PROTEIN SYNTHESIS IN LIVER DURING SEPSIS

脓毒症期间肝脏中的蛋白质合成

• 批准号: 3241074
• 负责人: PER-OLOF J HASSELGREN
• 金额: $ 9.81万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-01 至 1991-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3241074
• 关键词: acute phase protein; adrenalectomy; albumins; aminoacid metabolism; complement; corticosterone; epinephrine; glucagon; glycoproteins; hormone regulation /control mechanism; interleukin 1; laboratory rat; liver metabolism; muscle metabolism; perfusion; protein biosynthesis; radiotracer; transferrin; tumor necrosis factor alpha

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.

对败血症的代谢反应各不相同，涉及变化 蛋白质，碳水化合物，脂肪，痕量金属和氨基代谢。 一个 通常，新兴的概念是 肌肉和肝脏可以通过增加的氨基流量来总结 从外周体/肌肉到肝脏的酸。 虽然 败血症期间肝脏中蛋白质合成的增加已有 报道说，其他研究尚未证实这些发现。 还， 肝脏中蛋白质合成改变的介质和机制 在Spesis期间尚不清楚。 提议的目标 研究是：（1）确定肝蛋白合成的变化 败血症期间体内和灌注的大鼠肝脏中； （2）测试 假设增加肝蛋白合成的假设是由 白介素1（IL-1），肿瘤坏死因子（TNF）或其他 monokines; （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，用于加速肝 蛋白质合成； （4）检验肝蛋白的假设 可以通过给予刺激性大鼠的合成 不同的底物，其中包括 不同的组成。 盲肠连接在大鼠中诱导败血症 和穿刺（CLP）；对照动物是假手术的。 在 CLP或假手术后的各种时间点，总肝 蛋白质合成用洪水剂量测量 技术，使用14C-达氨酸作为前司司氨基酸。 在其他 动物生产分泌的蛋白质白蛋白的生产 转铁蛋白，补体组件C3和Alpha 1-酸 糖蛋白在灌注的分离肝脏中测量 循环系统和放射标记的免疫沉淀 特定蛋白质。 在其他研究中，总计和分泌的肝 腹膜内将确定蛋白质合成 激活的大鼠巨噬细胞上清液 重组IL-1α或重组TNF。 因为已经 提出IL-1的某些影响是继发的 糖皮质激素，肝蛋白合成也将测量 在给予IL-1对肾上腺切除术大鼠后。 在 另一组实验，分解代谢激素将是 同时注入大鼠和肝蛋白合成将 被笑。 最后，输注18-20 h或46-48 h 各种新颖组成的氨基酸溶液的 将确定败血症期间肝脏中的蛋白质合成。 在 同样的实验，化粪池大鼠的灌注肝脏的作用， 将确定。