人血浆高密度脂蛋白对大鼠内毒素血症的治疗及防护作用研究

目的:观察人血浆高密度脂蛋白(HDL)对大鼠内毒素血症的治疗和防护效果。方法:采用鲎试剂法和放射免疫分析法于3个时点动态测定对照组、治疗组和防护组大鼠血浆内毒素(ET)水平和肿瘤坏死因子(TNF)浓度并观察血压及存活时间。结果:①输注ET后对照组大鼠血压进行性下降(P<0.01);治疗组大鼠输注HDL后其血压虽也降低但下降程度明显弱于对照组(P<0.01);防护组大鼠在输注ET后血压无明显下降(P>0.05)。治疗组及防护组大鼠存活时间均明显长于对照组(P<0.01)。②3组大鼠血浆ET水平在各时点均无明显变化(P>0.05)。③治疗组及防护组大鼠血浆TNFα水平于第3时点均明显降低(P>0.05)。结论:人血浆HDL能减轻或抑制内毒素血症大鼠血压下降并明显延长其存活时间,对内毒素血症具有良好的治疗和防护作用,此作用可能与其抑制TNF释放有关。     

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。     

人参提取物对内毒素所致小鼠脾细胞损伤的保护作用

目的 观察人参提取物在内毒素脂多糖(LPS)所致的SIRS／MODS中对脾细胞的作用。方法 通过HE、TUNEL染色和透射电镜比较注射人参提取物(GS)后再注射LPS时的脾脏形态学及凋亡情况，并用免疫组织化学的方法检测Bcl-2，Fas，FasL的表达。结果 随LPS作用时间的延长，脾损伤逐渐加重。动脉周围淋巴鞘细胞碎片及TUNEL阳性细胞增多，电镜观察可见到凋亡的淋巴细胞。而人参组细胞损伤明显减轻。Bcl-2的表达随着LPS作用时间的延长而减少，Fas，FasL则增强。人参提取物主要阻止Bcl-2表达减少。结论 人参提取物对LPS脾细胞损伤有保护作用，其作用机制与增强Bcl-2表达有关。     

黄芪多糖对内毒素血症性肺损伤治疗作用的实验研究

目的:探讨中药黄芪多糖(APS)对脂多糖(LPS)诱导的内毒素血症性肺损伤小鼠的治疗作用。方法:40只健康10-12周龄成年C57BL/6J小鼠随机分为正常对照组、肺损伤模型组、地塞米松治疗组和APS治疗组,每组10只。除正常对照组外,其余三组小鼠均采用腹腔注射LPS 5mg/Kg,成功制模。成模后2h、24h和48h,地塞米松治疗组和APS治疗组分别通过腹腔注射地塞米松(5mg/Kg·次)或APS(200mg/Kg·次),正常对照组和肺损伤模型组则在各时间点通过平行注射等量磷酸盐缓冲液。72h后处死各组小鼠,先行支气管肺泡灌洗,并检测支气管肺泡灌洗液(BALF)蛋白含量;留取肺组织标本,行肺组织湿干重比值(W/D)测定和肺组织病理学观察。结果:肺损伤模型组BALF中蛋白含量(0.25±0.09mg/ml)和肺组织W/D(6.13±0.63)均显著高于正常对照组(分别为0.09±0.04mg/ml和4.72±0.63,P0.01);地塞米松治疗组和APS治疗组BALF蛋白含量(0.13±0.05mg/ml,0.17±0.04mg/ml)、肺组织W/D(5.31±0.48,5.43±0.47)均较肺损伤模型组显著降低,差异有统计学意义(P0.05)。肺组织病理学结果显示,与正常对照组相比,肺损伤模型组肺泡间隔明显增宽,肺组织有明显炎性细胞浸润、小血管充血、出血,部分肺泡内可见水肿;地塞米松治疗组和APS治疗组肺组织的上述炎性损伤较肺损伤模型组显著改善。结论:APS实验性治疗内毒素血症性肺损伤是可行和有效的。     

