脓毒症小鼠死亡高发期腹腔脏器血流动力学观察

目的: 研究脓毒症小鼠死亡高发期腹腔脏器血流动力学的变化。方法: 应用高分辨小动物超声成像系统对正常雄性昆明小鼠先行心脏收缩功能和血流动力学指标的超声检测(0 h)后,行盲肠结扎穿孔术(CLP)。术后分5 个时点(12 h、24 h、36 h、48 h、60 h) 对小鼠进行相应超声指标检查。每只小鼠均进行编号,以便对小鼠进行连续性的观测,7 d仍存活的小鼠视为存活动物。结果: CLP小鼠在脓毒症死亡高发期心输出量(CO)大致保持在正常水平或高动力学状态。左心收缩功能出现明显的代偿性改变。腹主动脉血流量的变化表现为先升高后降低,其阻力指数(RI)和搏动指数(PI)从24 h 开始出现明显升高。右侧肾动脉的血流量从12 h开始便出现明显的下降,直到60 h仍明显低于正常,其RI和PI变化不明显。门静脉血流量12 h明显升高,24 h明显下降,其后血流量与0 h相比未见显著差异。充血指数从12 h即明显升高,其后维持在高于正常的水平。结论: 脓毒症小鼠腹腔各脏器在死亡高发期发生血流动力学的特征性变化。研究这些变化有助于阐明脓毒症的发病机制。     

脓毒症大鼠心肌功能障碍的常规超声心动图与组织多普勒成像分析

目的:利用脓毒症大鼠模型,比较常规超声和组织多普勒超声指标在早期诊断脓毒症大鼠心肌内在收缩与舒张功能障碍中的价值。方法:利用盲肠结扎穿孔(CLP)建立脓毒症大鼠模型,22只大鼠随机分成CLP组与假手术组,每组11只。利用ELISA和Western blot检测肿瘤坏死因子α(TNF-α)、细胞间黏附分子1(ICAM-1)和血管细胞黏附分子1(VCAM-1)的表达水平;离体心脏灌流、常规超声心动图和心脏组织多普勒成像测定心脏收缩与舒张功能。结果:与假手术组比较,CLP术后6 h,大鼠血清中TNF-α水平及左心室ICAM-1和VCAM-1表达显著升高,左心室±dp/dtmax显著降低,左心室每搏输出量与舒张末期容积显著降低,但左室射血分数的差异没有统计学显著性,二尖瓣血流速度E波峰值和A波峰值显著降低,二尖瓣环舒张早期运动速度E'波峰值和二尖瓣环舒张晚期运动速度A'波峰值显著降低,而E/E'比值的差异没有统计学显著性。相关分析显示,E'波峰值和A'波峰值分别与-dp/dtmax呈正相关(r分别为0. 460和0. 520,P0. 05)。结论:组织多普勒成像可以有效评价脓毒症早期心肌内在舒张功能障碍,E'与A'峰值可以作为检测左室心肌舒张功能障碍的指标。     

轻度CLP模型大鼠在脓毒症早期即发生心肌收缩与舒张功能障碍

目的:利用轻度盲肠结扎穿孔术(CLP)复制脓毒症大鼠模型,比较脓毒症大鼠心功能与其它器官功能障碍发生的时间。方法:将大鼠随机分为假手术组和盲肠结扎穿孔术组,分别于手术后6 h、9 h和12 h用Langendorff装置检测大鼠心肌收缩与舒张功能,并测定心肌肿瘤坏死因子α(TNF-α)、细胞间黏附分子1(ICAM-1)和血管内皮细胞黏附因子1(VCAM-1)的表达;同时检测血清TNF-α水平以及大鼠肝、肾功能和肺湿/干重比值。结果:轻度CLP术后10 d,大鼠的死亡率为26.7%。CLP术后9 h与12 h左心室内压最大上升与下降速率显著低于假手术组;CLP术后6 h,心肌TNF-α、ICAM-1和VCAM-1的mRNA表达显著高于假手术组,CLP术后9 h心肌TNF-α和VCAM-1的蛋白表达显著升高。CLP术后9 h血清天冬氨酸氨基转移酶活性和12 h丙氨酸氨基转移酶活性高于假手术组。而术后6 h、9 h和12 h,大鼠血尿素氮水平、肺湿/干重比与相应时点的假手术组比较,差异没有统计学显著性。结论:轻度CLP模型大鼠在脓毒症发生后6 h心肌炎症因子表达增多,9 h后即发生心肌内在收缩与舒张功能障碍,其发生早于肝、肾功能损伤。     

