Yumet Gladys, Shumate Margaret L, Bryant D Patrick, Lang Charles H, Cooney Robert N
Departments of Surgery, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
Crit Care Med. 2006 May;34(5):1420-7. doi: 10.1097/01.CCM.0000215113.66070.E0.
During sepsis, a two- to four-fold increase in circulating growth hormone (GH) is seen with 40-50% reductions in plasma insulin-like growth factor (IGF)-I. The suppressors of cytokine signaling (SOCS), inhibitors of cytokine, and growth factor signaling via the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway have been implicated in the development of hepatic GH resistance. In this study we examine the effects of sepsis on GH-induced IGF-I expression and potential mechanisms for GH resistance.
Prospective experimental study.
University research laboratory.
Male Sprague-Dawley rats.
Rats were randomized to laparotomy alone (control) or implantation of fecal agar pellets inoculated with Escherichia coli and Bacteroides fragilis (sepsis). GH was injected intravenously to assess hepatic IGF-I synthesis and GH signaling.
Plasma IGF-I was measured in both groups at baseline (4 hrs postoperatively) and then again at 12 hrs and 24 hrs after GH administration. Basal IGF-I levels were similar in both groups, but controls had a 35% increase in IGF-I at 12 hrs, whereas septic rats demonstrated reductions in circulating IGF-I at 12 and 24 hrs after GH. Hepatic expression of SOCS-1, -2, -3, and cytokine-inducible SH2-containing protein (CIS) were determined at 1, 4, 8, and 24 hrs in septic and control rats by Northern blot. SOCS-1, SOCS-3, and CIS messenger RNA in liver were increased from 4 to 8 hrs after the induction of sepsis (p < .05 for SOCS-1 and -3). Total GH receptor (GHR), JAK2, and STAT5 signaling proteins and the time course of STAT5 activation were also measured in liver after recombinant human GH administration by immunoblot and electrophoretic mobility shift analysis. Levels of total GHR, JAK2, and STAT5 were unaltered in liver from septic rats. However, phosphorylated STAT5 and STAT5 DNA binding were significantly reduced 30 mins after GH administration in liver from septic rats.
Sepsis diminished STAT5 phosphorylation and activity in liver as well as plasma IGF-I following GH administration. Hepatic messenger RNA expression of SOCS-1, SOCS-3, and CIS was transiently increased during abdominal sepsis and temporally associated with the development of hepatic GH resistance.
在脓毒症期间，循环生长激素（GH）增加2至4倍，而血浆胰岛素样生长因子（IGF）-I降低40%-50%。细胞因子信号转导抑制因子（SOCS）、细胞因子抑制剂以及通过Janus激酶（JAK）/信号转导子和转录激活子（STAT）途径的生长因子信号转导抑制因子与肝脏GH抵抗的发生有关。在本研究中，我们研究了脓毒症对GH诱导的IGF-I表达的影响以及GH抵抗的潜在机制。
前瞻性实验研究。
大学研究实验室。
雄性Sprague-Dawley大鼠。
将大鼠随机分为单纯剖腹术组（对照组）或植入接种大肠杆菌和脆弱拟杆菌的粪便琼脂小球组（脓毒症组）。静脉注射GH以评估肝脏IGF-I合成和GH信号转导。
在基线时（术后4小时）以及GH给药后12小时和24小时测量两组大鼠的血浆IGF-I。两组的基础IGF-I水平相似，但对照组在12小时时IGF-I增加35%，而脓毒症大鼠在GH给药后12小时和24小时循环IGF-I降低。通过Northern印迹法在脓毒症大鼠和对照大鼠中于1、4、8和24小时测定SOCS-1、-2、-3和细胞因子诱导含SH2蛋白（CIS）的肝脏表达。脓毒症诱导后4至8小时，肝脏中的SOCS-1、SOCS-3和CIS信使RNA增加（SOCS-1和-3，p<0.05）。通过免疫印迹和电泳迁移率变动分析在重组人生长激素给药后还测量了肝脏中的总GH受体（GHR）、JAK2和STAT5信号蛋白以及STAT5激活的时间进程。脓毒症大鼠肝脏中的总GHR、JAK2和STAT5水平未改变。然而，脓毒症大鼠肝脏在GH给药后30分钟时磷酸化STAT5和STAT5 DNA结合显著降低。
脓毒症降低了GH给药后肝脏中STAT5的磷酸化和活性以及血浆IGF-I。在腹部脓毒症期间，肝脏中SOCS-1、SOCS-3和CIS的信使RNA表达短暂增加，并与肝脏GH抵抗的发生在时间上相关。