金多靶对内毒素血症作用的实验研究

目的研究减肥降脂中药金多靶防治内毒素血症的疗效及机理。方法用静脉注射内毒素（ＬＰＳ ０．５ｍｇ／１ｍｌ／１００ｇ Ｂ．Ｗ．）的方法复制急性内毒素血症家兔（ｎ＝１２）模型，事先灌服金多靶（１．５ｍｇ／１００ｇ Ｂ．Ｗ．）后观察 ０ｈ、１ｈ、２ｈ、４ｈ平均动脉血压（ＭＢＰ，颈动脉插管法）、血清内毒素浓度（赏试验法）、血清ＴＮＦα浓度（ＥＬＩＳＡ法）及肠内容物移动距离（美兰法）。结果与灌服生理盐水对照组比，金多靶组ＭＢＰ下降不明显，内毒素及ＴＮＦα浓度均明显下降（Ｐ＜Ｏ．０５），肠内容物移动距离明显加快（Ｐ＜０．０５），与血清内毒素浓度间呈显著负相关（ｒ＝－０．９４，Ｐ＜０．０５）。结论金多靶能降低内毒素浓度，减少ＴＮＦα的生成，有效维持动脉血压，对内毒素血症有一定防治效果。上述作用与金多靶引起肠内容物移动距离加大、大便排出增多有关。     

谷氨酰胺对大鼠梗阻性黄疸内毒素血症影响的实验研究

目的 探讨谷氨酰胺对大鼠梗阻性黄疸内毒素血症的影响,为临床减少梗阻性黄疸患者内毒素血症的发生提供理论依据.方法 采用健康SD大鼠96只,随机分成三组,每组32只,分为假手术组、谷氨酰胺组(GLN组)、梗阻性黄疸组(OJ组).采用偶氮显色法检测血浆内毒素的含量,观察不同时间段各组大鼠内毒素的变化情况,并采用HE染色法观察肠粘膜的组织学改变.结果 梗阻性黄疸组血浆内毒素水平较假手术组有显著升高,且随时间的增长内毒素水平也随之升高,与同一时间段假手术组相比有显著差异(P＜0.01);梗阻性黄疸后服用谷氨酰胺,血浆内毒素可以得到明显的控制,与同期的不经任何治疗的梗阻性黄疸组相比差异显著(P＜0.01);梗阻性黄疸组大鼠和谷氨酰胺组大鼠的胆总管直径明显大于假手术组,但梗阻性黄疸组与谷氨酰胺组大鼠胆总管直径无明显差异(P＞0.05).结论 谷氨酰胺具有保护和修复肠粘膜屏障,减轻梗阻性黄疸时伴发的内毒素血症的作用,且价格较低,易于在临床推广.     

罗红霉素对大鼠内毒素性血症的治疗作用

目的探讨罗红霉素对大鼠急性肺损伤模型的治疗作用.方法动物随机分为⑴正常对照组(NC),经胃灌入生理盐水10mL/kg;⑵内毒素组(LPS),静脉注射lipopolysaccharide(LPS,2mg/kg)建立大鼠急性肺损伤(ALI)模型,5min后灌胃生理盐水10mL/kg;⑶罗红霉素治疗组(Rx),静脉注射LPS2mg/kg5min后,经胃灌入罗红霉素20mg/kg.测定各组平均动脉压、动脉血氧分压、氧饱和度、二氧化碳分压、肺系数、肺水含量、肺通透性指数,观察肺组织病理学变化.结果注射LPS后大鼠平均动脉压立即下降,0.5min降至最低后回升,1.5h升高达峰值,之后逐渐下降,4h后LPS组大鼠平均动脉压[(56.64±7.45)mmHg]与NC组比较[(97.94±7.73)mmHg]显著下降(P＜0.01);而Rx组[(103.40±8.56)mmHg]变化不明显(P＞0.05).Rx组动脉血氧分压[(85.36±7.67)mmHg]、二氧化碳分压[(42.75±4.24)mmHg]和pH(7.37±0.03)分别与LPS组[(52.43±8.25)mmHg,(67.38±7.21)mmHg,7.28±0.06]相比有明显改善(P＜0.05),Rx组与LPS组相比肺系数(0.58±0.03vs0.67±0.04,P＜0.05);肺水含量(78.76±2.13vs82.81±3.87,P＜0.05);肺通透性指数(6.25±0.74vs12.47±0.89,P＜0.05)有明显下降,病理学观察Rx组肺组织病变减轻.结论罗红霉素能改善大鼠内毒素血症时血液动力学变化和气体交换能力,减轻大鼠内毒素造成的肺损伤,该治疗作用是否与罗红霉素调节机体细胞炎性因子与抗炎性因子平衡有关,尚需进一步探讨.     