两种脓毒症模型小鼠血清白细胞介素-6与其早期生存率的关系

目的探讨盲肠结扎穿孔( CLP)、腹腔持续置管引流( CASP)脓毒症模型小鼠血清白细胞介素-6(IL-6)与其早期生存率的关系。方法将60只雄性BALB/c小鼠编号,采用数字表法随机分为3组,即假手术组( Sham组)、CLP组、CASP组,各20只。 CLP组小鼠麻醉后,于中下腹正中线做纵行切口,充分暴露并结扎盲肠,用18 G注射器针头在结扎部位远端穿孔并来回贯穿2次,将少量肠内容物挤出,回纳盲肠,缝合腹壁切口。 CASP组术前准备、开腹方式同CLP模型,暴露小鼠升结肠系膜,在其对侧处插入静脉导管,退出针芯,荷包缝合并固定、剪断静脉导管,将游离端放置于腹腔内。用棉签挤压肠管,使少量肠内容物从导管口溢出,以确认导管通畅。 Sham组术前准备、开腹、术后处理同CLP组,不行盲肠结扎、穿孔。观察各组小鼠术后12、24、36、48、60、72 h的生存率。术后6 h采集各组小鼠尾静脉血,采用 ELISA 检测血清 IL-6,比较此时间点3组存活小鼠间 IL-6水平以及CLP组、CASP组的存活和死亡小鼠间IL-6水平。结果 Sham组、CLP组和CASP组术后72 h生存率分别是100.0%(20/20)、45.0%(9/20)和10.0%(2/20),3组间总体比较差异有统计学意义(字2=32.970,P<0.01),两两比较3组间差异均有统计学意义(P值均<0.05);3组小鼠生存时间曲线经Log-rank检验,差异有统计学意义(字2=34.030,P<0.05)。术后6 h,Sham组、CLP组、CASP组存活小鼠血清 IL-6水平分别是(36.62依10.30) ng/L、(2443.47依970.50) ng/L、(4057.93依827.41)ng/L,差异均有统计学意义(Hc=29.270,P<0.01);CLP组和CASP组各组内存活小鼠血清IL-6水平平均分别为(1348.80依276.25) ng/L、2100.00 ng/L,明显低于死亡小鼠的(3157.29依330.94)ng/L、(4275.48依512.71)ng/L,CLP组差异有统计学意义(t=13.071,P<0.01)。结论两种脓毒症模型小鼠的转归都有一定的病死率,较好地模拟了脓毒症的病理生理过程,CLP模型侧重于模拟局限性腹腔脓肿,CASP模型则侧重于模拟弥漫性腹膜炎。 CLP组模型术后6 h血清IL-6水平较低的小鼠,术后72 h生存率较高。     

Nrf2激动剂萝卜硫素通过抑制肝组织铁死亡减轻小鼠脓毒症肝损伤

目的:探讨核因子E2相关因子2(nuclear factor E2-related factor 2,Nrf2)激动剂萝卜硫素(sulfora?phane,SFN)对脓毒症小鼠肝脏铁死亡的影响及其分子机制.方法:用盲肠结扎穿孔术(cecal ligation and punc?ture,CLP)复制C57BL/6小鼠的...     

