Gaseous mediators in resolution of inflammation

There are numerous gaseous substances that can act as signaling molecules, but the best characterized of these are nitric oxide, hydrogen sulfide and carbon monoxide. Each has been shown to play important roles in many physiological and pathophysiological processes. This article is focused on the effects of these gasotransmitters in the context of inflammation. There is considerable overlap in the actions of nitric oxide, hydrogen sulfide and carbon monoxide with respect to inflammation, and these mediators appear to act primarily as anti-inflammatory substances, promoting resolution of inflammatory processes. They also have protective and pro-healing effects in some tissues, such as the gastrointestinal tract and lung. Over the past two decades, significant progress has been made in the development of novel anti-inflammatory and cytoprotective drugs that release of one or more of these gaseous mediators.     

Serum miRNA profiling identifies miR-150/30a as potential biomarker for workers with damaged nerve fibers from carbon disulfide

As crucial small regulatory molecules, serum microRNAs (miRNAs) have been widely identified as potential noninvasive biomarkers. To survey and identify serum miRNAs associated with workers who had experienced injury to their nerve system from carbon disulfide (CS₂), we profiled abnormally expressed miRNAs using the microarray technique and further performed qRT-PCR validation in case and control samples (n=20). Microarray profiling in pooled RNA samples showed that many miRNAs in workers exposed to CS₂ were aberrantly expressed. Based on control samples exposed to CS₂, a great amount of abnormal miRNAs, including some miRNA gene clusters and families, were obtained from microarray datasets. Most of deregulated miRNAs were up-regulated, and almost all miRNAs showed consistent expression patterns between workers with different numbers of damaged nerve fibers. Functional enrichment analysis suggested that these abnormal miRNAs showed versatile roles by contributing to multiple biological processes. Some aberrantly expressed miRNAs were characterized as miRNA gene clusters or families, and they always showed consistent expression patterns. miR-150 and miR-30a were selected to be further validated by qRT-PCR as up-regulated species, and they could discern case samples from control samples. miR-150 and miR-30a may be potential noninvasive biomarkers for a damaged nervous system.     

rhKD/APPvar对实验性急性肝损伤小鼠肝细胞增殖能力的影响

目的探讨重组人淀粉样蛋白前体Kunitz型蛋白酶抑制剂结构域变异体(Reorganization human Kunitz protease inhibitor domain of amyloid protein precursor variant,rh KD/APPvar)对实验性急性肝损伤小鼠肝细胞增殖能力的影响。方法利用实验鼠的四氯化碳(CCl4)慢性肝损伤模型,采用免疫组化方法,检测各组增殖细胞核抗原(Proliferating cell nuclear antigen,PCNA)阳性细胞数。结果正常对照组的PCNA阳性细胞数为(2±2)个/视野,模型组的PCNA阳性细胞数为(6±3)个/视野,rh KD/APPvar小、中、大剂量组的PCNA阳性细胞个数分别为(29±110)个/视野、(38±10)个/视野、(55±12)个/视野,抑肽酶组的PCNA阳性细胞个数为(24±9)个/视野,rh KD/APP组的PCNA阳性细胞个数为(19±5)个/视野。与模型组相比,rh KD/APPvar各剂量组PCNA阳性细胞数目均显著增加(P<0.05),并且存在剂量依赖关系。rh KD/APPvar各剂量组阳性细胞数多于抑肽酶组。结论 rh KD/APPvar能够促进急性肝损伤小鼠肝细胞增殖,其作用随着剂量的增加而增强。     

绞股蓝总皂甙对原代培养大鼠肝细胞四氯化碳损伤的影响

采用四氯化碳(CCl_4)制成原代培养大鼠肝细胞损伤模型,观察了绞股蓝总皂甙(GPS)对肝细胞损伤的保护作用。结果表明,预先用 GPS 处理肝细胞 lhr,可明显减轻 CCl_4引起的肝细胞 DNA 合成速率降低,减少肝细胞 ALT 逸出,抑制培养上清液中 MDA 含量的升高和 SOD/MDA 比值的缩小,并与 GPS 浓度呈依赖关系。提示 GPS 能减轻 CCl_4对离体培养的大鼠肝细胞损伤,保护肝细胞 DNA 合成,其作用机理与抗脂质过氧化有关。     

Effect of low-molecular-weight heparin on the commitment of bone marrow cells to liver sinusoidal endothelial cells in CCl(4)-induced liver injury.

