Suppression of hemopoiesis during CCl4-induced hepatic fibrosis: Role of systemic endotoxemia

CCl₄-induced hepatic fibrosis in mice was accompanied by insufficiency of bone marrow myelo- and erythropoiesis. Polymyxin B completely abolished these changes. This phenomenon can be explained by the development of macrophage endotoxin tolerance during hepatic fibrosis. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 130, No. 8, pp. 172–175, August, 2000     

抗LPS-IgY防治烧伤小鼠肠源性内毒素血症的实验研究

目的实验研究抗LPS-IgY对烧伤肠源性内毒素血症的作用。方法标准LPS免疫鸡,采用改良水溶法(WD)从蛋黄中提取特异性抗内毒素IgY。将纯系昆明种小鼠制成30%体表面积(TBSA)Ⅲ°烧伤合并内毒素血症的动物模型,喂服抗LPS-IgY并定期检测血中LPS、二胺氧化酶(DAO)、肿瘤坏死因子(TNF-α)等相关指标。结果喂服抗LPS-IgY后,能明显降低烧伤小鼠的死亡率;明显降低血浆中LPS、DAO和TNF-α的含量;回肠黏膜的损伤程度明显减轻。结论抗LPS-IgY有效拮抗LPS,减少其移位入血,减轻回肠黏膜的损害,对烧伤小鼠肠源性内毒素血症疗效较好。     

A mechanism for shock following stomach rupture in the newborn

BACKGROUND: Stomach rupture often leads to shock and death within a short period, but the mechanism for this is not well-known. Shock may be due, in part, to endotoxin translocation and endotoxemia. METHODS: Sterile, endotoxin-free HCl (0.1 mol/L), with or without endotoxin-feeding, was injected intraperitoneally into 10-day-old rats, simulating stomach rupture in the newborn. The plasma endotoxin concentration was measured. Plasma glucose and lactate concentrations were monitored to assess physiologic response to endotoxemia and shock. RESULTS: Endotoxin feeding alone caused endotoxemia (0.49 +/- 0.12 ng/mL; P < 0.05) in 10-day-old rats, while plasma endotoxin concentration in controls was less than 0.04 ng/mL. However, the endotoxemia did not cause disruption of glucose regulation or death. Injection of HCl alone did not increase plasma endotoxin concentrations and did not alter glucose regulation. However, HCl injection into endotoxin-fed rats induced endotoxemia (211.1 +/- 70.5 ng/mL; P < 0.05), hypoglycemia, lactacidemia and mortality (45%; P < 0.05). CONCLUSION: Early development of shock following stomach rupture may be in part due to endotoxin translocation and endotoxemia.     

New Insights into the Biology of the Acute Phase Response

Innate or natural immunity is a highly conserved defense mechanism against infection found in all multicellular organisms. The acute phase response is the set of immediate inflammatory responses initiated by pattern recognition molecules. These germ cell-encoded proteins recognize microbial pathogens based on shared molecular structures and induce host responses that localize the spread of infection and enhance systemic resistance to infection. Innate immunity also influences the initiation and type of adaptive immune response by regulating T cell costimulatory activity and antigen presentation by antigen presenting cells and by influencing mediator production, which affects lymphocyte function and trafficking. Acute phase protein concentrations rapidly increase after infection, and their production is controlled primarily by IL-6- and IL-1-type cytokines. The acute phase proteins provide enhanced protection against microorganisms and modify inflammatory responses by effects on cell trafficking and mediator release. For example, serum amyloid A has potent leukocyte activating functions including induction of chemotaxis, enhancement of leukocyte adhesion to endothelial cells, and increased phagocytosis. The constellation of inflammatory responses seen after endotoxin administration to humans represents an in vivo model of the acute phase response. Studies with inflammatory modifying agents, such as soluble dimeric TNF receptor and IL-10, show that these responses are not dependent on a single mediator but result from multiple overlapping inflammatory pathways. Understanding the factors that initiate and alter the magnitude and duration of the acute phase response represents an important step in the development of new therapies for infectious and inflammatory diseases.     