脓毒症相关性脑病小鼠模型的建立及其认知功能障碍的初步研究

目的:建立脓毒症相关性脑病(sepsis-associated encephalopathy,SAE)小鼠模型并对其认知功能障碍进行初步研究。方法:选取8～10周龄SPF级雄性C57BL/6J小鼠。第1部分实验将小鼠随机分为4组,即正常对照组,盲肠结扎穿孔术(cecal ligation and puncture,CLP)1组和CLP2组(分别用7号和12号针头行小鼠腹腔CLP)和假手术组(小鼠仅开腹分离盲肠)。第2部分实验将小鼠随机分为3组,即正常对照组,假手术组和CLP组。采用Kaplan-Meier法分析小鼠术后存活率;神经行为学评分评价小鼠的神经行为变化;Morris水迷宫实验和避暗实验检测小鼠的认知记忆功能变化;爬杆实验和悬挂实验测试小鼠的运动协调性;ELISA法检测小鼠血清前列腺素E_2(prostaglandin E_2, PGE_2)水平变化。结果:第1部分实验中,CLP术后小鼠出现明显嗜睡、竖毛、寒颤和厌食等症状,CLP1组和CLP2组小鼠48 h死亡率分别为20%和30%。两部分实验中行小鼠腹腔盲肠结扎穿孔术组小鼠神经行为学评分均显著低于对照组和假手术组(P0.01);Morris水迷宫中逃避潜伏期时间均显著延长(P0.01),目标象限停留时间和穿越平台次数减少(P0.01);悬挂实验和爬杆实验中评分均出现显著降低(P0.01);在避暗实验开始后大部分小鼠活动量显著减小甚至未曾进入暗室(P0.05)。第2部分实验中,CLP术后小鼠血清中PGE_2释放量显著增加(P0.01)。结论:通过12号针行盲肠结扎穿孔术可成功建立稳定的脓毒症相关性脑病小鼠模型,用此法建立的SAE小鼠模型存在学习记忆认知功能障碍。     

雷帕霉素促进自噬减轻脓毒症相关性脑病(SAE)小鼠认知功能障碍

目的 明确雷帕霉素促进自噬在脓毒症相关性脑病(SAE)小鼠认知功能障碍中的作用。方法 通过盲肠结扎穿孔术(CLP)建立SAE小鼠模型,采用小鼠脓毒症严重程度评分(MSS)评估SAE小鼠脓毒症的严重程度,条件恐惧记忆实验观察小鼠认知功能。Western blot法检测SAE小鼠海马组织微管相关蛋白1轻链3(LC3)与P62的表达水平,免疫荧光组织化学染色观察LC3在海马区神经元中的表达和分布。结果 CLP术后14 d小鼠死亡率高达41.7%,而幸存小鼠存在显著认知功能障碍。同时,CLP术后14 d小鼠海马组织自噬水平降低。雷帕霉素可促进SAE小鼠海马神经元自噬,减轻其认知功能障碍。结论雷帕霉素促进SAE小鼠海马神经元自噬,减轻其认知功能障碍。     

NLRC4炎症小体介导自噬反应在脓毒症心肌功能障碍小鼠中的作用

背景：研究发现炎症小体及自噬在脓毒症患者的免疫功能中扮演了重要角色。但现阶段研究仅局限于探索脓毒症中某一自噬信号通路的变化特点,对脓毒症心肌功能障碍自噬调控的具体机制尚未阐明。目的：探讨核苷酸结合寡聚化结构域样受体蛋白4(NOD-like receptor family,pyrin domain-containing protein 4,NLRC4)炎症小体与自噬水平在小鼠脓毒症心肌功能障碍中的变化,以期为脓毒症心肌功能障碍的发生机制提供理论依据。方法：昆明雄性小鼠48只,随机分为6组,分别为假手术(6,12,24 h)组和盲肠结扎穿孔(6,12,24 h)组。盲肠结扎穿孔组结扎小鼠盲肠远端1/2,22号针头来回穿刺2次,挤出少许肠内容物;假手术组不结扎穿孔,其余操作与盲肠结扎穿孔术相同。观察小鼠术后一般情况,超声测定小鼠心功能,ELISA法检测肿瘤坏死因子α、肌钙蛋白T质量浓度;苏木精-伊红染色法观察心肌病理变化;透射电镜观察心肌线粒体及自噬体变化;实时荧光定量PCR检测心肌组织NLRC4 mRNA的表达,Western blot检测心肌组织炎症因子、LC3、Beclin-1、NLR...     

