lead to a continuous inflammation in exposed people. This is associated with a long term increase of macrophage, neutrophil and lymphocyte population in the irradiated tissues. As illustrated in Fig1, the increased activity of these cells leads to continuous production of pro-inflammatory cytokines and chemokines that are associated with prolonged ROS and NO generation. Thus, oxidative stress and cellular damages induced by radiation may continue for a long time. The long term effects of

inflammation can lead to various detrimental effects such as pathological damages and carcinogenesis due to progressive and persistent oxidative stress (Hayashi et al. 2005; Zhao Weiling and Robbins 2009). The effects on DNA repair response

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DNA repair system plays a key role in tolerance of normal tissues to radiotherapy. On the other

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hand, change in DNA repair response, tumor suppressor genes and oncogenes are involved in

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both early and late consequences of radiotherapy. However, there is a predictable increase in

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regulation of DNA repair genes after radiation exposure, evidences have been proposed that chronic inflammation cause suppression of DNA repair response, and mutation in tumor

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suppressor genes and oncogenes. Thus, chronic inflammation may lead to accumulation of

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unrepaired DNA. During chronic inflammation, cells may be exposed to high quantities of NO and ROS (Dedon and Tannenbaum 2004). Oxidative and nitrative DNA damage cause mutations

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of DNA repair genes which are involved in the initiation and promotion of carcinogenesis (Meira

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Lisiane B et al. 2008; Ohnishi et al. 2013; Lin Runhua et al. 2015). For example, decreased XRCC1 expression is associated with acute side effects in breast cancer patients that underwent

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radiotherapy (Batar et al. 2016).

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NO plays a key role in suppression of DNA damage responses during the inflammation. NO produced by immune cells including macrophages and neutrophils can inhibit DNA repair and alter the expression of certain genes, which would provide grounds for genomic instability (Jaiswal et al. 2000). There are three forms of nitric oxide sources, including iNOS (inducible NOS), nNOS (neuronal NOS) and eNOS (endothelial NOS). NO at abnormal level is mainly involved in homeostatic processes such as neurotransmission, host defense, and blood pressure regulation (Nathan 1992). The iNOS initially can be found in macrophages, eNOS is membrane-

bound and nNOS can be found in the cytosol. Among the family of nitric oxide synthesis enzymes, iNOS is the main source of NO production during inflammation (Zhao W et al. 2014). It is now understood that in addition to macrophages, several types of cells can express iNOS in the presence of inflammatory cytokines (Bogdan 2015). Studies have confirmed the upregulation of iNOS in irradiated cells too (MacNaughton 1998). NO is produced by iNOS enzyme from L-

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arginine in inflamed tissues (Rath et al. 2014). NO can react by DNA and leads base oxidation,

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deamination, and nitration (Tamir et al. 1996).

Previous studies have reported that mutations in BER genes and defects in MMR repair pathway

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is associated with chronic inflammation, which can result in incomplete repair of DNA damage,

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leading to mutation, chromosomal instability and predisposition to several types of epithelial cancer (Kidane et al. 2014). Chien and et al. have suggested that NO, peroxynitrite, and arsenite

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can inhibit DNA adduct excision in NER pathway (Chien et al. 2004). NO directly affects

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oxidative DNA damage repair including 8-oxoguanine repair processes. 8-Oxoguanine

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glycosylase (Ogg1) is responsible for the excision of 8-oxoguanine. An inhibition by NO has been investigated for homologue of Ogg1 protein. This is related to nitrosylation of cysteine

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residues in the zinc-finger motif of the Ogg1 protein after expose to a NO donor or iNOSinducing cytokines (Wink and Laval 1994; Jaiswal, LaRusso, Nishioka, et al. 2001). Ogg1

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inhibition by NO result in increased accumulation of oxidative DNA lesions (Jaiswal, LaRusso, Shapiro, et al. 2001). The failure to repair 8-oxodG increases mutagenesis and expected to promote cancer initiation and progression. Studies have shown that hOGG1 gene mutations are associated with several human cancers such as lung, kidney and gastric cancer (Chevillard et al. 1998; Shinmura et al. 1998; Rezapoor et al. 2017).

Continuous inhibition of DNA repair by NO may be proposed as a mechanism linking between chronic inflammation and carcinogenesis after exposure to radiation (Kidane et al. 2014). The production of NO by iNOS is a feature of the inflamed gastrointestinal tract and it has been known as risk factors for the esophagus, stomach, liver, pancreas, biliary tract, and bowel carcinogenesis (Kubes and McCafferty 2000; Jaiswal, LaRusso, Gores 2001).

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Effects on tumor suppressor genes

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A relationship between exposure to IR and deletion of tumor suppression genes have been

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demonstrated (Willey et al. 1993). Molecular genetic analysis have revealed that deletion or mutation of tumor suppressor genes in some chromosomes such as ch8, ch11, ch14 after

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exposure to IR (Mendonca et al. 1995; Weaver et al. 1997; Mendonca et al. 1998; Mendonca et

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al. 2004). A variety of studies have proposed that activation of inflammation responses and also anti-inflammatory genes such as TGFB1 reduces the activity of some tumor suppressor genes

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(Hei T. K. et al. 2011). Although, TGF-β have a suppressive effect on tumor induction, several

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evidences have indicated the clastogenic role of the following exposure to radiation (Krstić et al. 2015). This may continue for a long time after exposure (Randall and Coggle 1996). Abnormal

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upregulated TGF-β constantly induces the generation of ROS and NO from reduction/oxidation

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(redox) system enzymes such as NOX4, COX-2, iNOS and also mitochondrial electron transport chain (ETC) (Pazhanisamy et al. 2011; Najafi M. et al. 2014; Masoud Najafi 2018; Yahyapour et al. 2018). Moreover, TGF-β suppresses the activity of antioxidant system enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) (Liu R-M and Pravia 2010). Chronic oxidative damage induced by redox system may inactivate tumor suppressor genes and activate oncogenes leading to carcinogenesis (Hussain et al. 2003; Meira Lisiane B. et al. 2008; Lin R. et al. 2015).

There are several reports indicating the upregulation of inflammatory genes and cytokines suppressing p53 activity (Yonish-Rouach et al. 1991; Hudson et al. 1999). NF-κB plays a central role in the regulation of this pathway in cells (Gurova et al. 2005). It was demonstrated that NFκB and p53 negatively regulate the activities of each other. Also, long term up-regulation of NFκB during chronic inflammation inhibiting p53 activity is involved in pathologies associated with

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genotoxicity such as acute radiation syndrome and loss of normal function of organs (Gudkov

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and Komarova 2016). Suppression of NF-κB have been proposed as a strategy for activation of

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Effects of inflammatory responses on oncogenes

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p53 in cancer therapy and amelioration of inflammation (Gudkov et al. 2011).

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Inflammatory responses to IR have a potent relation to activation of pro-oncogenic pathways.

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Although, complete mechanisms of radiation induced oncogenes activation are unknown, some studies have proposed a role for inflammatory responses. Based on best knowledge, transcription

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factors and tyrosine kinases have key roles on oncogenesis following exposure to radiation.

