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

我们研究了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)的应用对细胞因子产生的调节及其结果。4)应用Northernblotting方法研究了GH对肝硬变大鼠氮代谢的影响及其机制。方法1)给予大鼠全肠外营养(TPN)或全肠内营养(TEN)喂养1周后，给予3×10~(-8)个大肠杆菌。2)连续6天皮下注射生长激素(GH)(4.8 mg/kg/d)、胰岛素样生长因子-I(24 mg/kg/d)或生理盐水后6d，小鼠腹腔注射10~(-8)个大肠杆菌。4)正常大鼠和肝硬变大鼠胃切除后给予生长激素(0.8IU/kg/d)或生理盐水，连续3d。结果(1)10例患者存活时间延长，腹膜渗出细胞数量增加，细菌…增强在攻击后2小时，随着局部肿瘤坏死因子产生的增加而更多的清除，同时抑制全身肿瘤坏死因子的反应。(2)GH和IGF-I均能提高小鼠的存活率，增加PEC数量，增加腹腔和肝脏的细菌清除率，同时抑制机体分泌过量的肿瘤坏死因子、白介素1和白介素6。3)接种NAME后4h，与对照组相比，NAME组小鼠存活时间缩短，腹膜腔细菌数量增加，全身肿瘤坏死因子产生增加。4)应用生长激素后，正常大鼠肝脏IGF-I-mRNA和血浆IGF-I水平升高，而肝硬变大鼠应用生长激素后IGF-I和IGF-I水平无明显变化。结论1、2)早期肠内营养可调节感染后的细胞因子反应，促进细菌清除。外源GH和IGF-I对细胞因子的产生也有调节作用，并提高了对细菌的杀灭能力。预先肠内营养的这些作用，以及GH和IGF-I的预处理，提高了宿主的防御能力，并可能防止术后腹膜感染的发生和进展。3)另一方面，使用NAME抑制一氧化氮的产生，在这个革兰氏阴性脓毒症模型中产生不利影响。(4)术后应用生长激素并不增加肝硬变患者肝脏IGF-I-mRNA和血浆IGF-I水平。因此，在肝硬变患者中，外源性IGF-I可能比GH更有效地改善术后的氮代谢。较少

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