Targets for protection and mitigation of radiation injury

Abstract

Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in clinical and environmental radiobiology. Investigations in recent decades have suggested potential targets that are involved in the protection against radiation-induced damages to normal tissues and can be proposed for mitigation of radiation injury. Emerging evidences have been shown to be in contrast to an old dogma in radiation biology; a major amount of reactive oxygen species (ROS) production and cell toxicity occur during some hours to years after exposure to ionizing radiation. This can be attributed to upregulation of inflammatory and fibrosis mediators, epigenetic changes and disruption of the normal metabolism of oxygen. In the current review, we explain the cellular and molecular changes following exposure of normal tissues to ionizing radiation. Furthermore, we review potential targets that can be proposed for protection and mitigation of radiation toxicity.

Keywords: Acute radiation syndrome (ARS); Fibrosis; Inflammation; Mitigation; Mitochondria; Normal tissue injury; Pneumonitis; ROS; Radiation; Redox.

Fig. 1

Apoptosis pathways after exposure to ionizing radiation. Exogenous and endogenous ROS trigger upregulation of apoptosis receptors which cause Bax upregulation and downregulation of Bcl-2. DNA damage and p53 also have key roles in the initiation of apoptosis signaling pathways. Apoptosis clearance by macrophages leads to their activation and is associated with NO generation. NO can interact with Ogg1, a key player in BER pathway, thus suppresses DDR. Neutralization of NO can boost DDR, thus reduces apoptosis. Furthermore, activation of TLR4&5 can increase the expression of NF-κB, leading to inhibition of Bax and upregulation of Bcl-2. P38 has a negative role and its suppression can preserve cell viability

Fig. 2

Radiation-induced senescence triggers the activity of pro-oxidant enzymes and fibrosis

Fig. 3

Inflammatory responses following exposure to ionizing radiation. Necrosis, necroptosis or autophagy can induce inflammatory responses following the release of DAMPs. NF-κB is a central regulator of inflammatory responses via triggering the release of cytokines and upregulation of COX-2 and iNOS. NF-κB also induces the development of inflammasome. Increased levels of inflammatory cytokines, iNOS and COX-2 amplify oxidative stress and DNA damage, which lead to continuous expression of NF-κB. The positive feedback between inflammatory cytokines, oxidative stress and transcription factors like NF-κB can cause chronic inflammation many years after exposure to radiation. Disruption of this crosstalk can mitigate radiation injury

Fig. 4

Mechanisms of radiation-induced redox metabolism and its role in the progression of radiation-induced normal tissue injury

Fig. 5

Suitable timelines for the mitigation of radiation injury in different organs. Each target may need a specific time in each organ. Information for some targets such as COX-2 require further studies. Furthermore, each antioxidant or anti-inflammatory agent may lead to different results, maybe because of their effects on other mechanisms. This timing is based on information adopted from animal studies