血小板激活因子在烧伤合并内毒素血症早期肠粘膜损害中的作用

目的：探讨血小板激活因子（ＰＡＦ）在烧伤合并内毒素内毒素粘膜损害中的作用。方法：采用２０％Ⅲ度体表烧伤合并小剂理内毒素（ＬＰＳ １ｍｇ／ｋｇ）注射的大鼠模型,动态检测了肠组织ＰＡＦ,磷脂酶Ａ２（ＰＬＡ２）,黄嘌呤氧化酶（ＸＯ）,丙二醛（ＭＤＡ）等的变化。     

温阳解毒化瘀颗粒对肝衰竭IETM大鼠TLR4 mRNA,TNF-α及肝细胞凋亡的影响

目的:研究Toll样受体4(TLR4) mRNA及其下游炎性因子肿瘤坏死因子-α(TNF-α)与肝衰竭肠源性内毒素血症(IETM)大鼠肝细胞凋亡的关系,并探索温阳解毒化瘀颗粒对内毒素介导的肝细胞凋亡的调控机制。方法:SPF级雄性SD大鼠85只,随机分为正常组,模型组,TLR4单克隆抗体组和温阳解毒化瘀颗粒组(8.925 g·kg^-1)。采用D-半乳糖胺(D-Gal)腹腔注射建立肝衰竭IETM模型,TLR4单克隆抗体组和温阳解毒化瘀颗粒组在造模前5 d给予温阳解毒化瘀颗粒溶液灌胃,正常组、模型组以等容积蒸馏水代替,直至处死。各组分别在24,48,72 h随机处死大鼠并采集标本。检测24,48,72 h各组时间点血清丙氨酸氨基转移酶(ALT),天门冬氨酸氨基转移酶(AST)水平,苏木素-伊红(HE)染色观察肝组织病理变化,实时荧光定量聚合酶链式反应(Real-time PCR)检测肝组织TLR4 mRNA表达,酶联免疫吸附测定法(ELISA)检测肝组织TNF-α表达,流式细胞仪检测肝细胞凋亡率。结果:与正常组比较,模型组ALT,AST升高,肝组织病理损伤程度明显加重,TLR4mRNA,TNF-α表达均增高(P<0.05,P<0.01),肝细胞凋亡率明显上升(P<0.05,P<0.01);与模型组比较,温阳解毒化瘀颗粒组ALT,AST显著降低(P<0.01),肝组织病理损伤程度明显减轻(P<0.05),TLR4 mRNA,TNF-α表达显著下降(P<0.01),肝细胞凋亡率亦显著降低(P<0.01)。结论:TLR4 mRNA,TNF-α在肝衰竭时与肝细胞凋亡呈正相关,温阳解毒化瘀颗粒能够改善肝衰竭IETM大鼠肝功能,减轻肝细胞损伤,减少肝细胞凋亡,其机制可能与其下调肝脏TLR4 mRNA表达,抑制TNF-α释放,降低肝细胞凋亡率有关。     

肺挫伤复合内毒素血症肺损伤模型的建立及其早期肺炎症反应变化

目的 建立一种可用于实验研究的急性肺损伤（ALI）模型,观察其早期肺炎症反应特点,并探讨此模型下肺炎症反应与肺损伤伤情的关系。方法 首先以生物撞击机复制肺挫伤模型。经尾静脉注射内毒素（LPS）,复制内毒素血症肺损伤模型;用同样的方法实施胸部撞击伤,然后注射LPS,建立肺挫伤复合内毒素血症肺损伤模型;观察三个模型下的死亡率、动脉血氧分压（PaO2）、肺含水率（RLW）及肺泡灌洗液（BALF）内多形核白细胞（PMN）和炎性介质变化。结果 肺挫伤复合内毒素血症肺损伤模型的48小时死亡率为57.5%,显著高于肺挫伤和内毒素血症肺损伤模型的死亡率;本模型致伤后早期PaO2降低和RLW升高程度均较其它两种模型明显,BALF内PMN计数和炎性介质水平出现显著变化,变化程度较其它两组明显。结论 肺挫伤复合内毒素血症肺损伤模型是一种严重的ALI模型,此模型的肺组织发生了明显的炎症反应;BALF中炎性介质于致伤后早期出现明显变化,创伤后早期肺炎症反应水平影响肺损伤程度及预后的重要因素。     

