Redox Interactions in Chemo/Radiation Therapy-induced Lung Toxicity; Mechanisms and Therapy Perspectives

Abstract

Abstract: Lung toxicity is a key limiting factor for cancer therapy, especially lung, breast, and esophageal malignancies. Radiotherapy for chest and breast malignancies can cause lung injury. However, systemic cancer therapy with chemotherapy may also induce lung pneumonitis and fibro-sis. Radiotherapy produces reactive oxygen species (ROS) directly via interacting with water mole-cules within cells. However, radiation and other therapy modalities may induce the endogenous generation of ROS and nitric oxide (NO) by immune cells and some nonimmune cells such as fi-broblasts and endothelial cells. There are several ROS generating enzymes within lung tissue. NADPH Oxidase enzymes, cyclooxygenase-2 (COX-2), dual oxidases (DUOX1 and DUOX2), and the cellular respiratory system in the mitochondria are the main sources of ROS production follow-ing exposure of the lung to anticancer agents. Furthermore, inducible nitric oxide synthase (iNOS) has a key role in the generation of NO following radiotherapy or chemotherapy. Continuous genera-tion of ROS and NO by endothelial cells, fibroblasts, macrophages, and lymphocytes causes apop-tosis, necrosis, and senescence, which lead to the release of inflammatory and pro-fibrosis cyto-kines. This review discusses the cellular and molecular mechanisms of redox-induced lung injury following cancer therapy and proposes some targets and perspectives to alleviate lung toxicity.