腹腔感染脓毒症小鼠外周血淋巴细胞CD30的动态表达

目的:探讨腹腔感染脓毒症的病理过程中Th2细胞的分化情况。方法:盲肠结扎穿孔(CLP)复制腹腔感染脓毒症小鼠模型,在不同时点取外周全血进行三色荧光标记,以流式细胞术对CD4⁺细胞表面CD30分子的表达情况进行分析。结果:不同时点的CLP组其CD30分子的表达有所不同,以术后38h为最高,随后呈现总体下降趋势。结论:在脓毒症腹腔感染小鼠的动物模型中,Th2细胞的分化情况随病程的发展有所不同,可能和疾病的严重程度及预后相关。     

银杏内酯B对CLP诱导脓毒症小鼠的保护作用

目的: 银杏内酯B (GB)是已知的天然而强效的血小板激活因子受体拮抗剂。本实验通过研究GB对盲肠结扎穿孔(CLP)诱导的脓毒症小鼠的存活、外周血一氧化氮(NO)、活性氧簇(ROS)及细胞因子TNF-α、IL-1β、IL-6和IL-10的影响来评价其对脓毒症的免疫调节效果。方法: 采用CLP的标准化程序建立小鼠脓毒症模型,术前30 min对药物组模型小鼠进行GB(10 μg/g)预处理;统计存活率;以Griess法检测小鼠外周血NO 水平;以H₂DCFDA标记结合流式细胞术检测外周血ROS 水平;以流式细胞微球阵列法与ELISA法检测外周血细胞因子水平。结果: CLP手术后24 h,小鼠胸腺和脾脏萎缩明显,外周血炎症介质NO和ROS及细胞因子TNF-α、IL-1β、IL-6和IL-10的水平均显著上升,术后5 d内CLP模型小鼠全部死亡,而10 μg/g GB于术前30 min预处理,能缓解胸腺和脾脏萎缩,有效抑制炎症介质与炎性细胞因子风暴,显著提高脓毒症存活率。 结论: GB预处理能显著降低CLP小鼠死亡率,下调外周血炎症介质NO和ROS及细胞因子TNF-α、IL-1β、IL-6和IL-10的水平,对脓毒症小鼠有明显的保护作用。     

内源性雌激素调控脓毒症小鼠心肌L型钙离子通道α1C亚基的表达

目的　探讨内源性雌激素对脓毒症小鼠心肌钙离子通道α1C亚基（CACNA1C）的影响。 方法　雌性昆明小鼠行双侧卵巢摘除术，术后30 d利用盲肠结扎穿刺术（CLP）建立脓毒症小鼠模型，分为5组：脓毒症组（S组），去卵巢+脓毒症组（QS组），假手术组（C组），去卵巢+假手术组（QC组），去卵巢+苯甲酸雌二醇（QE组）。荧光定量PCR和Western blot检测造模后3 h，6 h，12 h，24 h左心室CACNA1C表达水平，免疫组化检测造模后12 h左心室CACNA1C表达及分布情况。 结果　（1）QC组CACNA1C的表达水平显著高于C组，QE组CACNA1C的表达水平显著低于QC组。（2）CLP后3 h，S组CACNA1C表达显著高于对照组和其它时间点。（3）CLP后3 h、6 h、12 h和24 h，QS组CACNA1C表达均显著低于对照组，且各时间点之间无差异。 结论　（1）双侧卵巢摘除后CACNA1C表达显著升高，双侧卵巢摘除后补给苯甲酸雌二醇可以逆转CACNA1C的升高。（2）正常小鼠CLP后3 h CACNA1C的表达出现短暂的升高，而双侧卵巢摘除的小鼠CLP后各时间点CACNA1C的表达均显著低于对照组。     

内源性雌激素调控脓毒症小鼠心肌L型钙离子通道α1C亚基的表达

目的　探讨内源性雌激素对脓毒症小鼠心肌钙离子通道α1C亚基（CACNA1C）的影响。 方法　雌性昆明小鼠行双侧卵巢摘除术,术后30 d利用盲肠结扎穿刺术（CLP）建立脓毒症小鼠模型,分为5组：脓毒症组（S组）,去卵巢+脓毒症组（QS组）,假手术组（C组）,去卵巢+假手术组（QC组）,去卵巢+苯甲酸雌二醇（QE组）。荧光定量PCR和Western blot检测造模后3 h,6 h,12 h,24 h左心室CACNA1C表达水平,免疫组化检测造模后12 h左心室CACNA1C表达及分布情况。 结果　（1）QC组CACNA1C的表达水平显著高于C组,QE组CACNA1C的表达水平显著低于QC组。（2）CLP后3 h,S组CACNA1C表达显著高于对照组和其它时间点。（3）CLP后3 h、6 h、12 h和24 h,QS组CACNA1C表达均显著低于对照组,且各时间点之间无差异。 结论　（1）双侧卵巢摘除后CACNA1C表达显著升高,双侧卵巢摘除后补给苯甲酸雌二醇可以逆转CACNA1C的升高。（2）正常小鼠CLP后3 h CACNA1C的表达出现短暂的升高,而双侧卵巢摘除的小鼠CLP后各时间点CACNA1C的表达均显著低于对照组。     

