Lipoic acid suppresses portal endotoxemia-induced steatohepatitis and pancreatic inflammation in rats

AIM: To examine the effect of α-lipoic acid (LA) on mild portal endotoxemia-induced steatohepatitis and associated pancreatic abnormalities in fructose-fed rats. METHODS: Rats were randomly assigned into two groups with a regular or 60% fructose-enriched diet for 8 wk. After fructose feeding for 4 wk, rats were further divided into four subgroups: with intraportal saline (F PV ), with intraportal saline plus administration of LA (F PV + LA ), with lipopolysaccharide (LPS) infusion (F PLPS ), and with LPS infusion plus administration of LA (F PLPS + LA ). Rats were treated with LPS using intraportal infusion while LA was administered orally. Metabolite levels, superoxide levels, inflammatory markers, malondialdehyde content, glutathione content and toll-like receptor 4 (TLR4 ) gene expression were all measured using standard biochemical techniques. Pancreatic insulin secretion was evaluated by a hyperglycemic clamp technique. Histology of liver and pancreas tissues were evaluated using hematoxylin and eosin staining and immunohistochemistry. RESULTS: Fructose-induced elevation in plasma C-reactive protein, amylase, superoxide, white blood cell count as well as in hepatic and pancreatic contents of malondialdehyde, tumor necrosis factor alpha and interleukin-6 were increased in animals treated with LPS and reversed with LA administration. The augmented hepatic gene expression of TLR4 in fructose-fed rats was further increased in those with intraportal LPS infusion, which was partially reversed by LA administration. Pathological examination showed inflammatory changes and leukocyte infiltration in hepatic and pancreatic islets of animals treated with LPS but were rarely observed in those with LA treatment. In addition to affects on the liver, impaired pancreatic insulin secretion seen in fructose-fed rats was deteriorated in with LPS treatment and partially reversed with LA administration. CONCLUSION: These data suggest LA could significantly suppress mild portal-endotoxemia but not fructoseinduced liver and pancr     

聚偏氟乙烯氨基酸纤维膜用于内毒素吸附的体外实验研究

目的：体外实验探讨使用聚偏氟乙烯氨基酸纤维膜灌流吸附内毒素的有效性和安全性。方法：动态吸附实验：取脓毒症患者血浆50mL,以蠕动泵控制血浆灌流速度0.4mL/min进行血浆灌流,灌流前及灌流30、60和120min取样测定血浆内毒素,并与空白管吸附相比较,计算吸附率,同时检测血液相容性。结果：聚偏氟乙烯氨基酸纤维膜吸附后,血浆中的内毒素含量显著降低（P〈0.05）;血浆中的蛋白质变化较小（P〉0.05）;电解质无显著变化（P〉0.05）。结论：聚偏氟乙烯氨基酸纤维膜对血浆中的内毒素有明显吸附效果,对电解质无明显影响,对蛋白质的影响也较小。     

内毒素血症大鼠心肌细胞骨架蛋白基因表达的变化

目的 探讨内毒素血症大鼠心肌细胞骨架蛋白基因表达的变化.方法 37只Wistar大鼠随机分两组,静脉注射精制内毒素或生理盐水,连续24h监测两组大鼠的心功能;另取54只大鼠注射精制内毒素之后不同时间点处死大鼠,取左心室心肌组织,给予常规病理切片、电子显微镜观察以及actin、tubulin、desmin等细胞骨架蛋白基因的转录水平检测.结果 内毒素组大鼠LVSP在8～24 h与对照组相比有显著降低,而LVEDP变化不明显,表明LPS以损害心肌收缩功能为主;显微结构实验显示给予内毒素处理不同时间段的大鼠心肌组织显微结构有明显的破坏,基因表达实验显示细胞骨架蛋白基因的转录水平变化随内毒索注射时间变化出现显著性差异.结论 LPS可引起大鼠心功能及心肌细胞结构出现明显的损害,并引起心肌组织细胞骨架蛋白α-actin、tubulin基因表达发生显著的变化.     

