Glutamine prevents activation of NF-κB and stress kinase pathways, attenuates inflammatory cytokine release, and prevents acute respiratory distress syndrome (ARDS) following sepsis
Glutamine prevents activation of NF-κB and stress kinase pathways, attenuates inflammatory cytokine release, and prevents acute respiratory distress syndrome (ARDS) following sepsis
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DOI：
10.1097/01.shk.0000185795.96964.71
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发表时间：
2005-12-01
期刊：
影响因子：
3.1
通讯作者：
Wischmeyer, PE
中科院分区：
文献类型：
--
作者：
Singleton, KD;Beckey, VE;Wischmeyer, PE
谷氨酰胺(Gln)可抑制脂多糖刺激的人外周血单核细胞释放细胞因子；然而，Gln在多菌败血症和ARDS中的体内抗炎作用尚不清楚。本研究评价了谷氨酰胺对炎性细胞因子释放的影响以及可能介导谷氨酰胺抗炎作用的途径。雄性大鼠盲肠结扎穿孔(CLP)后1周给予谷氨酰胺0.75g/kg或生理盐水安慰剂(SP)。检测CLP后6h肺组织中核因子-kappaB活化、LKBα降解、p38MAPK、ERK和MKP-1表达的变化。检测肺组织诱导型一氧化氮合酶、内皮型一氧化氮合酶、肿瘤坏死因子-α、白介素6、白介素18等细胞因子。最后，对ARDS的发生和存活率进行肺组织病理学检查。脓毒症后1h给予谷氨酰胺可抑制肺组织中核因子-kappaB的活化(P<；0.001 vs SP)，抑制肺组织1KBA的降解，并抑制p38MAPK和ERK的磷酸化，这两个通路是细胞因子释放的关键途径。Gln治疗可增加CLP后6h MKP-1多肽的表达，显著降低TNF-α和IL-6的表达。IL-18在CLP后多个时间点被Gln抑制。此外，Gln可抑制脓毒症后肺组织一氧化氮合酶表达的增加和肺组织eNOS的增强。最后，Gln预防了脓毒症后ARDS的组织病理学表现，显著提高了存活率。这些数据表明，Gln在脓毒症中发挥抗炎作用，其机制可能是通过抑制多种途径的炎症反应，如核因子-kappaB、p38MAPK、ERK和MKP-1。谷氨酰胺对一氧化氮合酶表达的增加也有抑制作用。谷氨酰胺的抗炎作用与ARDS的减轻和死亡率有关。
Glutamine (GLN) has been shown to attenuate cytokine release from LPS-stimulated human peripheral blood mononuclear cells; however, the in vivo antiinflammatory effect of GLN in polymicrobial sepsis and ARDS is unknown. This study evaluates the effect of GLN on inflammatory cytokine release and the pathways that may mediate anti inflammatory effects of GLN in the lung. Either 0.75 g/kg of GLN or saline placebo (SP) was administered to male rats 1 In after cecal ligation and puncture (CLP). NF-kappa B activation, lKB alpha degradation, phosphorylation of p38 MAPK, ERK, and MKP-1 expression were evaluated in lung tissue 6 h post-CLP. Lung tissue iNOS and eNOS, TNF-alpha, IL-6, and IL-18 cytokines were assayed. Last, lung histopathology for occurrence of ARDS and survival were examined. GLN given 1 h postsepsis led to inhibition of lung tissue NF-kappa B activation (P < 0.001 vs. SP), attenuated degradation of lKBa, and inhibited phosphorylation of p38 MAPK, and ERK, pathways critical for cytokine release. GLN treatment increased MKP-1 peptide expression and significantly attenuated TNF-alpha and IL-6 6 h after CLP. IL-18 was attenuated by GLN at multiple time points post-CLP. Further, GLN abrogated increases in lung NOS expression and enhanced lung eNOS postsepsis. Finally, GLN prevented the histopathologic appearance of ARDS after sepsis and significantly improved survival. These data reveal that GLN exerts an antiinflammatory effect in sepsis that may be mediated via attenuation of multiple pathways of inflammation such as NF-kappa B, p38 MAPK, ERK, and MKP-1. GLN also showed an inhibition of increases in NOS expression. The antiinflammatory effect of GLN was associated with attenuation of ARDS and mortality.