BACKGROUND/AIMS: Recently liver regeneration by bone marrow transplantation has been proposed as an alternative source of functional liver cells. We investigate commitment of bone marrow cells (BMCs) to liver regeneration and the effect of dalteparin sodium (DS) on regeneration of the damaged liver caused by carbon tetrachloride (CCl(4)) administration in the mice. METHODS: Liver injury was produced in 8-week-old mice by treating with CCl(4) for 4 weeks. Thereafter, mice received a lethal dose of irradiation (10Gy) to whole body, followed by injection of 1x10(7) green fluorescent protein (GFP)-positive BMCs via the tail vein. DS (50IU/kg, intraperitoneally) was administered daily for 28 consecutive days starting at 1 day post-BMC transplantation. Lineage marker analysis of GFP-positive liver cells was performed immunostaining with a CD31 antibody. RESULT: Four weeks after BMC transplantation, GFP-positive cells in the CCl(4)-damaged liver could be detected in the lobule displaying a meshwork architecture extending from the periportal to pericentral regions, a pattern simulating sinusoidal lining. This localization of GFP-positive cells suggested that these cells were closely associated with sinusoidal endothelial cells. By staining the GFP-positive cells for CD31, it was confirmed that the majority of the GFP-positive cells are also positive for CD31. The GFP(+)CD31(+) cells were barely detected in the control group (1.0+/-1.2 per field). In marked contrast, a numerous number of GFP(+)CD31(+) cells were detected in the liver section obtained from the CCl(4)-induced liver damage group (3.8+/-1.3 per field, P<0.05 versus control). The number of GFP(+)CD31(+) cells in CCl(4) plus DS-treated group was further increased to 8.3+/-1.3 per field (P<0.05 versus CCl(4)-induced liver damage group). CONCLUSION: The majority of GFP-positive BMCs was committed to sinusoidal endothelial cells. DS promoted BMC differentiation into sinusoidal endothelial cells in the CCl(4)-damaged liver.     

Mechanism of autoimmune hepatic fibrogenesis induced by an adenovirus encoding the human liver autoantigen cytochrome P450 2D6

Autoimmune hepatitis type 2 (AIH-2) is a severe autoimmune liver disease with unknown etiology. We recently developed the CYP2D6 mouse model for AIH-2, in which mice are challenged with an adenovirus (Ad-2D6) expressing human cytochrome P450 2D6 (hCYP2D6), the major autoantigen in AIH-2. Such mice develop chronic hepatitis with cellular infiltrations and generation of hCYP2D6-specific antibodies and T cells. Importantly, the CYP2D6 model represents the only model displaying chronic fibrosis allowing for a detailed investigation of the mechanisms of chronic autoimmune-mediated liver fibrogenesis. We found that hCYP2D6-dependent chronic activation of hepatic stellate cells (HSC) resulted in an increased extracellular matrix deposition and elevated expression of α-smooth muscle actin predominantly in and underneath the liver capsule. The route of Ad-2D6 infection dramatically influenced the activation and trafficking of inflammatory monocytes, NK cells and hCYP2D6-specific T cells. Intraperitoneal Ad-2D6 infection caused subcapsular fibrosis and persistent clustering of inflammatory monocytes. In contrast, intravenous infection caused an accumulation of hCYP2D6-specific CD4 T cells throughout the liver parenchyma and induced a strong NK cell response preventing chronic HSC activation and fibrosis. In summary, we found that the location of the initial site of inflammation and autoantigen expression caused a differential cellular trafficking and activation and thereby determined the outcome of AIH-2-like hepatic damage and fibrosis.     

