Attenuation of Sepsis-Induced Organ Injury in Mice by Vitamin C
Attenuation of Sepsis-Induced Organ Injury in Mice by Vitamin C
复制标题
DOI：
10.1177/0148607113497760
复制
发表时间：
2014-09-01
影响因子：
3.4
通讯作者：
Natarajan, Ramesh
中科院分区：
文献类型：
--
作者：
Fisher, Bernard J.;Kraskauskas, Donatas;Natarajan, Ramesh
背景：多器官功能障碍综合征（MODS）是脓毒症患者死亡的主要原因。最近的工作支持的概念，肠外维生素C（VitC）是通过多效性机制在脓毒症的保护。次优水平的循环VitC是否会增加脓毒症诱导的MODS的易感性尚不清楚。材料与方法：与小鼠不同，人类缺乏合成维生素C的能力，因为L-古洛糖酸-内酯氧化酶（Gulo），维生素C生物合成的最后一种酶的损失。为了检查是否需要生理水平的VitC来防御灾难性感染，我们通过腹腔内输注粪便干溶液（FIP）在VitC充足和VitC缺乏的Gulo（-/-）小鼠中诱导脓毒症。一些VitC缺乏的Gulo（-/-）小鼠在诱导FIP后30分钟接受抗坏血酸（AscA，200 mg/kg）的胃肠外输注。我们使用分子、组织学和生化分析来评估MODS以及凝血系统和循环血细胞的异常。结果：FIP可引起VitC缺乏Gulo（-/-）小鼠肺、肾、肝的损伤（MODS）。MODS在FIP暴露的VitC充足的Gulo（-/-）小鼠中不明显，并且在输注AscA的VitC缺乏的Gulo（-/-）小鼠中减弱。脓毒症VitC缺陷Gulo（-/-）小鼠在凝血系统和循环血细胞中出现显著异常。在败血症Gulo（-/-）小鼠中，这些通过VitC充足/输注而减弱。结论：VitC缺乏的Gulo（-/-）小鼠更易发生脓毒症所致的MODS。诱导脓毒症后，维生素C充足或静脉输注维生素C可使生理功能正常化，从而减轻脓毒症中MODS的发展。
Background: Multiple organ dysfunction syndrome (MODS) is the principal cause of death in patients with sepsis. Recent work supports the notion that parenteral vitamin C (VitC) is protective in sepsis through pleiotropic mechanisms. Whether suboptimal levels of circulating VitC increase susceptibility to sepsis-induced MODS is unknown. Materials and Methods: Unlike mice, humans lack the ability to synthesize VitC because of loss of L-gulono--lactone oxidase (Gulo), the final enzyme in the biosynthesis of VitC. To examine whether physiological levels of VitC are required for defense against a catastrophic infection, we induced sepsis in VitC sufficient and VitC deficient Gulo(-/-) mice by intraperitoneal infusion of a fecal stem solution (FIP). Some VitC deficient Gulo(-/-) mice received a parenteral infusion of ascorbic acid (AscA, 200 mg/kg) 30 minutes after induction of FIP. We used molecular, histological, and biochemical analyses to assess for MODS as well as abnormalities in the coagulation system and circulating blood cells. Results: FIP produced injury to lungs, kidneys and liver (MODS) in VitC deficient Gulo(-/-) mice. MODS was not evident in FIP-exposed VitC sufficient Gulo(-/-) mice and attenuated in VitC deficient Gulo(-/-) mice infused with AscA. Septic VitC deficient Gulo(-/-) mice developed significant abnormalities in the coagulation system and circulating blood cells. These were attenuated by VitC sufficiency/infusion in septic Gulo(-/-) mice. Conclusions: VitC deficient Gulo(-/-) mice were more susceptible to sepsis-induced MODS. VitC sufficiency or parenteral infusion of VitC, following induction of sepsis, normalized physiological functions that attenuated the development of MODS in sepsis.