Interleukin-10 controls the onset of irreversible septic shock

Lethality from sepsis is believed to be mediated by a proinflammatory cytokine cascade, yet blocking the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) fails to prevent mortality in human disease and a mouse model of sepsis induced by cecal ligation and puncture (CLP). The role of the antiinflammatory cytokine IL-10 in the CLP model of sepsis is unclear, with either protective or harmful effects demonstrated, depending upon the time of intervention. We therefore hypothesize that IL-10 functions as a temporal regulator of the transition from early reversible sepsis to the late phase of irreversible shock. Transition from reversible sepsis to irreversible shock in the CLP model was defined as the time when removal of the necrotic cecum by rescue surgery is no longer effective. We subjected IL-10-deficient (IL-10(-/-)) and wild-type (IL-10(+/+)) mice to CLP and monitored the progression of sepsis, the onset of irreversible shock, and mortality. Onset of lethality in IL-10(-/-) mice occurred significantly earlier than in IL-10(+/+) mice and was associated with 15-fold-higher serum levels of TNF-alpha and IL-6. Consistent with these findings, the efficacy of rescue surgery after lethal CLP is lost 10 h earlier in IL-10(-/-) mice than in IL-10(+/+) mice. Treatment with recombinant human IL-10 5 h after CLP significantly improved survival and lengthened the therapeutic window for rescue surgery in both strains of mice. These results demonstrate that IL-10 controls the onset of irreversible septic shock after CLP.     

Effects of dexmedetomidine on early and late cytokines during polymicrobial sepsis in mice

Objective

We investigated whether dexmedetomidine provided protective effects on cecal ligation and puncture (CLP)–induced septic mice, through suppressing the expression of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6)] and high mobility group box 1 (HMGB1).

Methods

The model of sepsis was set up by CLP in 136 male BALB/c mice (40 mice for survival studies and 96 for cytokine studies) which were divided into four groups, including a C, CLP, DEX + CLP and CLP + DEX group. The serum levels of TNF-α, IL-6 and HMGB1 were detected at 6, 12, 24 and 48 h after operations, and lung HMGB1 mRNA were analyzed at 24 and 48 h. The mortality rates were calculated 7 days after the operations.

Results

The mortality rates 7 days after operations were significantly lower in the CLP + DEX (50 %) and DEX + CLP (30 %) groups than in the CLP group (90 %). Serum concentrations of IL-6 and TNF-α decreased significantly in dexmedetomidine administration groups compared with the CLP group. The levels of HMGB1 and lung HMGB1 mRNA were lower in the dexmedetomidine administration groups than in the CLP group. There was a significant correlation between lung HMGB1 mRNA and serum HMGB1(r = 0.858).

Conclusions

Dexmedetomidine could reduce the mortality rate and inhibit pro-inflammatory cytokine responses during polymicrobial sepsis in mice.     

肉苁蓉对败血症大鼠胸腺细胞的保护作用

目的：探讨肉苁蓉提取物对败血症休克大鼠胸腺细胞凋亡的影响及其可能机制。方法: 盲肠结扎穿孔术（CLP）造成大鼠败血症休克。防治组术前14 d开始给药（1.25 g/kg），分别于术后12 h、24 h取材。流式细胞仪检测细胞凋亡率和线粒体膜电位，分光光度法测定细胞线粒体ATP酶活力。结果 预先给予肉苁蓉提取物的大鼠，行CLP术后12、24 h胸腺细胞凋亡率均低于模型组（P<0.01），线粒体膜电位和ATP酶活力则显著上升（P<0.01）。结论： 肉苁蓉提取物对败血症休克时胸腺细胞有保护作用，其机制可能是提高ATP酶活力，维持了细胞线粒体膜电位。     

Glucose homeostasis in two degrees of sepsis lethality induced by caecum ligation and puncture in mice