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Signal transducers and activators of transcription members (STATs) are a family of transcription factors that have a potent effect on tumorigenesis. STATs including STAT1, STAT3, and

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STAT5 have a key role in cell death and controlling cell-cycle progression and growth arrest

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through cyclin D1 and c-Myc, thus are included among the oncogenes (Calo et al. 2003). STATs which are activated following irradiation in a dose-dependent manner promote cell proliferation (Gao et al. 2014). Blockade of STAT3 using JAK2 inhibitors inhibits tumor proliferation following irradiation (Lau et al. 2015). Thus, blockade of STAT signaling pathways in combination with cancer therapy modalities including radiotherapy may be useful for overcoming tumor radio-resistance (Yu et al. 2009; Sun Y. et al. 2013).

Tyrosine kinases are the other oncogenic signals that serves as a link between inflammatory responses to radiation and cell proliferation. The oncogenes such as EGFR, PDGFR, AKT and RAF have found mutations in different types of human cancers. Abnormal activated tyrosine kinases have also been found among Chernobyl survivors that have been exposed to nuclear disaster (Ricarte-Filho et al. 2013). These kinases are able to stimulate aberrant cell proliferation

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and malignancy through MAPKs and PI3K pathway (Ciampi et al. 2005). Also, these kinases inhibit apoptosis by activating transcription factors AP1 and NF-κB through suppression of pro-

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apoptotic genes including Bax and Bad (Tsatsanis 2000). Hence, aberrant regulation of tyrosine

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Inflammation in radiation-induced bystander effect

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kinases may be consistently associated with genetic perturbations and carcinogenesis.

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The radiation-induced bystander/non-targeted effect is a phenomenon that leads to damage in tissues that have not been directly exposed to IR. Although mechanisms of this phenomenon are

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not exactly known, studies indicate that the immune system and inflammatory response signals

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play a central role in distant tissue damages after localized irradiation. As noted earlier, exposure to IR causes damage to living cells, and can result in mutation and immunological cell death.

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Inflammatory cytokines such as IL-1, IL-6, IL-8, IL-33, TNF-α and TGF-β released by

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macrophages and lymphocytes influence gene expression and epigenetic programming at distant tissues (Liu SZ et al. 2004; Calveley et al. 2005; Koturbash et al. 2008; Fardid et al. 2017). The most important pathways in bystander effect are associated with free radical production induced by inflammatory signaling. Increased COX-2, NADPH Oxidase and iNOS are confirmed in in vitro and in vivo studies (Hei Tom K et al. 2008; Fardid R 2017; Yahyapour, Motevaseli, et al. 2017). An in vitro study by Chai et al. showed that abdominal irradiation enhances COX-2 gene expression in lung by 20-fold and in bronchi by 30-fold. They showed

that COX-2 expression has a key role in pathologic processes characterized by increased local prostaglandins and ROS production. The evidences indicated that the increased COX-2 expression induced by out-of-field effect is regulated in a tissue specific manner (Chai Y., Calaf G. M., et al. 2013; Wang TJC et al. 2015). TGFβ-TGFβR1–COX-2 pathway has key roles in ROS production in distant lung tissues. The expression level of TGβR1 in the lung was

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significant but not for the liver (Chai Y., Lam R. K., et al. 2013). Moreover, TGFβ can upregulate ROS production in non-irradiated cells through miR-21 and suppression of

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superoxide dismutase regulation (Jiang et al. 2014; Xu et al. 2014; Tian et al. 2015). These

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consequences result in oxidative damage, chromosome aberrations, gene mutations, genomic

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instability and aneuploidy, as well as epigenetic changes such as DNA hypomethylation, histone modification, alteration in methyltransferases enzymes and RNA-associated silencing

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(Kovalchuk and Baulch 2008; Mothersill and Seymour 2012; Ghobadi et al. 2017).

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As mentioned above, immunological consequences induced by radiation at non-targeted tissues

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can result in cellular and molecular changes involved in the carcinogenesis. Fractionated radiotherapy leads to cell death, the release of DAMPs such as oxidized DNA by damaged cells

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and upregulation of inflammatory cytokines for several weeks (Ermolaeva and Schumacher 2013; Pateras et al. 2015). At the same time with localized cancer radiotherapy, the non-targeted

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effect induced by radiation cause cellular and molecular damages in distant tissues (Nikitaki et al. 2016). So, this is an important issue for patients that undergo localized radiotherapy, because it may be a threat for second malignancies and decreased survival rate in cancer patients (Najafi M 2017). It is thought that the high incidence of secondary lung cancer in patients that underwent pelvic radiation therapy has a relationship to this phenomenon (Najafi M. et al. 2016).

Inflammatory responses to radiation and pathological damages Radiation pathology is one of the most important radiobiological phenomena among cancer patients undergoing radiation treatment. Histopathologic changes in human cells after exposure to radiation are commonly evident in routine radiation treatments. Pathological changes are the late effects of IR that are seen after exposure to high doses received with organs. The lesions can

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be divided into the parenchyma or epithelia changes (e.g. atrophy, necrosis, metaplasia), the

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stromal elements changes (e.g. fibrosis, fibrinous exudates, necrosis), and the vascular damages (e.g. damage to the endothelial cells, thrombosis and atherosclerosis) (Fajardo 2005). These

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damages are caused by massive DNA damage and unrepaired damages, cell death and

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continuous ROS/NO production for a long time after exposure. Continuous elevated levels of inflammatory cytokines, chemokines, growth factors and adhesion molecules lead to several

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irreversible changes. The most crucial tissues affected by these immune responses and

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subsequent pathological changes includes the lung, heart, brain, liver, intestine, kidneys, spleen

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and colon. In this section, we present the most important long term pathological changes which include fibrosis, vascular damages and subsequent consequences followed by radiation-activated

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Fibrosis

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immune responses.

Radiation can lead to the formation of excess fibrous connection that cause tissue thickness and stiffness. Fibrosis is a late effect of high dose radiation exposure that can affect functions of some irradiated tissues and organs such as the lung, heart, liver, skin, gastrointestinal system, and breast. Radiation-induced fibrosis is highly dependent on multiple factors, which include the radiation dose, irradiated volume and fractionation schedule (Borger et al. 1994).

Fibrosis process is similar to wound healing. Normal wound healing is regulated by the balance between pro-fibrotic cytokines and proteins such as TGF-β versus anti-fibrotic proteins such as IFN-γ. During wound healing, IFN-γ released by T cells downregulate the expression of matrix genes. But, chronic inflammatory reactions induced by a high dose of IR cause long term deposition of extracellular matrix components including collagen (Zhao Weiling and Robbins

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2009). Then, collagen deposition is amplified, resulting in enhanced formation of myofibroblasts as the main source of extracellular matrix proteins. During normal wound healing,

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myofibroblasts undergo apoptosis, but during fibrosis, increased fibrogenic to anti-fibrogenic

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agents ratio is associated with resistance of this cell to apoptosis and accumulation of collagen in

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the extracellular matrix (Wynn TA and Ramalingam 2012).

The immune responses that are induced post IR-exposure mediate the radiation-induced fibrosis

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over a long period of time. Upregulation of pro-inflammatory cytokines (e.g. TNFα, IL1, IL-4,

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IL6, IL-13), fibrogenic cytokines like TGF-β, chemokines (e.g. MCP-1, MIP-1beta), microRNA-

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21, peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), vascular endothelial growth factor (VEGF), renin-angiotensin-system, and platelet-derived growth factor

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(PDGF) in the irradiated tissue are involved in the proliferation of fibroblasts and the synthesis of protein matrix and extracellular matrix metalloproteinases (Wynn T 2008; Yamada et al.

