Fisher Bernard J, Kraskauskas Donatas, Martin Erika J, Farkas Daniela, Puri Puneet, Massey H Davis, Idowu Michael O, Brophy Donald F, Voelkel Norbert F, Fowler Alpha A, Natarajan Ramesh
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, Virginia, USA.
JPEN J Parenter Enteral Nutr. 2014 Sep;38(7):825-39. doi: 10.1177/0148607113497760. Epub 2013 Aug 5.
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.
Unlike mice, humans lack the ability to synthesize VitC because of loss of L-gulono-γ-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.
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.
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.
多器官功能障碍综合征（MODS）是脓毒症患者死亡的主要原因。最近的研究支持肠外维生素C（VitC）通过多效性机制对脓毒症具有保护作用的观点。循环中VitC水平不足是否会增加脓毒症诱导的MODS易感性尚不清楚。
与小鼠不同，由于维生素C生物合成的最后一种酶L-古洛糖酸-γ-内酯氧化酶（Gulo）缺失，人类缺乏合成VitC的能力。为了研究防御灾难性感染是否需要生理水平的VitC，我们通过腹腔注射粪便菌液（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FIP诱导后30分钟接受肠外注射抗坏血酸（AscA，200mg/kg）。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情况。
FIP在VitC缺乏的Gulo（-/-）小鼠中导致肺、肾和肝损伤（MODS）。在暴露于FIP的VitC充足的Gulo（-/-）小鼠中未出现明显的MODS，而在注射AscA的VitC缺乏的Gulo（-/-）小鼠中MODS有所减轻。脓毒症VitC缺乏的Gulo（-/-）小鼠在凝血系统和循环血细胞中出现显著异常。脓毒症Gulo（-/-）小鼠中VitC充足/注射可减轻这些异常。
VitC缺乏的Gulo（-/-）小鼠对脓毒症诱导的MODS更易感。脓毒症诱导后，VitC充足或肠外注射VitC可使生理功能恢复正常，减轻脓毒症中MODS的发展。
