Inflammation and Chronic Oxidative Stress in Radiation-Induced Late Normal Tissue Injury: Therapeutic Implications

Abstract

The threat of radiation-induced late normal tissue injury limits the dose of radiation that can be delivered safely to cancer patients presenting with solid tumors. Tissue dysfunction and failure, associated with atrophy, fibrosis and/or necrosis, as well as vascular injury, have been reported in late responding normal tissues, including the central nervous system, gut, kidney, liver, lung, and skin. The precise mechanisms involved in the pathogenesis of radiation-induced late normal tissue injury have not been fully elucidated. It has been proposed recently that the radiation-induced late effects are caused, in part, by chronic oxidative stress and inflammation. Increased production of reactive oxygen species, which leads to lipid peroxidation, oxidation of DNA and proteins, as well as activation of pro-inflammatory factors has been observed in vitro and in vivo. In this review, we will present direct and indirect evidence to support this hypothesis. To improve the long-term survival and quality of life for radiotherapy patients, new approaches have been examined in preclinical models for their efficacy in preventing or mitigating the radiation-induced chronic normal tissue injury. We and others have tested drugs that can either attenuate inflammation or reduce chronic oxidative stress in animal models of late radiation-induced normal tissue injury. The effectiveness of renin-angiotensin system blockers, peroxisome proliferator-activated receptor (PPAR) gamma agonists, and antioxidants/antioxidant enzymes in preventing or mitigating the severity of radiation-induced late effects indicates that radiation-induced chronic injury can be prevented and/or treated. This provides a rationale for the design and development of anti-inflammatory-based interventional approaches for the treatment of radiation-induced late normal tissue injury.

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

“…Our observation on the importance of upregulation of the antioxidant enzyme SOD1 for MSC-mediated protection supports the current hypothesis that late pulmonary fibrosis develops from early damage to resident lung cells and that this early damage involves radiation-induced oxidative stress (29,48,80,87). Oxidative stress as a consequence of chemotherapy or radiotherapy or tissue inflammation promotes tissue damage, including damage to the vasculature by activating a series of signaling pathways (47,65).…”

Association between Mitochondrial Bioenergetics and Radiation- Related Fatigue: A Possible Mechanism and Novel Target

“…Moreover, changes in gene expression in peripheral leukocytes have been seen in fatigue cancer patients receiving XRT [18,33]. Reactive oxygen species (ROS) are considered one of the major direct causes of ionizing radiation-induced damage [34], resulting in a number of adverse effects including fatigue [35].…”

Moyamoya Syndrome Associated With Gamma Knife Surgery for Cerebral Arteriovenous Malformation

“…Therefore, direct radiation injury may not be the main cause of moyamoya syndrome after GKS for AVM. Recently, radiation therapy was suggested to induce chronic oxidative stress and inflammation, 18) and irradiated tissue may undergo long-term changes in the expression of cytokines and growth factors. 5) The guidelines of research on intractable diseases of the Ministry of Health Labour and Welfare, Japan, suggest that inflammation leads to moyamoya syndrome.…”