SKELETAL MUSCLE PROTEIN RESPONSE TO INJURY AND REPLETION

调节身体和组织特异性蛋白质周转 与损伤的严重程度和持续时间成正比意味着 复杂的代谢控制水平。 除了不动性和 营养状况，这既影响能力， 和瘦组织恢复率，神经体液环境也 有助于调节组织特异性（骨骼肌） 蛋白质质量和细胞功能。 肽介质（细胞因子） 在组织损伤部位局部产生和/或 全身出现可进一步调节瘦组织功能 和代谢过程。 损伤后，肠功能丧失 粘膜屏障功能和随后的门静脉和/或全身 细菌或内毒素暴露可进一步提高生产 细胞因子和应激激素的作用。 努力保持肠道 通过肠内营养支持的完整性然后可以 代表了一种临床相关的方法， 伤害反应。 本提案将力求评估 应激激素和内毒素对身体的个体贡献， 区域和骨骼蛋白质代谢和功能稳态。 内毒素诱导急性扰动期间观察到的反应 和/或压力激素输注在正常志愿者将是 与中度损伤（围手术期）的反应相比 以及更严重的受伤患者（创伤/危重病）。 在上述研究中，代谢和功能 将比较接受定义的 肠内配方或肠外营养。 后续我们将 试图确定L-谷氨酰胺的功效，作为一种免疫调节剂， 重要的肠道燃料源，可能能够调节 应激激素和细胞因子对内毒素血症反应以及 维持肠粘膜质量。 在上述研究中， 能量消耗、应激激素和 细胞因子（恶病质/TNF、光毒素、γ-干扰素和 白细胞介素1）对受控刺激或损伤的反应将是 执行。 此外，身体和区域蛋白质代谢将 使用稳定同位素技术（L-（1-C13，N15）leu- 甘氨酸; L-（苯基-2H5）苯丙氨酸）。 急性骨骼肌 还将通过活检确定的溶质：水来评估缓解 比率，高能磷酸盐水平和相对速率 肌球蛋白和Na K ATP酶mRNA表达。 后一项意见 将与跨膜电位的变化相关 差异和区域氨基酸代谢，以进一步获得 关于这些事件的规模和时间的信息 损伤后的参数。

Modulation of body and tissue-specific protein turnover proportional to the severity and duration of injury implies a complex level of metabolic control. In addition to immobility and antecedent nutritional status which influence both the capacity for and rate of lean tissue recovery,the neuro-humoral milieu also contributes to the regulation of tissue-specific (skeletal muscle) protein mass and cellular function. Peptide mediators (cytokines) produced either locally at the site of tissue damage and/or appearing systemically may further modulate lean tissue functional and metabolic processes. Following injury, loss of intestinal mucosal barrier function and subsequent portal vein and/or systemic bacterial or endotoxin exposure may further enhance the production of cytokines and stress hormones. Efforts to maintain intestinal integrity by means of enteral nutritional support may then represent a clinically relevant approach to modulating the post- injury response. This proposal will seek to evaluate the individual contributions of stress hormones and endotoxin to body, regional and skeletal protein metabolic and functional homeostasis. Responses observed during acute perturbations induced by endotoxin and/or stress hormone infusions in normal volunteers will be compared to those responses in moderately injured (perioperative) and more severely injured patients(trauma/critical illness). Throughout the above studies, the metabolic and functional responses will be compared between patients receiving a defined enteral formula or parenteral nutrition. Subsequently, we will seek to determine the efficacy of L-glutamine which, as an im- portant intestinal fuel source, may be capable of modulating the stress hormone and cytokine response to endotoxinemia as well as maintaining intestinal mucosal mass. During the above studies, prospective evaluation of energy expenditure, stress hormone and cytokine (cachectin/TNF, lymphotoxin, gamma-interferon, and interleukin 1) responses to controlled stimulae or injury will be performed. In addition, body and regional protein metabolism will be evaluated using stable isotope techniques (L-(1-C13,N15) leu- cine; L-(phenyl-2H5) phenylalanine). Acute skeletal muscle responses will also be assessed by biopsy-determined solute:water ratios, high energy phosphate levels and the relative rate of myosin and Na K ATPase mRNA expression. The latter observations will be correlated to changes in transmembrane potential differences and regional amino acid metabolism to gain further information regarding both the magnitude and timing of these parameters following injury.