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2013).

There are several studies which claimed that TGF-β1 is responsible for normal tissue remodeling through the initiation, development, and maintenance of fibrosis following irradiation (Minshall et al. 1997; Martin et al. 2000; Wynn TA 2007). The most important signaling pathways for TGF-β1 which stimulates fibrosis after exposure to radiation are TGF-β1-smad2/3 and TGF-β1Rho/ROCK pathways (Bourgier C. et al. 2005; Pohlers et al. 2009). In addition to synthesis of

matrix metalloproteinases and matrixproteins, TGF-β1 suppresses the production of matrix proteases that accelerate accumulation of collagen and fibronectin in extracellular matrix (ECM) (Han et al. 2011; Ding et al. 2013). IL-4 and IL-13 are other cytokines that through IL-4R1 and IL-13R2 stimulate radiation induced fibrosis (Jakubzick et al. 2004; Chung S. I. et al. 2016). Radiation induced fibrosis in the lung can disrupt normal pulmonary actions, including gas

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exchange and ventilation (Ghafoori et al. 2008). Fibrosis in heart tissue leads to increased

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mechanical stiffness of the myocardium, abnormal thickening of the heart valves, destroys normal tissue architecture and disrupts electrical coupling that results in several changes in

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ventricular properties, and systolic and diastolic dysfunction (Khan and Sheppard 2006; Song

an

and Wang 2015). Pathophysiological changes and ROS formation in the kidney that is associated with increased production of extracellular matrix components and renal hypertrophy may be

M

involved in diabetic nephropathy (Wolf 2004). Fibrosis in the liver can cause cirrhosis, distortion

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of the hepatic architecture, liver failure, and portal hypertension. Advanced liver fibrosis may

pt e

require liver transplantation (Bataller and Brenner 2005). Inhibition of TGF-β, inflammatory cytokines and oxidative stress can be considered as a strategy

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for modulation of fibrosis process. ROS and RNS have a key role in the initiation and

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maintenance of tissue remodeling after radiation treatment. Use of antioxidants and radioprotectors can reduce pathological effects of IR, such as fibrosis and vascular disease. Inhibitors of TGF-β such as Pentoxyfyllin, Relaxin, SB-525334 have been shown to exert important activity against lung fibrosis (Tsoutsou and Koukourakis 2006). Administration of some radioprotectors such as melatonin, amifostine and herbal agents such as curcumin and hesperidin have shown promising results (Erol et al. 2004; Sharma and Haldar 2006; Aghazadeh

et al. 2007; Shirazi et al. 2013), (Arora et al. 2014; Rezaeyan Abolhasan et al. 2016; Rezaeyan A 2016; Ghobadi et al. 2017; Haddadi GH 2017). In addition to clinical side effects, radiation accidents or terrorist radiation exposure are threats for the development of long term pathological changes from months to years after exposure to radiation (Gauter-Fleckenstein et al. 2010). Appropriate mitigators are needed to reduce these

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effects when administered after the exposure. Some agents such as genistein have shown

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promising mitigating effects on pneumonitis and fibrosis even when drug administration was initiated 1 week after exposure. This may be related to the antioxidant and anti-NF-κB activity of

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genistein (Mahmood et al. 2011).

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Vascular damage

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Studies have shown that patients who have undergone radiotherapy for various malignancies such as breast cancer, lung cancer, lymphoma, and head and neck cancers have an increased risk

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for developing vascular damage (Russell et al. 2009). Understanding of the mechanisms involved

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in radiation-induced vascular damage is very important and can help modify the disease process. Studies have shown that the high radiation sensitivity of the vasculature has been linked to the

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endothelial dysfunction (Fajardo and Berthrong 1988; Milliat et al. 2006). Histological analyses

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have shown that lesions in medium and large vessels exhibit features such as lipid accumulation, inflammation, and thrombosis (Weintraub Neal L. et al. 2010). Chronic inflammation and upregulation of matrix metalloproteinases increases intimal thickness and connective tissue content (Raffetto and Khalil 2008). Radiation increases the secretion of pro-inflammatory cytokines and upregulates adhesion molecules in the endothelium that recruits inflammatory cells to sites of vascular injury (Hallahan D et al. 1996; Liu Shinuo et al. 2012). These are associated with induction of continuous oxidative damage in vascular endothelial cells. Evidence

supports the hypothesis that acute and chronic inflammatory responses and subsequent oxidative damage have a central role in late brain vascular injury induced by IR, including cognitive impairment (Robbins MEC and Zhao 2004; Robbins Michael et al. 2012). Interventions designed to reduce chronic inflammatory responses can provide an opportunity to mitigate chronic radiation-induced brain injury, including demyelination and impairment of hippocampal

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neurogenesis (Wong C Shun and Van der Kogel 2004; Greene-Schloesser and Robbins 2012).

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Molecular processes contributing to vascular damage induced by IR includes increased production of pro-inflammatory cytokines, pro-thrombotic factors, adhesion molecules and

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increased endothelin-1 secretion (Gaugler M 2014). Clinical and experimental studies have

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shown that the inflammatory responses induced by radiation can accelerate thickening and clogging of cerebral and heart vascular, increasing the risk of vascular stenosis and stroke

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(Stewart et al. 2010). Atherosclerosis is an inflammatory disease that is associated with

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upregulation of P-selectin, E-selectin, ICAM-1 and VCAM-1, monocyte recruitment and foam

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cell formation (Montecucco and Mach 2009). Irradiation of carotid arteries with fractionated or high single doses of radiation accelerates the development of atherosclerosis (Hoving et al.

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2008). These are associated with rapid upregulation of ICAM-1, VCAM-1, P-selectin and Eselectin gene expression during some hours, and may remain for a long time after exposure to IR

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(Fliss and Menard 1994; Heckmann et al. 1998; Hallahan D. E. and Virudachalam 1999; Mollà et al. 2003). The long term expression of adhesion molecules such as ICAM-1 have a direct link with radiation dose in microvascular endothelium, and it is required for cell infiltration and monocyte recruitment (Hallahan Dennis E. and Virudachalam 1997). Moreover, the sustained upregulation of genes that are involved in remodeling of blood vessels such as plasminogen

activator inhibitor (PAI-1) in irradiated micro-vascular recipient veins can be involved in microvascular occlusion (Halle, Ekström, et al. 2010). NF-κB is a central regulator of inflammation and leukocyte adhesion in endothelial cells (Weintraub Neal L et al. 2010). Martin et al. claimed that the upregulated NF-κB in vascular wall cells, with specific localization to macrophages in the skin of head-and-neck cancer patients who

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had undergone radiotherapy since 500 weeks ago (Halle, Gabrielsen, et al. 2010). Upregulation

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of NF-κB leads to alterations in the production of inflammatory cytokines and chemokines, and leukocyte adhesion molecules. These changes in irradiated vasculature promote adherence of

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leukocyte and platelet to endothelial cells that result in thrombus formation (Salame et al. 2000).

