Abstract
Radiation-induced endothelial/vascular injury is a major complicating factor in radiotherapy and a leading cause of morbidity and mortality in nuclear or radiological catastrophes. Exposure of tissue to ionizing radiation (IR) leads to the release of oxygen radicals and proteases that result in loss of endothelial barrier function and leukocyte dysfunction leading to tissue injury and organ damage. Microvascular endothelial cells are particularly sensitive to IR and radiation-induced alterations in endothelial cell function are thought to be a critical factor in organ damage through endothelial cell activation, enhanced leukocyte-endothelial cell interactions, increased barrier permeability and initiation of apoptotic pathways. These radiation-induced inflammatory responses are important in early and late radiation pathologies in various organs. A better understanding of mechanisms of radiation-induced endothelium dysfunction is therefore vital, as radiobiological response of endothelium is of major importance for medical management and therapeutic development for radiation injuries. In this review, we summarize the current knowledge of cellular and molecular mechanisms of radiation-induced endothelium damage and their impact on early and late radiation injury. Furthermore, we review established and emerging in vivo and in vitro models that have been developed to study the mechanisms of radiation-induced endothelium damage and to design, develop and rapidly screen therapeutics for treatment of radiation-induced vascular damage. Currently there are no specific therapeutics available to protect against radiation-induced loss of endothelial barrier function, leukocyte dysfunction and resulting organ damage. Developing therapeutics to prevent endothelium dysfunction and normal tissue damage during radiotherapy can serve as the urgently needed medical countermeasures.
【저자키워드】 thrombomodulin, Neutrophil extracellular traps, interleukin-1, cardiovascular disease, Gastrointestinal, Central nervous system, reactive oxygen species, Endothelial cell, tight junctions, major histocompatibility complex, macrophage colony-stimulating factor, platelet activating factor, stereotactic radiosurgery, acute radiation syndrome, CNSCentral Nervous System, CVDCardiovascular disease, PAI-1plasminogen activator inhibitor type 1, plasminogen activator inhibitor type 1, TMthrombomodulin, MHCMajor Histocompatibility Complex, TNF-αtumor necrosis factor-α, tumor necrosis factor-α, PDGFplatelet-derived growth factor, platelet-derived growth factor, ROSreactive oxygen species, IL-1interleukin-1, NETsNeutrophil Extracellular Traps, White blood cells, G-CSFgranulocyte-colony stimulating factor, granulocyte-colony stimulating factor, IRionizing radiation, ionizing radiation, TBItotal body irradiation, total body irradiation, ARSAcute radiation syndrome, AJAdherens junctions, Adherens junctions, ATMAtaxia telangiectasia-mutated, Ataxia telangiectasia-mutated, bMFAbiomimetic microfluidic assay, biomimetic microfluidic assay, DAMPDamage-associated molecular patterns, Damage-associated molecular patterns, GM-CSFGranulocyte/Macrophage Colony Stimulating Factor, Granulocyte/Macrophage Colony Stimulating Factor, GIGastrointestinal, GGAGeranylgeranylacetone, Geranylgeranylacetone, HUVECHuman umbilical vein endothelial cells, Human umbilical vein endothelial cells, ICAM-1Intercellular adhesion molecule 1, Intercellular adhesion molecule 1, ECEndothelial cell, JAK1Janus kinase 1, Janus kinase 1, JAM-CJunctional adhesion molecule-C, Junctional adhesion molecule-C, LETLinear energy transfer, Linear energy transfer, M-CSFmacrophage colony-stimulating factor, MnSODManganese-dependent superoxide dismutase, Manganese-dependent superoxide dismutase, MPSMicrophysiological systems, Microphysiological systems, PAFPlatelet activating factor, PKCδProtein Kinase C-delta, Protein Kinase C-delta, SRSStereotactic radiosurgery, TEERTransendothelial electrical resistance, Transendothelial electrical resistance, TGFβTransforming Growth Factor-Beta, Transforming Growth Factor-Beta, TJTight junctions, TYK2Tyrosine Kinase 2, Tyrosine Kinase 2, WBCWhite blood cells, WMDWeapons of mass destruction, Weapons of mass destruction, 【초록키워드】 Treatment, pathology, knowledge, protease, Endothelium, Radiotherapy, management, therapeutic, morbidity and mortality, in vivo, Critical, mechanism, Inflammatory response, Injury, Vascular damage, exposure, tissue injury, apoptotic pathways, leukocyte, cell interactions, dysfunction, Radiation, endothelial, Activation, Medical countermeasures, tissue, tissue damage, alteration, organ damage, organs, in vitro model, nuclear, Prevent, radiological, PROTECT, thought, resulting, develop, Developing, cellular and molecular, oxygen radical, 【제목키워드】 Endothelium,