Sepsis is associated with high mortality. Both critically ill humans and animal models of sepsis exhibit changes in their glucose homeostasis, that is, hypoglycaemia, with the progression of infection. However, the relationship between basal glycaemia, glucose tolerance and insulin sensitivity is not well understood. Thus, we aimed to evaluate this glucose homeostasis triad at the late stage of sepsis (24 h after surgery) in male Swiss mice subjected to lethal and sublethal sepsis by the caecal ligation and puncture (CLP) model. The percentage of survival 24 h after CLP procedure in the Lethal and Sublethal groups was around 66% and 100% respectively. Both Lethal and Sublethal groups became hypoglycaemic in fasting and fed states 24 h after surgery. The pronounced fed hypoglycaemia in the Lethal group was not due to worsening anorexic behaviour or hepatic inability to deliver glucose in relation to the Sublethal group. Reduction in insulin sensitivity in CLP mice occurred in a lethality‐dependent manner and was not associated with glucose intolerance. Analysis of oral and intraperitoneal glucose tolerance tests, as well as the gastrointestinal motility data, indicated that CLP mice had reduced intestinal glucose absorption. Altogether, we suggest cessation of appetite and intestinal glucose malabsorption are key contributors to the hypoglycaemic state observed during experimental severe sepsis.     

Ghrelin clearance is reduced at the late stage of polymicrobial sepsis

The cardiovascular response to sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase. Ghrelin, a newly-identified endogenous ligand for growth hormone secretagogue receptor (i.e., ghrelin receptor), was recently demonstrated to be a potent vasoactive peptide in addition to its effects on growth hormone release and energy homeostasis. We have shown that ghrelin (via its receptor) may play an important role in regulating cardiovascular responses in the progression of polymicrobial sepsis. However, it remains unknown whether the clearance of this peptide is altered in sepsis. To determine this, male adult rats were injected with 125I-ghrelin through the jugular vein at 5 or 20 h after cecal ligation and puncture (CLP, i.e., sepsis model) or sham operation. The blood sample was collected every 2 min for 30 min for determining half-life (t1/2). Tissue samples (i.e., kidneys, liver, brain, heart, lungs, spleen, stomach, small intestine, large intestine, skin and muscle) were then harvested. The radioactivities of samples were counted. The results indicate that 125I-ghrelin's t1/2 and its distribution were not significantly altered in early sepsis (5 h after CLP). However, the t1/2 increased significantly in late sepsis (20 h after CLP). Tissue distribution of 125I-ghrelin was far greater in the kidneys than in any other tissues tested in both sham and septic animals. Moreover, the kidneys and liver had significantly less radioactive uptake at 20 h after CLP, but the radioactivity in blood was much higher at the same time point. There were no significant changes in 125I-ghrelin distribution in other organs at the late stage of sepsis. These results indicate that the kidneys are the primary site of ghrelin clearance, which is significantly diminished in late sepsis. In addition, the liver also plays a role in the clearance of ghrelin, which was also reduced in late sepsis. The decreased clearance of ghrelin by the kidneys and liver may be due to renal and hepatic dysfunctions under such conditions.     

Cytochrome c oxidase as the target of the heat shock protective effect in septic liver

Liver function failure is one of the characteristics of critically ill, septic patients and is associated with worse outcome. Our previous studies have demonstrated that heat-shock response protects cells and tissue from subsequent insults and improves survival during sepsis. In this study, we have shown that mitochondrial cytochrome c oxidase (CCO) is one of the major sources of that protective effect. Experimental sepsis was induced by the cecal ligation and puncture (CLP) method. Heat-shock treatment was induced in rats by hyperthermia 24 h before CLP operation. The results showed that ATP content of the liver declined significantly, and the enzymatic activity of mitochondrial CCO was apparently suppressed during the late stages of sepsis. The mitochondrial ultrastructure of septic liver showed the deformity, mild swelling and inner membrane budding. Heat-shock treatment led to heat-shock protein 72 overexpression and prevented the downregulation of Grp75 during sepsis. On the contrary, the expression of the enzyme complex and its activity were preserved, associated with the minimization of ultrastructural deformities. In conclusion, the maintenance of mitochondrial function, especially the CCO, may be an important strategy in therapeutic interventions of a septic liver.