大鼠低纤维连接蛋白血症时循环内皮细胞变化的研究

用静脉注射明胶的方法复制大鼠低纤维连接蛋白血症模型，结果发现，低Ｆｎ血症大鼠循环内皮细胞明显多于对照组，且与血浆Ｆｎ减少呈正相关。低Ｆｎ血症时，ＣＥＣ表面的Ｆｎ免疫荧光明显减弱，主动脉壁管腔面内皮Ｆｎ免疫荧光也明显减弱。作者提出，血浆Ｆｎ减少引起内皮细胞表面Ｆｎ减少，使内皮细胞间的链链作用和伸展作用削弱，从而引起ＣＥＣ在形态上的皱缩、折叠并成为ＣＥＣ增加的一个重要原因。     

内毒素血症与肝脏疾病相关临床与实验研究进展

内毒素是革兰阴性细菌细胞壁中的脂多糖(LPS)组分.只有当细菌死亡溶解或用人工方法破坏菌细胞后才释放出来.血中细菌或病灶内细菌释放出大量内毒素至血液,或输入大量内毒素污染的液体而引起的一种病理生理表现称作内毒素血症.内毒素血症可以导致多种肝脏疾病的产生,其发生机制比较复杂,其中Toll样受体-4(TLR4)、CD14受体及Kupffer细胞在内毒素性肝损害的发生发展中起着重要作用.近年来,对于内毒素血症和肝脏疾病的临床和实验研究有了较大进展.     

失血性休克对内毒素血症小鼠CD14 mRNA表达的影响

观察家兔失血性休克合并门静脉源性轻度内毒素血症动物血压，血浆乳酸，β－Ｇ水平和死亡率的变化，结合小鼠腹腔巨噬细胞内ＣＤ１４ｍＲＮＡ的表达，并对休克增敏内毒素作用的机制进行初步分析。结果表明：输入ＬＰＳ后，失血休克＋ＬＰＳ组动物血压持续显著下降，血浆乳酸。β－Ｇ水平显著升高，且分别明显低于或高于单纯ＬＰＳ或ＨＳ组。     

用血液灌流治疗内毒素血症的研究进展

内毒素血症是由于血中细菌或病灶释放出大量内毒素至血液,或输入大量内毒素污染的液体而引起,它可促进全身炎症反应综合征、脓毒症、多器官功能障碍综合征的发生、发展,早期诊断并及时阻断,对于阻止细菌感染的进一步加剧、防治脓毒症等并发症具有积极意义。近年来,用血液灌流方法治疗内毒素血症已取得一些进展。通过直接吸附清除血液中的内毒素和炎性细胞因子,可使其浓度迅速降低,既减弱了其本身的活性,又抑制了其它有害因子的释放,从而改善感染症状。迄今为止,具有临床应用价值的特异性高效亲和吸附剂仍处于探索阶段,这些吸附材料对内毒素血症患者的治疗虽然取得了一定疗效．但仍需讲行深入的研究．以便更好地确定临床入诜标准,获得更满意的疗效。     

Fibronectin

Summary Fibronectin is a dimeric glycoprotein with a molecular weight of 440,000. It is a soluble constituent of plasma and other body fluids and a fibrillar matrix protein of connective tissue. The two components are structurally similar and convertible. The possibility of multiple molecular interactions gives rise to a variety of biological functions. The regulation of cell growth and the reduced shedding of fibronectin from malignant cells raises the question as to whether fibronectin is valid as a tumour marker. In wound healing and chronic inflammation fibronectin serves as a scaffold for the formation of collagen. As opsonic protein it maintains reticuloendothelial function. Especially in shock, fibronectin may become the limiting factor of unspecific host defence mechanisms. The value of a substitution therapy will be discussed.

     

甘氨酸对严重烧伤后脓毒症大鼠肝肾功能保护作用

目的探讨严重烧伤大鼠应用甘氨酸（Gly）拮抗内毒素（LPS）、保护肝肾功能的作用。方法选用Wistar大鼠24只,雌雄不拘,将动物按实验设计随机分为3组：单纯烧伤组（A组）;烧伤＋LPS攻击组（B组）;烧伤＋LPS攻击＋Gly治疗组（C组）,各组8只大鼠。将大鼠造成20%深Ⅱ度以上烧伤,伤后6h腹腔注射乳酸林格氏液（40ml/kg）延迟复苏,复苏后3hC组于腹腔注射LPS溶液10mg/kg,B组在LPS攻击的同时给予浓度为1g/3ml的Gly溶液灌胃。于伤后12h活杀全部大鼠,留取血液以及肝肾器官组织标本。结果成功复制脓毒症模型;各组血浆LPS水平均不同程度升高,其中B组显著高于A组、C组（P〈0.05）;脓毒症大鼠肝肾功能显著异常,甘氨酸灌胃后明显好转;大鼠单纯烫伤后肝、肾组织在12h内从总体上均呈现间质淤血、炎性反应的病理形态学改变,而同时给予Gly灌胃治疗后,各器官淤血、炎性反应程度明显减轻。结论Gly能降低烧伤后脓毒症大鼠血浆LPS水平,改善肝、肾功能及组织的病理形态学变化,具有器官功能保护作用。     