乌司他丁对梗阻性黄疸肠粘膜屏障功能影响的实验研究

目的 探讨梗阻性黄疸对肠粘膜屏障功能的影响及乌司他丁(UTI)的保护作用.方法 取雄性SD大鼠72只,随机均分为假手术组(A组)、梗阻性黄疸组(B组)、UTI干预组(C组),每组又分术后3、5、7、10 d4个时相.采用胆总管结扎法建立梗阻性黄疸模型.C组从术后第1天始每天腹腔注射UTI 40 000IU/kg,A组和B组用等量生理盐水作对照.检测各时相肝功能,血浆内毒素,取肠系膜淋巴结、肝、脾组织行细菌培养,光镜观察末端回肠粘膜形态改变,并用病理图像分析系统测量肠绒毛高度及粘膜厚度.结果 各时相肝功能指标、血浆内毒素B组较A组升高(P＜0.01);C组较B组降低(P＜0.01);血浆内毒素C组较A组术后3 d时相差异无统计学意义(P＞0.05).细菌移位率B组较A组升高(P＜0.01);C组较B组降低(P＜0.05);C组与A组相比,差异无统计学意义(P＞0.05).B组术后第3天即见肠粘膜受损改变,随时间推移进行性加重;C组较B组肠粘膜损害明显减轻.B组各时相小肠绒毛高度、粘膜厚度均低于A组(P＜0.01);C组则较B组升高(P＜0.01或P＜0.05);C组较A组术后3 d时相差异无统计学意义(P＞0.05).结论 梗阻性黄疸早期即可导致肠粘膜屏障功能受损,且随时间延长进行性加重;UTI对梗阻性黄疸时受损的肠粘膜屏障功能具有保护作用,对早期病变效果更好.     

Metabolic endotoxemia promotes neuroinflammation after focal cerebral ischemia

Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria and a potent inflammatory stimulus for the innate immune response via toll-like receptor (TLR) 4 activation. Type 2 diabetes is associated with changes in gut microbiota and impaired intestinal barrier functions, leading to translocation of microbiota-derived LPS into the circulatory system, a condition referred to as metabolic endotoxemia. We investigated the effects of metabolic endotoxemia after experimental stroke with transient middle cerebral artery occlusion (MCAO) in a murine model of type 2 diabetes (db/db) and phenotypically normal littermates (db/+). Compared to db/+ mice, db/db mice exhibited an altered gut microbial composition, increased intestinal permeability, and higher plasma LPS levels. In addition, db/db mice presented increased infarct volumes and higher expression levels of LPS, TLR4, and inflammatory cytokines in the ischemic brain, as well as more severe neurological impairments and reduced survival rates after MCAO. Oral administration of a non-absorbable antibiotic modulated the gut microbiota and improved metabolic endotoxemia and stroke outcomes in db/db mice; these effects were associated with reduction of LPS levels and neuroinflammation in the ischemic brain. These data suggest that targeting metabolic endotoxemia may be a novel potential therapeutic strategy to improve stroke outcomes.     

脾皮下易位门体分流对肝移植大鼠菌血症及内毒素血症的影响

目的：探讨脾皮下易位门体分流（STS）对肝移植大鼠菌血症及内毒素血症的影响。方法：Wistar大鼠2组：STS后原位肝移植组（STS OLT组,n=30）,原位肝移植组（OLT组,n=30）。OLT组动物无肝期前后30和60min时间点门静脉及外周血细菌培养阳性率均明显高于STS OLT组。阳性菌分别为肠杆菌、粪杆菌或梭型杆菌类。OLT组动物无肝期后各时间点门静脉及外周静脉血中的内毒素水平均明显高于STS OLT组。结论：STS可明显地预防大鼠及肝移植无肝期菌血症及内毒素血症。     

Neural circuitry mediating inflammation-induced central pain amplification in human experimental endotoxemia

Background & aims: To elucidate the brain mechanisms underlying inflammation-induced visceral hyperalgesia in humans, in this functional magnetic resonance imaging (fMRI) study we tested if intravenous administration of lipopolysaccharide (LPS) involves altered central processing of visceral pain stimuli. Methods: In this randomized, double-blind, placebo-controlled fMRI study, 26 healthy male subjects received either an intravenous injection of low-dose LPS (N = 14, 0.4 ng/kg body weight) or placebo (N = 12, control group). Plasma cytokines (TNF-α, IL-6), body temperature, plasma cortisol and mood were assessed at baseline and up to 6 h post-injection. At baseline and 2 h post-injection (test), rectal pain thresholds and painful rectal distension-induced blood oxygen level-dependent (BOLD) responses in brain regions-of-interest were assessed. To address specificity for visceral pain, BOLD responses to non-painful rectal distensions and painful somatic stimuli (i.e., punctuate mechanical stimulation) were also analyzed as control stimuli. Results: Compared to the control group, LPS-treated subjects demonstrated significant and transient increases in TNF-α, IL-6, body temperature and cortisol, along with impaired mood. In response to LPS, rectal pain thresholds decreased in trend, along with enhanced up-regulation of rectal pain-induced BOLD responses within the posterior insula, dorsolateral prefrontal (DLPFC), anterior midcingulate (aMCC) and somatosensory cortices (all FWE-corrected p < 0.05). Within the LPS group, more pronounced cytokine responses correlated significantly with enhanced rectal pain-induced neural activation in DLPFC and aMCC. No significant LPS effects were observed on neural responses to non-painful rectal distensions or mechanical stimulation. Conclusions: These findings support that peripheral inflammatory processes affect visceral pain thresholds and the central processing of sensory-discriminative aspects of visceral pain.     

