Mechanisms of Growth Hormone Resistance in Sepsis

脓毒症生长激素抵抗机制

• 批准号: 6733557
• 负责人: ROBERT N. COONEY
• 金额: $ 26.35万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6733557
• 关键词: binding proteins; biological signal transduction; cytokine receptors; enzyme activity; gene expression; growth factor; hormone inhibitor; hormone receptor; hormone regulation /control mechanism; insulinlike growth factor; interleukin 1; laboratory rat; liver cells; messenger RNA; northern blottings; phosphorylation; protein metabolism; receptor expression; septicemia; somatotropin; transcription factor; tumor necrosis factor alpha; western blottings

DESCRIPTION (provided by applicant): The catabolism of protein after injury or infection results in multiple complications which prolong recovery and cause death. Nutrient intake is unable to prevent protein catabolism suggesting other factors are important. Growth hormone (GH) induces circulating insulin-like growth factor-I (IGF-I) synthesis by liver, which stimulates muscle protein synthesis. During sepsis, a 2-4 fold increase in circulating GH is seen with a 50% decrease in plasma IGF-I, a 40% reduction in muscle protein synthesis, and decreased muscle mass. The onset of GH resistance and loss of muscle in sepsis is mediated by the inflammatory cytokines, TNF and IL-I. Treating septic rats with IL-1 or TNF antagonists ameliorates the effects of sepsis on plasma IGF-I levels and muscle catabolism. The liver is the major source of circulating IGF-I, and will be the focus of this project to elucidate the mechanisms responsible for GH resistance. Postreceptor defects in GH signaling represent the predominant mechanism for GH resistance in sepsis. The magnitude of the IGF-I response to GH is determined by three distinct processes: the activation/propagation of JAK/STAT and MAP kinase signaling by GH, the regulation of IGF-I gene expression, and the termination of GH signaling. To investigate the mechanisms responsible for GH resistance, we developed a hepatocyte model of cytokine-mediated GH resistance. This novel hepatocyte model uniquely positions us to delineate the mechanisms responsible for defective GH signaling and IGF-I expression. TNF inhibits both the activation and termination of GH signaling by the JAK/STAT and MAP kinase pathways. IL-1 also inhibits the induction of IGF-I by GH, but the time course differs from TNF, potentially involving different mechanisms. The mechanisms responsible for GH resistance will be determined with in vitro studies involving TNF and IL-1, and in vivo studies in our rat model of sepsis. Our hypothesis is that cytokine-rnediated alterations in GH signaling mediate hepatic GH resistance and muscle catabolism during sepsis. The specific aims are: (1) to delineate the effects of sepsis, TNF and IL-1 on the activation/propagation of GH signaling; (2) to elucidate the mechanisms by which sepsis, TNF and IL-1 regulate IGF-I gene expression; and (3) to determine the mechanisms by which sepsis, TNF and IL-1 terminate GH signaling. An understanding of how cytokines and growth factors regulate protein catabolism is important for the care of septic patients.

描述(由申请人提供)： 损伤或感染后蛋白质的分解代谢会导致多种并发症，延长康复时间并导致死亡。营养摄入不能阻止蛋白质分解代谢，这表明其他因素也很重要。生长激素(GH)通过肝脏诱导循环胰岛素样生长因子-I(IGF-I)的合成，从而刺激肌肉蛋白质的合成。在脓毒症期间，循环生长激素增加2-4倍，血浆IGF-I减少50%，肌肉蛋白质合成减少40%，肌肉质量减少。脓毒症时生长激素抵抗和肌肉丧失的发生是由炎性细胞因子、肿瘤坏死因子和白介素I介导的。用IL-1或肿瘤坏死因子拮抗剂治疗脓毒症大鼠可改善脓毒症对血浆IGF-I水平和肌肉分解代谢的影响。肝脏是循环IGF-I的主要来源，并将是本项目的重点，以阐明GH抵抗的机制。GH信号受体后缺陷是脓毒症GH抵抗的主要机制。胰岛素样生长因子-I对生长激素的反应由三个不同的过程决定：生长激素激活/传播JAK/STAT和MAP激酶信号，调节胰岛素样生长因子-I基因的表达，终止生长激素信号。为了研究生长激素抵抗的机制，我们建立了细胞因子介导的生长激素抵抗的肝细胞模型。这个新的肝细胞模型独特地定位了我们描述GH信号和IGF-I表达缺陷的机制。肿瘤坏死因子通过JAK/STAT和MAP激酶途径抑制生长激素信号的激活和终止。IL-1也抑制GH诱导的IGF-I，但其时程与肿瘤坏死因子不同，可能涉及不同的机制。生长激素抵抗的机制将通过涉及肿瘤坏死因子和白介素1的体外研究和我们的脓毒症大鼠模型的体内研究来确定。我们的假设是，细胞因子引起的生长激素信号的改变介导了脓毒症时肝脏生长激素抵抗和肌肉分解代谢。其具体目的是：(1)阐明脓毒症、肿瘤坏死因子和IL-1对生长激素信号的激活/增殖的影响；(2)阐明脓毒症、肿瘤坏死因子和IL-1调节IGF-I基因表达的机制；以及(3)确定脓毒症、肿瘤坏死因子和IL-1终止生长激素信号的机制。了解细胞因子和生长因子是如何调节蛋白质分解代谢的，对于脓毒症患者的护理很重要。