Exacerbation of Mild Hypoxia on Acute Radiation Syndrome and Subsequent Mortality.
Exacerbation of Mild Hypoxia on Acute Radiation Syndrome and Subsequent Mortality.
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DOI：
10.4247/am.2017.abg170
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发表时间：
2017-01-01
期刊：
影响因子：
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通讯作者：
Kiang, Juliann G
中科院分区：
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作者：
Kiang, Juliann G
20%出血引起的轻度缺氧导致血液中少量细胞因子浓度和硬化素水平升高，但骨形成、骨髓细胞结构和胃肠道（GI）完整性没有变化，没有系统性细菌感染，也没有随后的死亡。另一方面，40%出血引起的严重缺氧导致大多数细胞因子浓度显著升高，胃肠道损伤、肺损伤、全身细菌感染、细胞ATP减少和随后的死亡。严重缺氧严重损害胃肠道和肺部形态，升高血液中细胞因子浓度，增加细胞中诱导型一氧化氮合酶（iNOS）的表达，这是由转录因子NF-kappaB/NF-IL6介导的，随后产生破坏线粒体的自由基。发现ATP耗竭、p53磷酸化、caspase-3活化，提示细胞凋亡。因此，死亡率出现了。然而，当电离辐射后轻度缺氧时，轻度缺氧显著增加辐射致死亡率和急性辐射综合征，包括骨髓、胃肠道、肾脏和肺损伤。这种协同作用也发生在分子水平上，导致microrna改变、iNOS表达扩增、细胞因子增加、脓毒症和ATP耗竭。这是首次证明轻度缺氧和电离辐射之间的协同效应。
Mild hypoxia induced by 20% hemorrhage results in increases in few cytokine concentrations and sclerostin levels in blood, but shows no changes in bone formation, bone marrow cellularity, and gastrointestinal (GI) integrity and no systemic bacterial infection as well as no subsequent mortality. On the other hand, severe hypoxia induced by 40% hemorrhage causes significant increases in most cytokine concentrations, GI injury, lung injury, systemic bacterial infection, cellular ATP reduction and subsequent mortality. The severe hypoxia drastically damages GI and lung morphology, elevates cytokine concentrations in blood and increases inducible nitric oxide synthase (iNOS) expression in cells that is mediated by transcription factors NF-kappaB/NF-IL6, subsequently producing free radicals that disrupt mitochondria. ATP depletion, p53 phosphorylation, and caspase-3 activation are found, suggesting cell apoptosis. As a result, mortality occurs. However, when mild hypoxia follows ionizing radiation, the mild hypoxia significantly enhances radiation-induced mortality and acute radiation syndrome, including injury of bone marrow, GI, kidney, and lung. The synergism also occurs at the molecular level, resulting in alteration of microRNAs, amplification of iNOS expression, cytokine increases, sepsis, and ATP depletion. This is the first demonstration of synergistic effects between mild hypoxia and ionizing radiation.