Glutamine attenuates lung injury and improves survival after sepsis: Role of enhanced heat shock protein expression
Glutamine attenuates lung injury and improves survival after sepsis: Role of enhanced heat shock protein expression
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DOI：
10.1097/01.ccm.0000166357.10996.8a
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发表时间：
2005-06-01
影响因子：
8.8
通讯作者：
Wischmeyer, PE
中科院分区：
文献类型：
--
作者：
Singleton, KD;Serkova, N;Wischmeyer, PE
目的：热休克蛋白（HSP）的表达对应激或损伤后细胞和组织的保护至关重要。然而，这种强大的工具在人类疾病中的应用受到限制，因为已知的热休克蛋白增强剂是有毒的，没有临床相关性。谷氨酰胺（GLN）可增强非临床相关动物损伤模型中HSP的表达。本研究的目的是评估GLN增强脓毒症大鼠肺热休克蛋白表达、减轻肺损伤和提高脓毒症后存活的能力。设计：前瞻性、随机、对照动物试验。大学研究实验室。实验对象：雄性Sprague-Dawley大鼠。采用大鼠盲肠结扎穿刺诱导脓毒症模型。脓毒症开始后1小时通过单尾静脉注射GLN或生理盐水。我们通过Western blot分析热休克因子-1磷酸化、HSP-70和HSP-25。用磁共振波谱法测定组织代谢。通过组织病理学检查确定肺损伤的发生。利用热休克蛋白表达抑制剂槲皮素来评估热休克蛋白表达在预防败血症相关死亡中的作用。测量结果及主要结果：脓毒症开始后给予GLN，可增强肺热休克因子-1磷酸化、热休克因子-70、热休克因子-25，减轻脓毒症后肺损伤，改善脓毒症后肺组织代谢功能指标（腺苷5′-三磷酸/腺苷5′-二磷酸比值、烟酰胺腺嘌呤二核苷酸）。GLN对肺组织还原性谷胱甘肽无明显影响。GLN治疗导致死亡率显著降低（GLN治疗大鼠33%[18 / 6]，盐水治疗大鼠78%[17 / 14]）。给予热休克蛋白抑制剂槲皮素阻断了GLN介导的热休克蛋白表达增强，并消除了GLN的生存益处。GLN已被安全地应用于危重患者，并显示出在不清楚保护机制的情况下改善预后。我们的研究结果表明，GLN可能通过增强肺热休克因子-1磷酸化/激活缺陷和HSP表达来预防败血症后肺损伤、肺组织代谢功能障碍和死亡率的发生。
Objective: Heat shock protein (HSP) expression is vital to cellular and tissue protection after stress or injury. However, application of this powerful tool in human disease has been limited, as known enhancers of HSPs are toxic and not clinically relevant. Glutamine (GLN) can enhance HSP expression in nonclinically relevant animal injury models. The aim of this study was to assess the ability of GLN to enhance pulmonary HSP expression, attenuate lung injury, and improve survival after sepsis in the rat.Design: Prospective, randomized, controlled animal trial.Setting. University research laboratory.Subjects: Male Sprague-Dawley rats.Interventions. We utilized a rat model of cecal ligation and puncture to induce sepsis. GLN or saline was administered 1 hr after initiation of sepsis via single tail-vein injection. We analyzed heat shock factor-1 phosphorylation, HSP-70, and HSP-25 via Western blot. Tissue metabolism was assayed by magnetic resonance spectroscopy. Occurrence of lung injury was determined via histopathologic examination. An inhibitor of HSP expression, quercetin, was utilized to assess role of HSP expression in prevention of sepsis-related mortality.Measurements and Main Results: GLN, given after initiation of sepsis, enhanced pulmonary heat shock factor-1 phosphorylation, HSP-70, HSP-25, and attenuated lung injury after sepsis, Further, GLN improved indices of lung tissue metabolic function (adenosine 5 '-triphosphate/adenosine 5 '-diphosphate ratio, nicotinamide adenine dinucleotide) after sepsis. No significant effect of GLN on lung tissue-reduced glutathione was observed. GLN treatment led to a significant decrease in mortality (33% [6 of 18] GLN-treated rats vs. 78% [14 of 17] saline-treated rats). Administration of the HSP inhibitor quercetin blocked GLN-mediated enhancement of HSP expression and abrogated GLN's survival benefit.Conclusions. GLN has been safely administered to critically ill patients and shown to improve outcome without clear understanding of the protective mechanism. Our results indicate GLN may prevent the occurrence of lung injury, lung tissue metabolic dysfunction, and mortality after sepsis via enhancement of deficient lung heat shock factor-1 phosphorylation/activation and HSP expression.