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Another important factor in vascular damage following irradiation is the balance between NO

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and ROS production in vascular endothelium. One of the most important molecular changes involved in endothelial dysfunction is decreased NO secretion and increased generation of ROS

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(Bauersachs and Widder 2008). A major source of endothelial ROS is NADPH oxidases family,

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including NOX1, NOX2, NOX4 and NOX5. Other sources include COX-2, mitochondria, xanthine oxidase, lipoxygenase and nitric oxide synthase (NOS). Crosstalk between NF-κB,

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COX-2, NADPH Oxidases enzymes, iNOS and mitochondria electron transport chains (ETCs)

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are increasingly involved in cellular ROS production (Morgan and Liu 2011; Montezano and Touyz 2012; Yahyapour, Amini, et al. 2017). Studies have shown that IR decreases activity of eNOS in arteries (Qi et al. 1998; Soloviev Anatoly I et al. 2003; Soloviev Anatoly I. et al. 2003). NO has an inhibitory role on vascular muscle proliferation after pathological conditions (Garg and Hassid 1989). Proliferation of vascular muscle cells has a key role in repairing vessel wall following an injury. NO reduces intima formation by some mechanisms such as promoting cell death and some changes on the

expression of remodeling pathway genes, epigenetic mechanisms, and also interaction with ROS (Jeremy et al. 1999; Tsihlis et al. 2011). As NO has a role for prevention of thrombosis formation, the decrease in eNOS activity can cause ischemia and micro-vascular occlusion. Endothelial dysfunction and decrease of NO production after irradiation may cause an imbalance between growth-promoting and growth-inhibiting factors. These changes lead to vascular

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thickening and occlusion, dilation of the blood vessel lumen, and endothelial cell nuclear enlargement in irradiated tissues (Halle, Ekström, et al. 2010). It has been investigated that

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endothelial damage after exposure to radiation leads to a deficit of constitutive eNOS synthesis,

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which promotes adherence of leukocyte and platelet to endothelial cell and thrombosis

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development (Gaugler M-H et al. 2005; Gaugler M 2014). Experimental studies have revealed a thickening of intimal and medial vascular layers in irradiated vessels. It is possible that increased

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secretion of inflammatory cytokines and growth factors, and also suppression of eNOS are

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involved in these processes (Sugihara et al. 1999).

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The most important concern for vascular damage during radiation treatment is related to ischemia and necrosis of brain white matter and heart cells. Chronic radiation-induced brain

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injury is characterized by vascular damage, demyelination, and white matter necrosis. Studies have shown that the irradiation of rat brains with 17.5-25 Gy of X-rays lead to a time and dose-

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dependent vascular/glial changes, reduction in the endothelial cell and vascular density and the hypertrophy of the perivascular astrocytes. The severity of these changes are highly correlated with numbers of necrosis cells (Calvo et al. 1988; Reinhold et al. 1990). After radiation injury in the brain, microglia becomes activated and elevates the production of ROS, and pro-inflammatory cytokines and chemokines such as IL-1β, IL-6, and TNFα, and also MCP-1 and ICAM-1. These factors mediate long term neuro-inflammation and may be

associated with impairment of hippocampal neurogenesis and cognitive function. COX-2 is another gene that is induced in astrocyte and microglial cells and modulates brain inflammation after irradiation (Kyrkanides et al. 2002). Some clinical studies have suggested some changes such as progressive cognitive impairment after brain radiotherapy or chemotherapy among the patient survivors (Giovagnoli and Boiardi

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1994; Meyers and Brown 2006). These complications resulted in cerebral and spinal cord

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radionecrosis, which cause damage to white matter, and is associated with severe vascular lesions such as fibrinoid vascular necrosis, hemorrhage, stenosis and thrombosis (Soussain et al.

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2009).

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Several common NF-κB modulators such as melatonin, pravastatin, aspirin, omega-3 fatty acids,

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and PPARα ligand, can be proposed for inhibition of VCAM-1 and E-select in vascular damage followed by irradiation (Weber et al. 1995; Mishra et al. 2004; Ramanan et al. 2008; Holler et al.

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2009; Hu et al. 2013). Inhibition of the other pathways involved in vascular oxidative damage,

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such as renin-angiotensin system can be regarded as a target for ameliorating of vascular damage

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2014).

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after radiation therapy (Sun Yao 2002; Cohen et al. 2010; Medhora et al. 2012; Mahmood et al.

Inflammatory responses in radiation-induced normal tissue toxicity Hematopoietic system Hematopoietic system injury is one of the most common limiting factors for patients undergoing radiation therapy and is the most important cause of mortality after nuclear or radiological disasters. Moreover, hematopoietic malignancies such as leukemia, known as the most prevalent

cancers which have been reported among irradiated peoples. Evidences have revealed that some mechanisms which are activated after exposure to IR, play a key role in hematopoietic stem cells (HSCs) injury and mortality rate. Primary studies showed that whole body irradiation causes induction of chronic oxidative stress in hematopoietic stem cells. Analyses showed a role for mitochondria and some other ROS/NO producing enzymes in hematopoiesis regulation. The

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results stated that NADPH oxidase induced ROS production has more important role in HSCs regulation compared to other factors such as mitochondria (Piccoli et al. 2005; Piccoli et al.

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2007). The evaluation of different source of ROS production in HSCs including NADPH

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Oxidases (NOX1-NOX5), cyclooxygenases, lipoxygenases, and mitochondrial electron transport

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chain-1 (ETC1) showed that NOXs system is primarily responsible for the increased ROS production in HSCs following irradiation. The results indicated that among five different NOXs

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enzymes, NOX4 significantly upregulated in bone marrow after irradiation. Moreover, results showed that increased NOX4 gene expression was prolonged upto 8 weeks post irradiation. This

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indicated that the long term upregulation of NOX4 is a pathway for acute and late effects of IR exposure in the induction of hematopoietic stem cells senescence and residual bone marrow

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damages (Wang Y et al. 2010; Pazhanisamy et al. 2011). In addition to ROS, nitric oxide is another mediator for division, survival and mobilization of

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hematopoietic stem and progenitor cells (Aicher et al. 2003; Michurina et al. 2004; Gangoiti et al. 2008). Several experiments have shown that exposure to radiation can elevate the production of NO in irradiated bone marrow cells. The elevated NO production that in itself depends on the presence of inflammatory mediators leads to reduction of numbers of stem cells and their progeny (Punjabi et al. 1994; Aicher et al. 2003). This can cause detrimental effects on the immune responses following exposure to IR (Sato K et al. 2007). Increased DNA damage

associated with suppression of DNA repair pathways was considered as roles of NO in development of genomic instability and increase of cancer risk (Mikhailenko et al. 2013; Mikhailenko and Muzalov 2013; Rezapoor et al. 2017). Several studies have shown that administration of some radioprotectors and mitigators can alleviate

radiation

induced

hematopoietic

toxicity and

improve

the

survival

rate.

