PROTEIN SYNTHESIS IN LIVER DURING SEPSIS

脓毒症的代谢反应是多种多样的，包括 蛋白质、碳水化合物、脂肪、微量金属和氨基代谢。 一 一个普遍出现的概念是， 肌肉和肝脏中的氨基流量增加 酸从外周体重/肌肉到肝脏。 虽然 脓毒症期间肝脏蛋白质合成增加， 然而，其他研究并未证实这些发现。 还有， 肝脏蛋白质合成改变的介质和机制 在spesis不完全知道。 建议的目标 研究的目的是：（1）确定肝脏蛋白质合成的变化 在体内和在脓毒症期间灌注的大鼠肝脏中;（2）测试 假设肝脏蛋白质合成增加是由 白细胞介素-1（IL-1）、肿瘤坏死因子（TNF）或其他 单核因子;（3）确定分解代谢激素的作用 皮质酮、胰高血糖素和肾上腺素， 蛋白质合成;（4）检验肝蛋白质 通过给予以下物质可以刺激spetic大鼠的合成： 不同的底物，其中氨基酸溶液 不同的组合物。 通过盲肠结扎在大鼠中诱导脓毒症 和穿刺（CLP）;对照动物为假手术。 在 CLP或假手术后的各个时间点， 蛋白质合成在体内用泛血剂量测量 技术，使用14 C-亮氨酸作为前体氨基酸。 换句 动物分泌蛋白白蛋白的生产， 转铁蛋白、补体成分C3和α 1-酸 糖蛋白在灌注的离体肝脏中使用 再循环系统和放射性标记的免疫沉淀 特定蛋白质 在其他研究中，总的和分泌的肝脏 蛋白质合成将在腹膜内给药后测定。 施用活化的大鼠巨噬细胞上清液， 重组IL-1 α或重组TNF。 既然已经 表明IL-1的一些作用是继发于 糖皮质激素，肝蛋白质合成也将被测量 给肾上腺切除的大鼠施用IL-1后。 在 另一组实验中，分解激素将 同时输注大鼠和肝脏蛋白质合成将 被测量。 最后，18-20小时或46-48小时输注的效果 各种新颖组合物的氨基酸溶液， 将测定脓毒症期间肝脏中的蛋白质合成。 在 同样的实验，对脓毒症大鼠灌流肝的影响， 将被确定。

The metabolic responses to sepsis are varied, involving changes in protein, carbohydrate, fat, trace metal and amino metabolism. A generally emerging concept is that the interaction between muscle and liver may be summarized by increased flow of amino acids from peripherylean body mass/muscle to the liver. Although increased protein synthesis in liver during sepsis has been reported, other studies have not confirmed these findings. Also, mediator(s) and mechanism(s) of altered protein synthesis in liver during spesis are not fully known. The objectives of the proposed studies are to: (1) determine changes in hepatic protein synthesis in vivo and in perfused rat liver during sepsis; (2) test the hypothesis that increased hepatic protein synthesis is induced by interleukin-1 (IL-1), tumor necrosis factor (TNF), or other monokines; (3) determine the role of the catabolic hormones corticosterone, glucagon and epinephrine for accelerated hepatic protein synthesis; and (4) test the hypothesis that hepatic protein synthesis in spetic rats can be stimulated by the administration of different substrates, among them amino acid solutions of different compositions. Sepsis is induced in rats by cecal ligation and puncture (CLP); control animals are sham-operated. At various time-points after CLP or sham-operation, total hepatic protein synthesis is measured in vivo with a flooding dose technique, using 14C-leucine as precusor amino acid. In other animals the production of the secreted proteins albumin, transferrin, complement component C3, and alpha 1-acid glycoprotein is measured in perfused isolated liver using a recirculating system and immunoprecipitation of radiolabeled specific proteins. In still other studies, total and secreted hepatic protein synthesis will be determined following intraperitoneal administration of activated rat macrophage supernatant, recombinant IL-1 alpha or recombinant TNF. Since it has been suggested that some of the effects of IL-1 are secondary to glucocorticoids, hepatic protein synthesis will also be measured following administration of IL-1 to adrenalectomized rats. In another set of experiments, the catabolic hormones will be simultaneously infused in rats and hepatic protein synthesis will be meaured. Finally, the effects of an 18-20 h or 46-48 h infusion of amin acid solutions of various and novel compositions on protein synthesis in liver during sepsis will be determined. In the same of experiments, the effect in perfused liver of septic rats, will be determined.