Association between early arterial blood gas tensions and neurological outcome in adult patients following in-hospital cardiac arrest

ObjectiveThe early partial pressures of arterial O₂ (PaO₂) and CO₂ (PaCO₂) have been found in animal studies to be correlated with neurological outcome after brain injury. However, the relationship of early PaO₂ and PaCO₂ to the neurological outcomes of resuscitated patients after cardiac arrest was still not clear.MethodsThis was a retrospective observational cohort study in a single medical center. Adult patients who had in-hospital cardiac arrest between 2006 and 2012 and achieved sustained return of spontaneous circulation (ROSC) (ROSC > 20 min without resumption of chest compression) were included. Multivariable logistic regression analysis was used to identify factors associated with favorable neurological outcome at hospital discharge. The first PaO₂ and PaCO₂ values measured after first sustained ROSC were used for analysis.ResultsOf the 550 included patients, 154 (28%) survived to hospital discharge and 74 (13.5%) achieved favorable neurological outcome. The mean time from sustained ROSC to the measurement of PaO₂ and PaCO₂ was 136.8 min. The mean PaO₂ and PaCO₂ were 167.4 mmHg and 40.3 mmHg, respectively. PaO₂ between 70 and 240 mmHg (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.08–3.64) and PaCO₂ levels (OR 0.98, 95% CI 0.95–0.99) were positively and inversely associated with favorable neurological outcome, respectively.ConclusionsThe early PaO₂ and PaCO₂ levels obtained after ROSC might be correlated with neurological outcome of patients with in-hospital cardiac arrest. However, because of the inherent limitations of the retrospective design, these results should be further validated in future studies.     

不同细胞构筑在高压氧治疗迟发型脑病中的功能研究

目的：通过研究高压氧（ HBO）治疗急性CO中毒大鼠皮层不同细胞构筑在神经细胞凋亡中的差别,探讨HBO治疗急性CO中毒的机制及靶向定位。方法利用雄性SD大鼠,建立急性CO中毒模型。应用免疫组织化学以及免疫荧光的方法,测定在CO中毒和HBO治疗1 d、3 d、7 d、14 d和21 d后Caspase－3、NeuN和MMP－9的表达变化。结果急性CO中毒后,皮层神经细胞凋亡随中毒后时间延长而加重;不同细胞构筑发生凋亡程度不同,内颗粒层和内锥体细胞层最明显;Caspase－3与MMP－9在内颗粒层与内锥体细胞层变化最明显,在1 d开始增多,3 d达到最大值,7 d开始减少;HBO治疗后,MMP－9和Caspase－3降低,尤其以内颗粒层与内锥体细胞层最明显;且HBO治疗7 d后,降低最明显。结论急性CO中毒后,皮层各层神经细胞均发生凋亡现象,内颗粒层和内锥体细胞层最明显;凋亡可能与MMP－9降解神经细胞周围的基质, Caspase－3促进凋亡有关;HBO治疗可能是通过调控复杂的蛋白表达机制,调节MMP－9以及Caspase－3的表达水平,最终抑制神经细胞的凋亡;HBO治疗7 d对凋亡的作用最明显。     

水药酢浆草对四氯化碳致小鼠肝损伤的保护性研究

目的 探讨水药酢浆草对四氯化碳CCl4诱导的小鼠肝损伤的保护作用。方法 将40只小鼠随机分为5组,正常组、CCl4模型组、酢浆草低、中、高剂量组,每组8只。正常组和CCl4模型组给予生理氯化钠溶液,酢浆草低、中、高剂量组给分别给100、300及600 mg/kg酢浆草灌胃,连续5 d。于末次给药2 h后,除正常组外,其余各组小鼠给予0.3% CCl4花生油溶液稀释、按0.02 ml/g的剂量皮下注射,在中毒后16 h取血和肝脏组织,分别检测各组小鼠肝功能相关的生化指标。结果 与CCl4模型组小鼠比较,不同剂量酢浆草治疗组小鼠肝脏指数、血清ALT、AST及TNF-α水平不同程度降低（P <0.05）;肝组织中CAT、GSH及SOD水平不同程度升高（P <0.05）,MDA水平不同程度降低（P <0.05）。结论 水药酢浆草对CCl4所致小鼠肝损伤具有明显的保护作用,其机制可能与酢浆草降低氧化酶活性和抗脂质过氧化作用有关。