Role of neutrophils in acute inflammatory liver injury.

Hepatic infiltration of polymorphonuclear leukocytes (neutrophils) is an early response to tissue injury, cellular stress or systemic inflammation. Neutrophil activation is vital for host-defense and the removal of cell debris but can also cause additional tissue damage or even liver failure. In order to prevent the detrimental effects of neutrophils without compromising host-defense reactions, it is important to understand the mechanisms of neutrophil hepatotoxicity. The first step in the pathophysiology is the priming and recruitment of neutrophils into the liver vasculature by inflammatory mediators, e.g. cytokines, chemokines, or complement factors. Most critical for parenchymal cell damage is the accumulation in sinusoids, which does not depend on cellular adhesion molecules. The next step is the extravasation into the parenchyma. This process requires a chemotactic signal from hepatocytes or already extravasated neutrophils and depends on cellular adhesion molecules on neutrophils (beta(2) or beta(1) integrins) and on endothelial cells (intercellular or vascular cell adhesion molecules). The third step is the direct contact with target cells (hepatocytes), which involves beta(2) integrins and triggers the full activation of the neutrophil with a long-lasting adherence-dependent oxidant stress and degranulation. The oxidants diffuse into hepatocytes and trigger an intracellular oxidant stress, mitochondrial dysfunction and eventually cause oncotic necrotic cell death. Neutrophil-derived proteases facilitate extravasation and are involved in the regulation of inflammatory mediator production. Based on these mechanisms, it appears that strengthening of the intracellular defense mechanisms in hepatocytes may be the most promising therapeutic approach to selectively prevent neutrophil-mediated tissue damage without compromising their host-defense function.     

The possible role of antimicrobial proteins in obesity-associated immunologic alterations

Currently, obesity-associated metabolic disturbances are envisioned as chronic inflammatory processes, characterized by activation of both innate and adaptive immunity. Although the features of chronic inflammation in obese subjects are clearly defined, the signals and mechanisms that trigger chronic inflammation are not well understood. Recent studies suggest an imbalance in circulating antimicrobial proteins as a possible cause of obesity-associated metabolic disturbances and insulin resistance. This imbalance promotes a relative failure in the capacity of buffering external insults and might cause the onset of chronic inflammation and immunologic alterations in obesity. Here, we review the current literature on the possible role of circulating antimicrobial proteins in obesity-associated immunologic alterations.     

颈脊髓切断对内毒素血症大鼠急性肺损伤的影响

目的 研究颈脊髓切断对内毒素血症大鼠急性肺损伤的影响及可能机制.方法 72只SD大鼠随机分为3组:正常对照组(NC组,8只),内毒素血症组(ET组,32只)及内毒素血症+颈脊髓切断组(TCSC组,32只),后两组按不同时间点(3、6、12和48 h)又分为4个亚组,每个亚组8只.静脉注射脂多糖(LPS)10 mg/kg制备内毒素血症模型.TCSC组注射LPS前切断大鼠颈7脊髓.在不同时间点采血,并留取肺组织.采用高效液相色谱仪-电化学检测法和酶联免疫吸附法(ELISA)分别测定血浆去甲肾上腺素(NE)和白细胞介素-6(IL-6)的浓度;用血气分析仪检测动脉血氧分压(PaO2);观察各组大鼠肺组织病理学改变及肺湿/干重(W/D)比值.结果 TCSC组6、12和48 h血浆NE浓度、肺W/D比值较ET组均显著降低,PaO2较ET组显著升高,差异均有统计学意义(P均<0.05);TCSC组肺损伤程度减轻;3、6、12和48 h血浆IL-6均明显低于ET组(P均<0.05).相关性分析显示,血浆NE与IL-6浓度呈显著正相关(r=0.458,P<0.05),与PaO2呈显著负相关(r=0.528,P<0.05).结论 切断大鼠颈脊髓后造成去交感神经支配可能通过抑制肾上腺素能受体的过度激活而减轻内毒素血症大鼠急性肺损伤的程度,继而改善肺的氧合.