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Supplementation with antioxidants before irradiation results in decreased apoptosis and TGF-β1

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mRNA expression in the bone marrow (Wambi et al. 2008). Surprisingly, Brown et al. indicated that antioxidant supplement diet administration starting at 24 hours after whole body irradiation

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with 8 Gy bring about a better survival when compared to sooner or later antioxidant

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administration started after the irradiation, and also before irradiation. The results indicated that mitigating of radiation injury is mediated by a reduction in ROS production and suppression of

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some pro-apoptosis pathways including MEK/ERK in bone marrow cells in response to

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increased levels of some cytokines and growth factors such as IL-3 and granulocyte-macrophage

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colony-stimulating factor (GM-CSF) (Brown et al. 2010). In another study, Sato et al. showed that the best survival with administration of ascorbic acid after exposure can be obtained at 12

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hours after whole body irradiation. This study showed that treatment with ascorbic acid after whole body irradiation with 7.5 Gy can reduce apoptosis in bone marrow cells and damage in

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hematopoietic function. Post-exposure treatment with ascorbic acid, ON 01210.Na (a chlorobenzylsulfone derivative) and antioxidant N-Acetyl-cysteine have shown ability to improve hematological parameters including peripheral white blood cell, platelet counts and GM-CFU counts. Also, supplements with these agents suppressed apoptotic cell death and DNA damage in bone marrow cells, and decreased inflammatory cytokines such as IL-1β, IL-6, IFN-γ

which are involved in ROS and RNS production (Jia et al. 2010; Suman et al. 2012; Sato T et al. 2015). The results of these studies indicated that ROS and RNS production after exposure to irradiation, that in itself is mediated with inflammatory responses or some other unknown pathways play a key role in acute radiation syndromes, genomic instability and maybe non-cancerous diseases.

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Improvement of survival rate by mitigators and antioxidants open a new window for

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management of side effects of radiotherapy and consequences of radiation accidents. Management of immune responses using appropriate supplements can improve lifesaving and

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decrease in chronic inflammation, cancer and non-cancerous diseases.

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Radiation dermatitis

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Radiation dermatitis (also known as radiodermatitis or radiation skin burning) is associated with

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epidermal basal cell and endothelial cell damage, commonly occurs following radiotherapy. Radiodermatitis can be divided into acute and chronic dermatitis. The most important changes

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associated with acute dermatitis are erythema, dry desquamation, and moist desquamation that result in epidermal necrosis, fibrinous exudates, pain and ulcer. Chronic detrimental changes

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induced by IR may develop during months to years after exposure. These pathological changes commonly included are hypopigmentation or hyperpigmentation, damage to hair follicles and sebaceous glands, persistent telangiectasia and fibrosis. The most serious chronic complication of radiation therapy on the skin is the development of ulceration during months to years after the end of treatment (Hymes et al. 2006; Salvo et al. 2010).

Evidences have remarked that radiation induced dermatitis affects approximately 95 percent of patients undergoing radiotherapy, especially patients with head and neck cancer, breast and lung malignancies (Ryan 2012). The mechanisms involved in radiation dermatitis and strategies for managing its side effects have been indicated in several studies. Studies have shown that inflammatory responses have a central role in dermatitis associated with radiotherapy. Acute

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radiodermatitis occurs within several hours to weeks after beginning of radiation treatment that is induced by initiation of inflammatory responses in the epidermis and dermis. Acute skin

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dermatitis is associated with vascular inflammation and vasodilation as well as swelling and

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sloughing of epithelial cells (Mancini and Sonis 2014; Arron 2016). Inflammatory responses are

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induced by structural tissue damage, necrosis and irreversible DSBs in nuclear and mitochondrial DNA. Severe inflammation after irradiation may result in a failure of the skin's barrier function

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and leads to bacterial infection (Flour 2009). Bacterial infections like Staphylococcus aureus can exacerbate dermatitis through activation of lymphocytes T and subsequent cytokine release (Hill

pt e

d

et al. 2004).

Previous studies have revealed that IL-1, IL-6, TNF-α, TGF-β, IL-8 and eotaxin are the major

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cytokines and chemokines that regulate the response of skin cells to IR (Müller and Meineke 2007). Janko et al. showed that IL-1 has an important role in the development of radiodermatitis.

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They showed that a lack of IL-1 or the IL-1 receptor in mice leads to less pathological changes in the skin. This study offered a potential therapeutic targeting of IL-1 for control of the severity of radiation dermatitis (Janko et al. 2012). The production of IL-1 in skin is primarily regulated by monocytes, macrophages, fibroblasts keratinocytes, and numerous other immune mediators. (Liu W et al. 2006; Janko et al. 2012).

In addition to inflammation, fibrosis process induced by TGF-β and other cytokines has an important role in promotion of chronic radiation dermatitis. Inhibition of TGF-β and Smad3 reduce scarring and local inflammatory infiltrate, and also accelerate wound healing process (Ashcroft and Roberts 2000; Flanders et al. 2002; Flanders et al. 2003; Flanders et al. 2008). Although, TGF-β is known as central player in the fibrotic process, other cytokines and growth

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factors such as IL-1, IL-4, IL-13, TNF-α , platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-1) and connective tissue growth factors (CTGF) are involved in this process

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in the skin (Martin et al. 2000).

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Several studies have been conducted to assess the outcome of different interventions such as

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administration of antioxidants, radioprotectors, corticosteroids, lotions, creams and antiinflammatory drugs for the prevention and management of radiodermatitis. However, many

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studies have not shown impressive results for antioxidants compared to anti-inflammatory

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agents. This may result in more important roles of immune responses than other factors such as

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direct effects of ROS produced by radiation. Halperin et al. in a randomized trial study have reported that there is no discernible benefit for administration of vitamin C to prevent radiation

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dermatitis (Halperin et al. 1993). However, the evaluation of the impact of amifostine against acute dermatitis for pelvic cancer patients showed that severity of dermatitis is significantly

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reduced in patients who have received amifostine (Kouvaris JR et al. 2001; Kouvaris J et al. 2002). In another study in a randomized, double-blind, controlled clinical trial radiotherapy, oral administration of curcumin showed that it can reduce the severity of dermatitis in breast cancer patients (Ryan et al. 2013). The effects in of radiation on skin reactions are thought to be caused by different changes such as vasoconstriction, reduced capillary permeability, and inhibition of leukocyte migration.

Inhibition of pro-inflammatory cytokines such as IL-1α/β, TNF-α, IL-6 and MCP-1, as well as TGF-β1 and COX-2 can improve the tolerance of skin to radiotherapy (Chen et al. 2010). Corticosteroids often prescribed in both the prevention and management of radiation dermatitis. Corticosteroids such as mometasonefuroate, emollient and betamethasone creams have shown to be effective in reducing acute radiation dermatitis during radiation therapy (Boström et al. 2001;

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Ulff et al. 2013). Beetz et al. suggested that corticosteroids through inhibition of IL-6 expression in irradiated human epithelial cells can reduce acute radiation dermatitis (BEETZ and P. KIND

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1997). Inhibition of COX-2 by celecoxib can reduce inflammation of the dermis, MCP-1 mRNA

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expression and skin damages in irradiated skin (Liang et al. 2003; Mohsen Cheki 2018). The

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targeting of TLR-5 showed a reduction in NF-κB expression and is effective in prevention of dermatitis in head and neck cancer patients that have undergone radiotherapy (Burdelya et al.

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2012). Evidences have demonstrated that using Aloe Vera gel improves radiation induced dermatitis and skin burning, and accelerates wound healing, especially for breast and head and

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neck cancer patients (Williams et al. 1996; Richardson et al. 2005; Atiba et al. 2011). Probably, anti-inflammatory effect of Aloe Vera gel has a key role in alleviation of skin toxicity (Yagi et

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al. 2002; Reuter et al. 2008). Mustafa et al. showed that administration of zinc reduces the severity of radiodermatitis and skin damage such as epidermal atrophy, dermal degeneration, and

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hair follicle atrophy in the rats. Moreover, administration of zinc can delay the start of dermatitis (Ertekin et al. 2004).

