title: Protracted Oxidative Alterations in the Mechanism of Hematopoietic Acute Radiation Syndrome.
abstract: The biological effects of high-dose total body ionizing irradiation [(thereafter, irradiation (IR)] are attributed to primary oxidative breakage of biomolecule targets, mitotic, apoptotic and necrotic cell death in the dose-limiting tissues, clastogenic and epigenetic effects, and cascades of functional and reactive responses leading to radiation sickness defined as the acute radiation syndrome (ARS). The range of remaining and protracted injuries at any given radiation dose as well as the dynamics of post-IR alterations is tissue-specific. Therefore, functional integrity of the homeostatic tissue barriers may decline gradually within weeks in the post-IR period culminating with sepsis and failure of organs and systems. Multiple organ failure (MOF) leading to moribundity is a common sequela of the hemotapoietic form of ARS (hARS). Onset of MOF in hARS can be presented as "two-hit phenomenon" where the "first hit" is the underlying consequences of the IR-induced radiolysis in cells and biofluids, non-septic inflammation, metabolic up-regulation of pro-oxidative metabolic reactions, suppression of the radiosensitive hematopoietic and lymphoid tissues and the damage to gut mucosa and vascular endothelium. While the "second hit" derives from bacterial translocation and spread of the bacterial pathogens and inflammagens through the vascular system leading to septic inflammatory, metabolic responses and a cascade of redox pro-oxidative and adaptive reactions. This sequence of events can create a ground for development of prolonged metabolic, inflammatory, oxidative, nitrative, and carbonyl, electrophilic stress in crucial tissues and thus exacerbate the hARS outcomes. With this perspective, the redox mechanisms, which can mediate the IR-induced protracted oxidative post-translational modification of proteins, oxidation of lipids and carbohydrates and their countermeasures in hARS are subjects of the current review. Potential role of ubiquitous, radioresistant mesenchymal stromal cells in the protracted responses to IR and IR-related septicemia is also discussed.
authors.affiliation: Department of Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. Nikolai.Gor@USUHS.edu.
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Gorbunov
authors.affiliation: Department of Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Pushpa
authors.initials: P
authors.lastname: Sharma
keywords: carbonylation; electrophilic stress; hematopoietic acute radiation syndrome; homeostatic tissue barriers; intracranial hemorrhage; ionizing radiation; nitration; non-targeted epigenetic and clastogenic effects; radiation-induced oxidation; vascular injury