Modulation of cytokine production and its effects on metabolism and immune responsiveness in surgical stress.

我们研究了以下因素对细胞因子产生的调节：1)先前的营养途径，2)外源性生长激素（GH）和胰岛素样生长因子I (IGF-I)，以及3)一氧化氮合酶抑制剂（NAME）。4)我们还利用northern blot分析研究了生长激素对肝硬化患者氮代谢影响减弱的机制。方法1)大鼠给予全肠外营养（TPN）或全肠内营养（TEN）喂养1周，然后用3*10^8大肠杆菌灌胃。2)经生长激素（4.8mg/kg/d）、igf - 1 （24mg/kg/d）或生理盐水刺激6天后，小鼠腹腔注射10^8个大肠杆菌。3)小鼠经NAME （100mg/kg）或生理盐水灌胃1 h后，以10^8大肠杆菌灌胃。4)正常大鼠和肝硬化大鼠术后3 d分别给予GH （0.8IU/kg/d）或生理盐水。结果：1)在攻毒后2小时，TEN改善了小鼠的生存，增加了腹膜渗出细胞（PEC）的数量，增强了细菌的数量，增加了局部TNF的产生，同时抑制了全身TNF的反应。2)促生长激素和igf -1提高了生存率，增加了腹腔和肝脏的PEC数量和细菌清除率，同时在攻毒后6小时抑制了过多的全身TNF、IL-1和IL-6的产生。3)在接种细菌4小时后，与对照组相比，给予NAME导致存活时间较差，腹腔细菌数量增加，全身TNF生成增加。4)正常大鼠接受GH后肝脏IGF-I mrna和血浆IGF-I水平升高，而肝硬化大鼠即使接受GH后肝脏IGF-I mrna和血浆IGF-I水平没有升高。结论1,2)与肠外营养相比，预先肠内营养可调节感染后的细胞因子反应并增强细菌清除。外源性生长激素和igf - 1也对细胞因子的产生有调节作用，提高细菌的杀伤能力。预先肠内营养以及GH和IGF-I预处理的这些作用可以改善宿主防御，并可能预防术后腹腔感染的发生和进展。3)另一方面，在革兰氏阴性脓毒症模型中，使用NAME抑制一氧化氮的产生会产生不利影响。4)术后给药生长激素不增加肝硬化患者肝脏IGF-I mrna和血浆IGF-I水平。因此，在肝硬化中，外源性igf - 1可能比生长激素更有效地改善术后氮代谢。少

We investigated modulation of cytokine production and consequent effects by 1) antecedent nutritional routes, 2) exogenous growth hormone (GH) and insulin-like growth factor I (IGF-I), and 3) administration of a nitric oxide synthase inhibitor (NAME). 4) We also studied the mechanism by which effects of GH on nitrogen metabolism are attenuated in cirrhosis, using northem blot analysis. Method 1) Rats were fed through total parenteral nutrition (TPN) or total enteral nutrition (TEN) for a week, and then challenged i.p.with 3*10^8 E.coli.2) After six days of s.c.treatments with GH (4.8mg/kg/day), IGF-I (24mg/kg/day) or saline, mice were challenged i.p.with 10^8 E.coli.3) One hour after i.p.treatment with NAME (100mg/kg) or saline, mice were challenged i.p.with 10^8 E.coli. 4) Normal and cirrhotic rats received GH (0.8IU/kg/day) or saline for 3 postoperative days after gastrectomy. Results 1) TEN improved survival, increased numbers of peritoneal exudative cells (PEC) and enhanced bacteri … More al clearance with increased local TNF production, while suppressing systemic TNF response, at 2 hours after challenge. 2) GH and IGF-I improved survival, increased PEC numbers and bacterial clearance from peritoneal cavity and liver, while suppressing excessive systemic production of TNF,IL-1 and IL-6, at 6 hours after challenge. 3) Administration of NAME resulted in poor survival times, increases in bacterial numbers in the peritoneal cavity, and an increase in systemic TNF production compared with controls, at four hours after bacterial inoculation. 4) Liver IGF-I-mRNA and plasma IGF-I level were increased in normal rats that received GH,although these values were not increased in cirrhotic rats even if they received GH.Conclusions 1,2) Antecedent enteral nutrition modulates cytokine responses and enhances bacterial clearance after infection, as compared to parenteral nutrition. Exogenous GH and IGF-I also exerts modulatory effects on cytokine production and improves killing of bacteria. These effects of antecedent enteral nutrition, and pretreatment with GH and IGF-I,improve host defense and may prevent the development and progression of postoperative intraperitoneal infection.3) On the other hand, inhibition of nitric oxide production, using NAME,produces detrimental effects in this gram-negative sepsis model. 4) GH administration after surgery does not increase both liver IGF-I-mRNA and plasma IGF-I level in cirrhosis. Therefore, in cirrhosis, exogenous IGF-I may be more effective than GH to improve nitrogen metabolism after surgery. Less