Nitric oxide mediates the inhibition of neutrophil migration induced by systemic administration of LPS

To investigate the role of NO in the inhibition of neutrophil migration by circulating endotoxin, mice were pretreated with NO synthase inhibitors or with a free radical scavenger (D-penicillamine), before intravenous LPS injection. LPS dose-dependently inhibited the thioglycollate-induced neutrophil migration into the peritoneal cavities. Aminoguanidine, a selective inducible NO synthase inhibitor, abolished the inhibition of neutrophil migration and the increase in serum nitrate levels induced by a nonlethal dose of LPS. During lethal endotoxemia aminoguanidine partially abolished the neutrophil migration inhibition. Additionally, D-penicillamine prevented the inhibition of neutrophil migration caused by LPS. However, Nitro-L-Arginine, a selective constitutive NO synthase inhibitor, did not prevent neutrophil migration inhibition. Aminoguanidine treatment did not affect the systemic increased levels of TNF-, IL-1, and IL-10, suggesting that NO is the final mediator involved in the inhibition of neutrophil migration. Our results suggest that NO released by the inducible NO synthase mediates the inhibition of neutrophil migration mediated by circulating LPS.     

利开灵对脑出血大鼠继发肠源性内毒素血症的干预作用

目的:探讨利开灵对脑出血后大鼠体内继发肠源性内毒素血症的干预作用。方法:采用Rosenberg法改良后建立大鼠脑出血模型,根据脑出血不同时点(12h、24h、48h和72h)分为4组,每个时间点再分为3组:假手术组、模型组、利开灵组,观察利开灵对肠组织相应病理改变的影响,并用终点显色法检测各组血浆内毒素(LPS)水平,ELISA法检测各组血清TNF-α、IL-1β水平。结果:模型组血浆LPS各时点均明显升高,在48h达高峰(P<0.01);血清TNF-α、IL-1β升高,均在24h达高峰(P<0.01)。同时发现利开灵可明显改善肠组织病理形态损伤,下调血浆LPS以及血清TNF-α、IL-1β过高表达。结论:脑出血大鼠继发肠源性内毒素血症,利开灵对其有较好的调控作用,这对改善脑出血预后具有积极意义。     

Cortisol exerts bi-phasic regulation of inflammation in humans

Natural and synthetic glucocorticoids (GCs) have been used for decades to suppress inflammation. In this paper, we re-examine the role of the endogenous GC, cortisol, as a primary homeostatic regulator of the human inflammatory response to injury. Our data show that cortisol regulation of innate immunity can be both pro-inflammatory and anti-inflammatory. Using a human model of in vivo cortisol depletion, we first show that baseline (diurnal) cortisol concentrations do not exert an anti-inflammatory effect. This is the first clue that cortisol regulation of inflammation is not represented by a linear dose-response relationship. We next show in surgical patients that cortisol does exert an acute anti-inflammatory effect over a carefully regulated range of physiologic cortisol concentrations. Finally, transient pre-treatment of healthy humans with cortisol induces a bi-phasic response during a later, delayed systemic inflammatory response: an intermediate cortisol concentration augments inflammation while a high cortisol concentration is neither pro- nor anti-inflammatory. Based on these findings and the work of others, we propose a new paradigm that identifies cortisol regulation of human inflammation as both dualistic-it is pro- and anti-inflammatory-and dynamic, it evolves over time.