Role of inflammatory responses to radiation-induced digestive tract injury Digestive system complications are a limiting factor for patients undergoing radiotherapy for thoracic, abdominal, or pelvic malignancies. These complications may limit the completion of radiotherapy and may reduce efficiency of cancer treatment. Moreover, radiation induced acute

gastrointestinal injury is a life threatening sickness in people that have exposed to a heavy dose of IR (Elhammali et al. 2015). Oral, gastric and bowel are the main organs of the digestive system that can be affected by different complications of radiation and chemotherapy (Shadad Abobakr K. et al. 2013). Acute effects may be observed during or shortly after irradiation, while late effects are experienced months to years after irradiation (Lips et al. 2008). Mucositis and

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xerostomia in patients receiving radiotherapy for head and neck cancers are the most important oral complications. Moreover, gastritis, telangiectasias and bleeding in gastric, and also

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mucositis and fibrosis are the most common complications induced by radiation treatment in the

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intestine. It seems that inflammatory cytokines and some physiological changes are responsible

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for these acute and late symptoms following exposure to radiation.

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Oral

Oral complications during and after of radiotherapy of head and neck malignancies primarily are

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caused by the detrimental effects of IR on the mucosa and salivary glands in the oral cavity and

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oropharynx. These damages can lead to an inflammatory condition in the mucosa and periodontium called mucositis (Vissink, Burlage, et al. 2003). It seems that mucositis and

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xerostomia are the most common adverse effects of head and neck cancer radiotherapy (Vissink,

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Jansma, et al. 2003). Mucositis is the inflammation, ulceration and swelling of the mucous membranes lining the digestive system that affects the patients at the pelvis and head and neck after undergoing radiation therapy (Shih et al. 2003; Keefe 2007). The initiation of mucositis is caused by the production of cell transcription factors such as NF-κB, MAPKs, COX-1 and COX2 which upregulate inflammatory cytokines, such as IL-1, IL-2, IL-6, TNF-α, β-actin and matrix metalloproteinases (MMPs) 1 and 3. These processes lead to the destruction of the mucosa (Keskek et al. 2006; Yeoh et al. 2006; Logan et al. 2007; Ong et al. 2010). Mucositis can be

associated with salivary hypo-function, necrosis and subsequent removal of dental pulp, infection, loss of taste and necrosis of the jaw bone. These complications in oral cavity can be due to high turnover rates and radiosensitivity of cells in oral mucosa. Mucositis manifests initially as erythema and may develop with necrosis, ulceration, and bleeding (Springer et al. 2005; Sciubba and Goldenberg 2006; Shiboski et al. 2007).

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Meirovitz et al. showed a correlation between IL-6 and IL-8 serum levels and severity of oral

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mucositis during head and neck cancer treatment (Meirovitz et al. 2010). While a study has proposed that there is no relationship between low-grade oral mucositis induced by

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chemotherapy and the systemic plasma IL-8 level (Stokman et al. 2006). Also, a study has shown

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no correlation between IL-1 and TNF-α serum levels and oral mucositis grade (Seyyednejad et al. 2012). Studies have indicated that acute mucositis is caused by the massive death of basal

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cells, decrease in the number of epithelial cells, and inflammatory responses mediated by NF-κB,

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pro-inflammatory cytokines, inflammasome and the ceramide pathway (Sonis 2004, 2007).

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Moreover, endotoxins produced by resident bacteria on ulcerated surfaces may amplify the inflammatory responses induced by IR and enhance local injury (Donnelly et al. 2003).

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The use of immunomodulatory drugs, cytokines and radioprotectors (e.g. amifostine, glutamine),

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and also antibiotics have been of much interest in the management of radiation-induced mucositis from many years ago. Administration of GM-CSF, IL-11 and TGF-β have provided an effective treatment protocols for preventing oral mucositis in patients with head and neck carcinoma that undergo radiotherapy (Kannan et al. 1997; Rosso et al. 1997; Raber-Durlacher et al. 2013). Also, several clinical trial studies have shown that the use of amifostine can preserve tissue function and can reduce the severity and duration of mucositis and xerostomia (Symonds et al. 1996; Bourhis et al. 2000; Brizel et al. 2000; Savarese et al. 2003). Oritiz et al. showed that

melatonin, through protection of mitochondria against radiation induced oxidative damage and suppression of the NF-κB/NLRP3 inflammasome signaling pathway can prevent development of oral mucositis (Ortiz et al. 2015). The use of low-energy laser as a noninvasive technique is another modality for the acceleration of wound healing, and alleviation of pain and severity of oral mucositis during and after chemo/radiotherapy (Sandoval et al. 2003).

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Gastric

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IR-induced gastritis is a serious complication in radiation therapy and can cause chronic gastric

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inflammation and bleeding. The initial injury is characterized by acute inflammation of gastric mucosa. Although the pathogenesis of radiation-induced gastritis is not fully understood, it is

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thought that increased levels of inflammatory cytokines and growth factors are involved in this

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process. Some evidences have shown that TNFα, IL-1β, IL-21, and cyclooxygenases play a key role in the development of gastritis (Li GQ et al. 2006; Santos et al. 2012; Nishiura et al. 2013).

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The presence of Helicobacter pylori may be related to gastritis caused by radiation (Abrunhosa-

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Branquinho et al. 2015). Chronic radiation gastritis can cause the multiple telangiectasia and gastric bleeding usually during 2-7 months after treatment It is thought that acute vasculopathy

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may be involved in obliteration of endarteritis that leading to mucosal ulceration and bleeding. A

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similar sign is seen in the rectum, intestine, and bladder following pelvic irradiation (Grover and Johnson 1997). The long term duration of these symptoms results in anemia and tumor progression. But taking appropriate drugs can relieve the complications effectively (RodríguezLago et al. 2013). In addition to external radiotherapy, gastrointestinal injury is an important side effect of internal radiation therapy, systemic chemotherapy and chemoradiation therapy for hepatic tumor (Chon et al. 2011). Selective internal radiation therapy (SIRT) by yttrium-90 (Y-90), can provide more

effective treatment and less side effects compared to external beam radiation, while selectively providing local irradiation to the tumor or metastases. However, this protocol may cause gastrointestinal ulcer, cholecystitis, pancreatitis, bone marrow toxicity, and inflammation. Gastrointestinal complications are the most common complications compared to other organs that have been reported (Crowder et al. 2009). Mucosal ulceration caused by Y-90 is seen as

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necroinflammatory slough associated with granulated tissue that occurs mostly in the gastric antrum, pylorus, and duodenum (Konda et al. 2009; Zimmermann et al. 2009; Omed et al. 2010).

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Evidences have revealed that these side effects typically are caused by significant inflammatory

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responses (Naymagon et al. 2010). Argon plasma coagulation and administration of growth

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hormone and oral prednisolone (an anti-inflammatory drug) have shown ability to control bleeding caused by radiation-induced gastritis (Shukuwa et al. 2007; Zhang Lan et al. 2012; Yun

M

et al. 2015; Zhang Liang et al. 2015).