Pim1 permits generation and survival of CD4+ T cells in the absence of γc cytokine receptor signaling

γ‐chain (γc) cytokine receptor signaling is required for the development of all lymphocytes. Why γc signaling plays such an essential role is not fully understood, but induction of the serine/threonine kinase Pim1 is considered a major downstream event of γc as Pim1 prevents apoptosis and increases metabolic activity. Consequently, we asked whether Pim1 overexpression would suffice to restore lymphocyte development in γc‐deficient mice. By analyzing Pim1‐transgenic γc‐deficient mice (Pim1^Tgγc^KO), we show that Pim1 promoted T‐cell development and survival in the absence of γc. Interestingly, such effects were largely limited to CD4⁺ lineage αβ T cells as CD4⁺ T‐cell numbers improved to near normal levels but CD8⁺ T cells remained severely lymphopenic. Notably, Pim1 over‐expression failed to promote development and survival of any T‐lineage cells other than αβ T cells, as we observed complete lack of γδ, NKT, FoxP3⁺ T regulatory cells and TCR‐β⁺ CD8αα IELs in Pim1^Tgγc^KO mice. Collectively, these results uncover distinct requirements for γc signaling between CD4⁺ αβ T cells and all other T‐lineage cells, and they identify Pim1 as a novel effector molecule sufficient to drive CD4⁺ αβ T‐cell development and survival in the absence of γc cytokine receptor signaling.     

乙型肝炎患者肠源性内毒素血症、高组胺血症与细胞免疫功能之间的关系

目的：探讨慢性乙型肝炎患者肠源性内毒素血症（IETM）、组胺与细胞免疫功能之间的关系。 方法： 慢性乙肝患者80例，根据测定的血浆内毒素水平，将其分为内毒素（ET）阳性组和阴性组，分别检测血清白细胞介素10、12（IL-10、IL-12）、干扰素γ（IFN-γ）、白细胞介素2、4（IL-2、IL-4）浓度，组胺（HA）水平、类胰蛋白酶（TS）释放和AP50单位。 结果： 各肝炎患者IL-4与 IL-10水平明显高于健康人，而 IL-12和 IFN-γ水平明显低于健康人（P<0.05）；按照内毒素分组，阳性组患者IL-4与 IL-10水平明显高于阴性组（P<0.05），而IL-12和 IFN-γ水平在两组之间无明显差别。AP50、HA、TS水平在肝炎患者均明显高于正常对照组（P<0.05），且在内毒素阳性组均明显高于阴性组。乙肝患者内毒素分别与IL-4、IL-10、AP50及HA呈显著正相关，而HA分别与IL-12、IFN-γ呈明显负相关，与AP50、TS呈明显正相关。内毒素阳性组患者，内毒素水平分别与IL-4、IL-10、AP50及HA水平呈显著正相关，而在阴性组则无此相关性。 结论： AP50可以作为IETM存在的标志物，IETM通过激活补体而导致高组胺血症并且长期持续存在，引起细胞免疫功能低下，对肝病非常不利。     

TSG-14 transgenic mice have improved survival to endotoxemia and to CLP-induced sepsis

