Synergistic therapeutic potential of dexamethasone and L-arginine in lipopolysaccharide-induced septic shock
Synergistic therapeutic potential of dexamethasone and L-arginine in lipopolysaccharide-induced septic shock
复制标题
DOI：
10.1016/j.jss.2006.09.002
复制
发表时间：
2007-06-01
影响因子：
2.2
通讯作者：
Poduval, T. B.
中科院分区：
文献类型：
--
作者：
Chatterjee, Saurabh;Premachandran, Sudha;Poduval, T. B.
背景地塞米松（DEX）被证明具有抗炎特性，并已知在脓毒症和脓毒性休克中诱导血流动力学改善。L-精氨酸（L-arg）是一种半必需氨基酸，取决于其代谢途径，在诸如中暑、烧伤、败血症、创伤和伤口愈合等应激情况下变得非常重要。本研究旨在评价地塞米松（DEX）和L-精氨酸（L-arg）对细菌脂多糖（LPS）诱导的实验性感染性休克小鼠的协同治疗作用。这些实验的目的是描绘负责增加治疗效益的联合治疗（CT）在LPS诱导的感染性休克的分子机制。在Swiss雄性小鼠中，于0 h腹腔注射LPS（18 mg kg（-1））诱导急性内毒素血症。将LPS处理的小鼠分为四组。第一组（DEX组）在LPS +2 h时腹腔注射DEX（2 mg kg（-1））。第二组（L-arg组）在注射LPS +6 h时以120 mg/kg的剂量腹腔注射L-arg。第三组（CT组）在LPS注射后2 h给予DEX（2 mg kg（-1）），随后在LPS注射后6 h给予L-arg。第四组用生理盐水代替L-arg或DEX（LPS组）。还包括假手术组，其中正常小鼠接受生理盐水代替LPS或L-arg或DEX。假手术组、LPS组和DEX组于+24 h处死。假手术组、DEX组、L-arg组和CT组小鼠处死，检测LPS内毒素血症相关的各项指标。DEX和L-arg的CT显著增加了注射致死剂量LPS的小鼠的存活率。以相同剂量和时间给予DEX或L-arg的单药治疗并没有增加注射LPS的小鼠的存活率。DEX给药可显著降低血清TNF-α、IL-10、IFN-γ、天冬氨酸转氨酶（ASAT）、丙氨酸转氨酶（ALAT）和亚硝酸盐水平。DEX还下调肝脏诱导型一氧化氮合酶（NOS）的表达，并上调血清抗炎细胞因子如TGF-β 1和IL-4，肝和脾细胞凋亡酶的水平。与施用任一种单一疗法的小鼠相比，CT的增强的治疗效果与减少的病理学症状、减少的Thl细胞因子、增加的TGF-β 1和β 2-淀粉酶水平相关。与DEX或L-Arg处理的小鼠相比，CT组的肝Hsp 70表达显著增加，肺和肝中脓毒性休克相关的组织病理学改变显著减少。在适当的剂量、时间和给药顺序下，DEX和L-arg的治疗性联合治疗改变了细胞因子谱，有利于减少炎症反应。在CT组中观察到的显著增强的存活率伴随着肝Hsp 70、肝过氧化物酶、脾过氧化物酶的增加和器官损伤的减少。这一新的综合治疗概念可能成为治疗脓毒症和脓毒性休克的有效治疗方法的基础。(C)2007年爱思唯尔公司All rights reserved.
Background. Dexamethasone (DEX) is demonstrated to have anti-inflammatory properties and known to induce hemodynamic improvement in sepsis and septic shock. L-arginine (L-arg), a semi-essential amino acid, depending on its metabolic pathway, becomes very essential in stress situations such as heatstroke, burns, sepsis, trauma, and wound healing. The aim of this study was to evaluate the synergistic therapeutic effect of DEX and L-arg in rescuing the mice from experimental septic shock induced by bacterial lipopolysaccharide (LPS). The experiments were designed to delineate the molecular mechanisms responsible for the increased therapeutic benefit of the combination therapy (CT) in LPS-induced septic shock.Methods. Acute endotoxemia was induced in Swiss male mice by i.p. injection of LPS (18 mg kg(-1)) at 0 h. LPS-treated mice were divided into four groups. The first group (DEX group) received DEX (2 mg kg(-1)) i.p. at +2 h of LPS. The second group (L-arg group) received L-arg i.p. at a dose of 120 mg/kg at +6 h of LPS injection. The third group (CT group) received DEX (2 mg kg(-1)) at +2 h LPS followed by L-arg at +6 h of LPS injection. The fourth group received saline in place of L-arg or DEX (LPS group). A sham group was also included, where normal mice received saline in place of LPS or L-arg or DEX. At +6 h, mice from sham group, LPS group, and DEX group were sacrificed at +24 h. Mice from sham group, DEX group, L-arg group, and CT group were sacrificed to examine various parameters associated with LPS endotoxemia.Results. The CT with DEX followed by L-arg significantly increased the survival of mice injected with a lethal dose of LPS. Monotherapy with either DEX or L-arg given at the same dose and time did not increase the survival of the mice injected with LPS. DEX administration could significantly reduce the levels of serum TNF-a, IL-10, IFN-gamma, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and nitrite. DEX also down-regulated the expression of liver-inducible nitric oxide synthase (NOS), and upregulated the levels of serum anti-inflammatory cytokines like TGF-beta 1 and IL-4, hepatic and splenic arginase, in LPS-injected mice. The enhanced therapeutic effect of CT correlated with reduced pathological symptoms, decreased Thl cytokines, increased TGF-)31 and arginase levels compared to the mice administered with either of the monotherapies. The CT group had significantly increased expression of hepatic Hsp 70 and reduced septic shock associated histopathology, in lung and liver, compared to the mice treated with either DEX or L-arg.Conclusions. The therapeutic combination therapy with DEX and L-arg, at the appropriate dose, time, and sequence of administration, changed the cytokine profile, in favor of reducing the inflammatory response. The significantly enhanced survival observed in the CT group was accompanied by an increased hepatic Hsp 70, hepatic arginase, splenic arginase, and decreased organ injury. This novel concept of combined therapy could form the basis of an effective therapeutic approach in the treatment of sepsis and septic shock. (C) 2007 Elsevier Inc. All rights reserved.