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Radiation Enteritis

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Radiation damage to the intestine occurs following whole body irradiation or radiotherapy of the abdomen and pelvis for gastrointestinal, urological and gynaecological cancers. Irradiation of

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these organs may cause acute and long term symptoms such as pain, nausea, diarrhea, weight

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loss, bloating, malabsorption, and rectal bleeding (Stacey and Green 2013; Abdollahi H. 2014; Abdollahi Hamid et al. 2015). These symptoms arise from massive tissue damage and inflammatory responses that reaches its peak at weeks 4 to 5. While the long term symptoms ranges to 30 years after exposure to radiation (Nguyen et al. 2002). Chronic radiation damages to bowel has been reported for 50% of patients receiving pelvic radiotherapy and characterized by inflammation, mucosal cell loss, crypt abscess and swelling of the endothelial lining of arterioles (Theis et al. 2010). Symptoms resulting from intestinal damage are mediated by immune

responses and chronic inflammation that are directly related to the radiation dose. These inflammatory responses may lead to mucositis in the gastrointestinal system (François et al. 2013). Alimentary tract mucositis is one of the most common side effects and dose-limiting factors for almost all patients undergoing radiation therapy and chemotherapy for gastrointestinal malignancies. Development of mucositis in the intestine arises from the cytotoxic effects of

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radiation on the basal cell of epithelium. These cells are vulnerable to the effects of IR because

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of their high mitotic index and cell turnover rate (Theis et al. 2010).

There are some suggestions that persistent oxidative stress is implicated in long term intestinal

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damages. Continuous ROS production correlates with upregulation of NADPH Oxidase and

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iNOS, and also increased mitochondria activity in intestine after exposure to radiation (Zhou H et al. 2008; Morgan and Liu 2011). Continuous oxidative damages can cause mutations and

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genomic instability in genes implicated in gastrointestinal carcinogenesis. This can lead to long-

d

term changes in intestinal stem cells dynamics (Datta et al. 2012).

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Use of anti-inflammatory cytokines and other modifiers such as amino acid supplementation, colony-stimulating factors, surgical and laser therapy have proposed for relief of the side effects

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of mucositis (Köstler et al. 2001; Regimbeau et al. 2001; Von Bültzingslöwen et al. 2006;

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Shadad Abobakr K et al. 2013). The short periods of use of growth factor and anti-inflammatory agents such as COX-2 and TNF-α inhibitors, growth factors like TGF-β, IL-1, IL-11, stem cell factor, keratinocyte growth factors, fibroblast growth factor, acidic and basic fibroblast growth factors FGFs, VEGF, and IGF-1 appear to ameliorate intestinal toxicity by reduction of early and late alimentary tract mucosal complications (Okunieff et al. 2005). As well as inhibition of NFκB, COX-2, iNOS and NADPH Oxidase can decrease normal tissue damages and enhance the tumor response to treatment (Erbil et al. 2006; Murakami and Ohigashi 2007; Yi et al. 2014).

A study showed that pre-treatment with ascorbic acid before the whole body irradiation with 13Gy can cause 20% survival compared to 0% survival without ascorbic acid administration. A combination of administration of ascorbic acid pre and post-irradiation leads to 100% survival. Immunohistochemistry analysis showed an increase of TNF-α level in the intestinal tissue and IL-6 in the plasma. This study suggested that TNF-α induced inflammatory responses (but not

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IL-1β or IL-6) have a key role in radiation-induced intestinal oxidative injury and radiation gastrointestinal syndrome. A combination of administration of ascorbic acid pre and post-

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irradiation could significantly reduce TNF-α level and free radical metabolite levels in the small

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intestine. Authors proposed that the boosting pre-treatment associated with post irradiation

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treatment by ascorbic acid is necessary to scavenging of ROS generated after irradiation (Ito et al. 2013).

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Another important side effect of radiotherapy on intestine is fibrosis. TGF-β signaling through the Rho/Rock and Smad3 pathways is involved in the development of sustained fibrogenic

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differentiation and small intestinal fibrosis after irradiation (Haydont et al. 2005; Zhu et al. 2011). Bourgier et al. reported that the intestinal cells isolated from radiation enteritis exhibit a

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high CTGF level, increased collagen secretory capacity and expression of Rho family. Authors proposed that the inhibition of this signaling pathway can protect intestinal fibrosis against

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radiation exposure (Bourgier C et al. 2005). Proctitis

Proctitis refers to inflammation of the lower parts of the colon including primarily, the sigmoid colon and the rectum. Acute radiation proctitis most commonly occurs in the first few weeks and chronic proctitis begin several months to years after radiation therapy such as external radiotherapy and brachytherapy for pelvic cancers such as prostate, cervical and colon cancers.

Acute radiation proctitis results from direct damage of the epithelium but chronic proctitis occurs because of damage to the blood vessels, especially the small vessels which supply the cells of the sigmoid colon and the rectum. The most important mechanisms involved in the development of chronic radiation proctitis are long term inflammation and free radical production (Do et al. 2011). Indaram et al. indicated that the mucosal levels of IL-2, IL-6, and IL-8 are abnormally

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high in patients with proctitis that have undergone radiation therapy (Indaram et al. 2000). Although, early changes may not lead to obvious symptoms but If inflammation progresses, it

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may evolve to mucosal ulceration, ischemia, ulceration, telangiectasia and bleeding, which can

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extend decreasing blood cells in patients that underwent radiotherapy (Grover and Johnson

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1997).

The inhibition of prostaglandin synthesis with administration of anti-inflammatory agents such

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as mesalamine, prednisone, betamethasone, hydrocortisone, and metronidazole alleviates chronic proctitis (Do et al. 2011). It is thought that free radical production during long term inflammation

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is one of the most important mechanisms involved in the development of chronic radiation proctitis (Do et al. 2011). The use of radioprotectors and antioxidants is another modality for

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amelioration of long lasting adverse effects of radiation treatment on the lower bowel and rectum. The randomized trials have proposed that pretreatment with amifostine can reduce

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toxicity in the lower bowel and rectum in patients undergoing radiotherapy for pelvic cancers without tumor protection (Liu T et al. 1992; Athanassiou et al. 2003). Moreover, the use of antioxidants agents such as vitamin A, E and C have shown ability to decrease the rate of proctitis symptoms such as hemorrhage, diarrhea and urgency (Kennedy et al. 2001; Patel et al. 2009).

Radiation induced lung injury The lung is a radiosensitive organ, especially for late effects of radiotherapy such as pneumonitis and fibrosis. On the other hand, lung cancer is one of the most common malignancies among cancer patients. Moreover, more than 60% of all patients with lung cancer needs radiation therapy for their disease (Tyldesley et al. 2001). It was estimated that up to 30% of patients with

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non-small cell lung carcinoma (NSCLC) are needed for management of lung tissue toxicity

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(Kong et al. 2006; Schallenkamp et al. 2007). So, a knowledge of the mechanisms of lung injury following radiation treatment is necessary for management of complications that are associated

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with radiotherapy.

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Pneumonitis as one of two important detrimental effects of radiation therapy on lung tissue, usually appears during 1 to 6 months after treatment. The most important symptoms of radiation

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induced pneumonitis consist of chest pain, dyspnea congestion and cough (Wang S et al. 2006).

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Pneumonitis is an acute reaction of lung to high doses of IR that is mediated by inflammatory

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cells. Macrophages, mast cells and lymphocytes play a key role in this phenomena. These cells secrete inflammatory cytokines such as IL-1, IL-4, IL-6, IL-13 and TNF-α that are responsible

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for appearance of lung pneumonitis (Ward PA and Hunninghake 1998; Wirsdörfer and Jendrossek 2016).

