TNF binding protein prevents hyperlactatemia and inactivation of PDH complex in skeletal muscle during sepsis.
TNF binding protein prevents hyperlactatemia and inactivation of PDH complex in skeletal muscle during sepsis.
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DOI：
10.1006/jsre.1998.5324
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发表时间：
1998-11
期刊：
影响因子：
--
通讯作者：
T. Vary;S. Hazen;G. Maish;R. Cooney
中科院分区：
文献类型：
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作者：
T. Vary;S. Hazen;G. Maish;R. Cooney
背景技术高乳酸血症是代谢亢进、高动力性脓毒症的代谢并发症。脓毒症中血浆乳酸浓度升高的一个重要机制是骨骼肌中丙酮酸脱氢酶复合物 (PDH) 的调节改变。我们研究了特定肿瘤坏死因子结合蛋白 TNFbp 在慢性腹部脓毒症啮齿动物模型中调节乳酸浓度和骨骼肌 PDH 活性的能力。材料和方法 我们检查了四组动物的乳酸代谢调节：对照、对照 + TNFbp、脓毒症和脓毒症 + TNFbp。使用接种了大肠杆菌和脆弱芽胞杆菌的无菌粪便琼脂颗粒作为异物病巢，通过产生稳定的腹内脓肿来诱导慢性（5天）脓毒症。每天皮下注射 TNFbp（1 mg/kg/天）。结果 与对照组相比，败血症使血浆和骨骼肌乳酸浓度增加了 2 倍。在用 TNFbp 治疗的脓毒症大鼠中，与未治疗的脓毒症大鼠相比，血浆和骨骼肌乳酸浓度显着降低。在骨骼肌中，与对照组相比，脓毒症导致活性形式的 PDH 比例减少 70%。 TNFbp 可阻止败血症诱导的 PDH 复合物活性抑制。 PDH 激酶在脓毒症中增强 1.8 倍，并且通过 TNFbp 治疗可阻止 PDH 激酶活性的增加。 TNFbp 治疗对对照动物的血浆乳酸或活跃骨骼肌 PDH 活性的比例没有任何影响。结论 TNFbp 可预防脓毒症引起的高乳酸血症以及骨骼肌乳酸浓度和 PDH 活性的紊乱。这些观察结果表明，TNF 是脓毒症期间乳酸稳态失衡的重要介质。
BACKGROUND Hyperlactatemia is a metabolic complication of hypermetabolic, hyperdynamic sepsis. An important mechanism responsible for elevating plasma lactate concentrations in sepsis is altered regulation of the pyruvate dehydrogenase complex (PDH) in skeletal muscle. We investigated the ability of a specific tumor necrosis factor binding protein, TNFbp, to modulate lactate concentrations and skeletal muscle PDH activity in a rodent model of chronic abdominal sepsis. MATERIALS AND METHODS We examined the regulation of lactate metabolism in four groups of animals: Control, Control + TNFbp, Septic, and Septic + TNFbp. Chronic (5 days) sepsis was induced by the creation of a stable intraabdominal abscess using a sterile fecal-agar pellet inoculated with E. coli plus B. Fragilis as the foreign body nidus. TNFbp (1 mg/kg/day) was injected subcutaneously daily. RESULTS Sepsis increased plasma and skeletal muscle lactate concentrations 2-fold compared with control. In septic rats treated with TNFbp, plasma and skeletal muscle lactate concentrations were significantly decreased compared with untreated septic rats. In skeletal muscle, sepsis resulted in a 70% decrease in the proportion of the PDH in the active form compared with controls. The sepsis-induced inhibition in the PDH complex activity was prevented by TNFbp. PDH kinase was enhanced 1.8-fold in sepsis, and the increase in PDH kinase activity was prevented by treatment with TNFbp. TNFbp treatment did not have any effects on plasma lactate or the proportion of active skeletal muscle PDH activity in control animals. CONCLUSIONS TNFbp prevents the sepsis-induced hyperlactatemia and derangements in skeletal muscle lactate concentrations and PDH activity. These observations suggest that TNF is an important mediator responsible for lactate dyshomeostasis during sepsis.