Tumor necrosis factor-stimulated gene 14 (TSG-14)/PTX3 was identified originally as a TNF-alpha and IL-1beta-stimulated gene from normal, human foreskin fibroblasts and vascular endothelial cells, respectively. TSG-14 gene encodes a 42-kDa-secreted glycoprotein with a carboxy-terminal half that shares homology with the entire sequence of C-reactive protein (CRP) and serum amyloid P component (SAP), acute-phase proteins of the pentraxin family. Some experimental evidence suggests that TSG-14 plays a role in inflammation, yet its function and mechanism of action remain unclear. We have generated transgenic mice that overexpress the murine TSG-14 gene under the control of its own promoter. From eight transgenic founders, two lineages were derived and better characterized: Tg2 and Tg4, carrying two and four copies of the transgene, respectively. TSG-14 transgenic mice were found to be more resistant to the endotoxic shock induced by LPS and to the polymicrobial sepsis caused by cecal ligation and puncture (CLP). Moreover, macrophages derived from the transgenic mice produced higher amounts of nitric oxide in response to IFN-gamma, TNF-alpha, and LPS as compared with macrophages from wild-type animals, and the augmented response appears to be the consequence of a higher responsiveness of transgenic macrophages to IFN-gamma. The data shown here are the first in vivo evidence of the involvement of TSG-14 in the inflammatory process and suggest a role for TSG-14 in the defense against bacterial infections.     

内毒素血症所致脑血管痉挛与体液及神经内皮素-1表达的关系

目的探讨内毒素血症大鼠内皮素-1与脑血管痉挛发生与发展的关系。方法 96只Wistar大鼠随机分为对照组、内毒素血症组(注射内毒素第3、6、12、24、48h),以放射免疫检测血浆内皮素-1水平的变化,免疫组织化学ABC法对大鼠大脑中动脉内皮素-1能神经纤维进行染色观察。结果内毒素血症后3、6、12h大鼠血浆内皮素-1水平较对照组明显升高(P0.05),内毒素血症后24和48h已趋于正常(P0.05)。对照组和内毒素血症大鼠大脑中动脉可见棕褐色、呈细线状内皮素-1能免疫反应阳性纤维,以内毒素血症后第6、12h大鼠大脑中动脉内皮素-1免疫反应最为显著(P0.05)。结论内毒素血症后,大鼠内皮素-1合成和释放入血水平升高,脑血管神经纤维内皮素-1的表达水平上调,这两种因素可能同时参与了脑血管痉挛的发生与发展。     

Endotoxin-induced liver damage in rats is minimized by β<Subscript>2</Subscript>-adrenoceptor stimulation

Objective and Design: To investigate the effects of ₂-adrenoceptor (₂-AR) stimulation on endotoxin-induced liver damage and systemic cytokine levels in rats.Subjects: Standard male Wistar rats.Treatment: A disease-model of lipolysaccharide (LPS)-induced acute systemic inflammation was used. The ₂-selective AR agonist clenbuterol was administered before, during, and after LPS-challenge to investigate its effects on the acute inflammatory response and associated liver-failure.Methods: The following parameters have been measured in plasma: TNF, IL-1, IL-6, IL-10, AST, ALT, and Bilirubin. Liver histological examination was performed to look for changes in tissue morphology.Results: Administration of clenbuterol (p.o.) one hour before, or intravenous at the same time as LPS-challenge resulted in a marked reduction of plasma levels of TNF, IL-1, and IL-6. A change both in plasma-level and in time-concentration profile of the anti-inflammatory cytokine IL-10 was found. Clenbuterol minimized LPS-induced liver damage, as represented by significantly lowered concentrations of several parameters for liver-failure (AST, ALT, Bilirubin), and improved hepatic tissue morphology. Clenbuterol administration after LPS challenge failed to inhibit TNF-release but reduced liver-damage. Simultaneous use of the ₂-AR antagonist propranolol augmented LPS-induced liver failure, suggesting a role of endogenous adrenoceptor-agonists in prevention of organ-failure during systemic inflammation.Conclusions: The results indicate that a selective ₂-AR agonist might be used as an additional therapeutic agent in the clinic for the treatment of (acute) systemic inflammatory disorders in order to reduce or prevent subsequent liver failure.Received 3 March 2003; returned for revision 4 April 2003; returned for final revision 3 October 2003; accepted by M.Parnham 29 October 2003     

A survival guide to early T cell development

The survival of immature T cell precursors is dependent on both thymus-derived extrinsic signals and self-autonomous pre-TCR-mediated signals. While the role of cytokines and the pre-TCR in promoting thymocyte survival has been well established, the relationship between pro- and anti-apoptotic signaling cascades remains poorly defined. Recent studies have established a link between cell survival and growth factor-mediated maintenance of cellular metabolism. In this regard, the Notch signaling pathway has emerged as more than an inducer of T lineage commitment and differentiation, but also as a potent trophic factor, promoting the survival and metabolic state of pre-T cells. In this review, we describe current concepts of the intracellular signaling pathways downstream of cell intrinsic and extrinsic factors that dictate survival versus death outcomes during early T cell development.