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Another important side effect of radiotherapy in the lung is fibrosis that occurs during months to years after radiotherapy. Fibrosis is characterized by deposition of collagen, damage to vascular structure and change in normal function of lung that may threaten the life of patients (Yarnold and Brotons 2010). Targeting of IL-4 and IL-13 is deemed strategic for management of lung fibrosis (Chung Su I. et al. 2016; Groves et al. 2016). Moreover, management of NF-κB, COX-2 and inflammatory cytokines have been suggested for this aim. So, several studies have evaluated

different antioxidants, radioprotectors and mitigators for amelioration of lung toxicity following exposure to radiation. Melatonin has shown a protective effect on inflammatory responses and pathological damage induced by radiation (Tahamtan et al. 2015; M. Najafi 2017; Najafi M et al. 2017). Natural antioxidants have attracted much interests for the management of radiation toxicity in the lung. Some herbal compounds such as hesperidin, curcumin, soy isoflavones and

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silibinin have been brought to our notice as radioprotective agents for amelioration of oxidative damage and pathological changes after exposure to radiation (Lee JC et al. 2010; Cho et al. 2013;

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Hillman et al. 2013; Son et al. 2015; Rezaeyan A. et al. 2016; Haddadi GH 2017).

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Radiation induced heart diseases

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Heart disease is one of the most common diseases and one of the main causes of mortality in the

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general population (Yusuf et al. 2001). The most common types of heart disease are inflammation, fibrosis, atherosclerosis and also diseases related to coronary and carotid arteries

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(Hansson 2005). There is a large body of data related to A-bomb survivors in Hiroshima and

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Nagasaki which reported significant increases in heart diseases (Chai Y et al. 2012; Chai Y et al. 2013). Moreover, Heart diseases in patients having undergone radiotherapy to treat breast cancer

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have had a significant rise. Heart diseases in this population is higher than the general population

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and it is one of the major causes of death during long years after the treatment. The incidence of these diseases was related to the radiation dose received by individuals and other risk factors for heart disease such as blood cholesterol and obesity (Bestor 2000; Bird 2009; Bonasio et al. 2010). The most important heart damages due to radiotherapy have been reported in the form of cardiac fibrosis, coronary and carotid vascular injury, atherosclerosis, heart valves disease and etc., that result in high incidence of heart attacks among people who had been exposed. These

complications lead to an increase in mortality among patients that have undergone radiotherapy (Zaratiegui et al. 2007). Mechanisms of heart disease due to exposure to radiation are not fully understood; although, symptoms are similar to those of other causes of heart diseases. Nevertheless, studies have suggested that immune system cells have a central role in cardiovascular disorders after exposure

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to IR. After heart irradiation, pericardium is the most sensitive area that is damaged. The main

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type of complication seen in this area is fibrosis (Zaratiegui et al. 2007). Fibrosis can interfere with blood supply and increase the probability of ischemia and heart attack (MOSLEMI and

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MOTEVALIZADEH 2009). The main factors that are involved in cardiovascular fibrosis due to

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radiation exposure are TGF-β and IL-1β. Increased level of these cytokines, especially TGF-β steadily continues for many years after exposure to acute radiation (Najafi M. et al. 2014). In

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addition to NO production, these cytokines can increase the production of collagen in the tissues

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that is the main cause of fibrosis after exposure to radiation (Das and Singal 2004; Bonasio et al.

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2010). Thus, high levels of TGF-β in cancer radiotherapy patients, which typically occur, may cause damages to the coronary arteries function. All of these changes augment the risk of heart

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ischemia and stroke during the years after radiotherapy (Kalinich et al. 1989).

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Mast cells are one of the most important immune cells that play an important role in radiationinduced heart diseases. There is a clear evidence that mast cells are involved in some heart problems such as inflammation, atherosclerosis, fibrosis and myocardial degeneration, resulting in tissue remodeling and increased risk of heart failure (Boerma et al. 2005). Abnormal increase in the numbers of these cells have been reported after exposure to thoracic irradiation (Ward WF et al. 1990). Moreover, mast cells hyperplasia upregulates the expression of genes such as endothelin-1 (ET-1). ET-1 is a powerful vasoconstrictor peptide that promotes inflammation and

fibrosis. Long term overexpression of ET-1 causes cardiac hypertrophy leading to many forms of heart disease, including hypertension, valvar disease and heart failure (Frey et al. 2004). Some radioprotectors such as melatonin and hesperidin have been recommended for amelioration of heart damage induced by IR (Gurses et al. 2014; Rezaeyan Abolhasan et al. 2016).

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Radiation myelopathy

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Radiation myelopathy is a detrimental effect of radiation on spinal cord that is characterized by

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white matter lesions. Based on clinical observations, myelopathy after exposure to high doses of

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radiotherapy occurs at two distinct clinical entities. Early delayed injury occurs during 2 to 4 months after exposure and is characterized by extremities upon neck flexion. However, this

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damage heals after a few months completely (Mul et al. 2012). In contrast to early radiation

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myelopathy, late myelopathy induced by radiation is typically permanent and irreversible. The symptoms of late myelopathy are very different including reactive gliosis, demyelination and

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diagnosis (Wong C. S. et al. 1994).

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white matter necrosis that may lead to death of irradiated patients up to 5 years after the date of

Mechanisms of radiation induced myelopathy is not completely recognized. A few studies have

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reported that massive necrosis over a long time after radiation plays a key role in this

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phenomena. It is well established that upregulation of genes involved in hypoxia such as HIF1-α and VEGF are implicated in necrosis of white matter. Upregulation of hypoxia-inducible factor 1-alpha (HIF1-α), VEGF, matrix metalloprotease-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1) are associated with disruption of blood spinal cord barrier that lead to necrosis (Tsao et al. 1999; Li YQ et al. 2001; Nordal and Wong 2004; Lee JY et al. 2012).

Targeting factors involved in hypoxia and inflammation are promising strategies for mitigation of radiation induced myelopathy. Suppression of TNF-α and ICAM-1 seem to be able to ameliorate inflammation and permeability in a rat cranial (Yuan et al. 2003). Also, amelioration of prostaglandins production by melatonin have shown promising results (Aghazadeh et al. 2007; Shirazi et al. 2009; Haddadi et al. 2013; Rasoul et al. 2017). In clinical studies, inhibition of

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VEGF has improved symptoms of myelopathy in radiotherapy patients (Chamberlain et al. 2011;

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Psimaras et al. 2016).

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Conclusion

As stated in this review, inflammation is responsible for several side effects and disorders that

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are seen in association with radiotherapy or radiation accident. IR causes upregulation and

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downregulation of several cytokines and immune mediators. Exposure to high doses of IR such as those seen in radiotherapy cause stimulation of inflammatory and anti-inflammatory reactions.

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Both of these reactions are responsible for most of radiotherapy complications. Although the

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exact mechanisms of some disorders such as diabetes after exposure to radiation remain to be elucidated, it seems that inflammatory reactions are involved. Use of some mitigators such as

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herbal agents has borne satisfactory results. However, selecting an appropriate radioprotector

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mitigator for a specified organ depends on the mechanisms involved in radiation response in that organ. Hence, a knowledge of radiation response to IR in different organs is useful for the management of detrimental effects of radiotherapy.

The authors report no conflicts of interest

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