Cruzat Vinicius F, Pantaleão Lucas C, Donato José, de Bittencourt Paulo Ivo Homem, Tirapegui Julio
Department of Food Science and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP 05508-900, Brazil; School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Perth, Western Australia.
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508 900, Brazil.
J Nutr Biochem. 2014 Mar;25(3):345-52. doi: 10.1016/j.jnutbio.2013.11.009. Epub 2013 Dec 7.
Sepsis is a leading cause of death in intensive care units worldwide. Low availability of glutamine contributes to the catabolic state of sepsis. L-Glutamine supplementation has antioxidant properties and modulates the expression of heat shock proteins (HSPs). This study investigated the effects of oral supplementation with L-glutamine plus L-alanine (GLN+ALA), both in the free form and L-alanyl-L-glutamine dipeptide (DIP), on glutamine-glutathione (GSH) axis and HSPs expression in endotoxemic mice. B6.129F2/J mice were subjected to endotoxemia (lipopolysaccharides from Escherichia coli, 5 mg.kg(-1), LPS group) and orally supplemented for 48 h with either L-glutamine (1 g.kg(-1)) plus L-alanine (0.61 g.kg(-1)) (GLN+ALA-LPS group) or 1.49 g.kg(-1) of DIP (DIP-LPS group). Endotoxemia reduced plasma and muscle glutamine concentrations [relative to CTRL group] which were restored in both GLN+ALA-LPS and DIP-LPS groups (P<.05). In supplemented groups were re-established GSH content and intracellular redox status (GSSG/GSH ratio) in circulating erythrocytes and muscle. Thiobarbituric acid reactive substance was 4-fold in LPS treated mice relative to the untreated CTRL group, and plasma TNF-α and IL-1β levels were attenuated by the supplements. Heat shock proteins 27, 70 and 90 (protein and mRNA) were elevated in the LPS group and were returned to basal levels (relative to CTRL group) in both GLN+ALA-LPS and DIP-LPS groups. Supplementations to endotoxemic mice resulted in up-regulation of GSH reductase, GSH peroxidase and glutamate cysteine ligase mRNA expression in muscle. In conclusion, oral supplementations with GLN+ALA or DIP are effective in reversing the conditions of LPS-induced deleterious impact on glutamine-GSH axis in mice under endotoxemia.
脓毒症是全球重症监护病房患者死亡的主要原因。谷氨酰胺供应不足会导致脓毒症患者出现分解代谢状态。补充L-谷氨酰胺具有抗氧化特性，并能调节热休克蛋白（HSPs）的表达。本研究调查了口服补充游离形式的L-谷氨酰胺加L-丙氨酸（GLN+ALA）和L-丙氨酰-L-谷氨酰胺二肽（DIP）对内毒素血症小鼠谷氨酰胺-谷胱甘肽（GSH）轴及HSPs表达的影响。将B6.129F2/J小鼠诱导产生内毒素血症（给予来自大肠杆菌的脂多糖，5 mg·kg⁻¹，LPS组），并分别口服补充L-谷氨酰胺（1 g·kg⁻¹）加L-丙氨酸（0.61 g·kg⁻¹）（GLN+ALA-LPS组）或1.49 g·kg⁻¹的DIP（DIP-LPS组），持续48小时。内毒素血症使血浆和肌肉中的谷氨酰胺浓度降低[相对于对照组]，而GLN+ALA-LPS组和DIP-LPS组的谷氨酰胺浓度均得以恢复（P<0.05）。补充组循环红细胞和肌肉中的GSH含量及细胞内氧化还原状态（GSSG/GSH比值）均恢复正常。与未处理的对照组相比，LPS处理小鼠的硫代巴比妥酸反应物质含量增加了4倍，而补充剂可使血浆TNF-α和IL-1β水平降低。LPS组中热休克蛋白27、70和90（蛋白质和mRNA）水平升高，而GLN+ALA-LPS组和DIP-LPS组均恢复至基础水平[相对于对照组]。对内毒素血症小鼠进行补充可使肌肉中GSH还原酶、GSH过氧化物酶和谷氨酸半胱氨酸连接酶mRNA表达上调。总之，口服补充GLN+ALA或DIP可有效逆转内毒素血症小鼠中LPS对谷氨酰胺-GSH轴的有害影响。
