Giamarellos-Bourboulis Evangelos J, Poulaki Helen, Kostomitsopoulos Nikolaos, Dontas Ismene, Perrea Despina, Karayannacos Panayotis E, Giamarellou Helen
4th Department of Internal Medicine, University of Athens Medical School, Athens, Greece.
Antimicrob Agents Chemother. 2003 Aug;47(8):2445-9. doi: 10.1128/AAC.47.8.2445-2449.2003.
Thalidomide, an agent which inhibits biosynthesis of tumor necrosis factor alpha (TNF-alpha) and which is used to treat a variety of chronic inflammatory conditions, was investigated as therapy for experimental sepsis. Sepsis was induced by intraperitoneal injection of 10(7) CFU of Escherichia coli per kg of body weight to 80 Wistar rats divided into four groups. Group A consisted of 24 control animals that did not receive any pretreatment, group B consisted of 18 vehicle-treated control animals pretreated with seed oil, group C consisted of 30 rats administered thalidomide diluted in seed oil at a dose of 50 mg/kg 30 min before bacterial challenge, and group D consisted of eight animals that were not challenged with E. coli but that were used for white blood cell count determination. Sepsis was determined by measurement of vital signs before and 6 h after bacterial challenge. After 6 h the animals were killed and blood was sampled for culture; white blood cell count determination; and determination of endotoxin (lipopolysaccharide), TNF-alpha, interleukin-1beta (IL-1beta), and IL-6 levels. The levels of these cytokines were also estimated in the supernatants of human monocytes pretreated with thalidomide after exposure to the isolate. Sepsis developed in all vehicle-treated control animals and controls by 6 h after bacterial challenge but in only 10 animals (33.3%) pretreated with thalidomide (P < 0.0001). Six hours after bacterial challenge all animals had similar levels of endotoxemia, IL-1beta, and IL-6. The mean white blood cell count for groups A, B, and C were 5,631.1, 2,638.9, and 8,169.3 cells/ micro l, respectively (P value between groups, <0.0001); the TNF-alpha levels were 77.3, 107.2, and 26.1 pg/ml, respectively (P values between groups, <0.0001). Pretreatment of human monocytes with thalidomide prevented the secretion of TNF-alpha and IL-1beta but not that of IL-6. It is concluded that thalidomide exerts a considerable anti-inflammatory effect by preventing evolution to sepsis and by decreasing the level of production of TNF-alpha and therefore deserves to be further evaluated in research for the therapy of sepsis.
沙利度胺是一种可抑制肿瘤坏死因子α（TNF-α）生物合成的药物，被用于治疗多种慢性炎症性疾病，本研究将其作为实验性脓毒症的治疗手段进行了调查。通过给80只体重为每千克10⁷CFU大肠杆菌腹腔注射诱导脓毒症，这些大鼠被分为四组。A组由24只未接受任何预处理的对照动物组成，B组由18只经植物油预处理的溶剂对照动物组成，C组由30只在细菌攻击前30分钟经植物油稀释后以50mg/kg剂量给予沙利度胺的大鼠组成，D组由8只未接受大肠杆菌攻击但用于白细胞计数测定的动物组成。通过测量细菌攻击前后的生命体征来确定脓毒症。6小时后处死动物并采集血液进行培养、白细胞计数测定以及内毒素（脂多糖）、TNF-α、白细胞介素-1β（IL-1β）和IL-6水平的测定。在用沙利度胺预处理后的人单核细胞暴露于分离株后的上清液中也对这些细胞因子的水平进行了评估。在细菌攻击后6小时，所有溶剂对照动物和对照动物均发生了脓毒症，但在仅10只（33.3%）接受沙利度胺预处理的动物中未发生（P<0.0001）。细菌攻击6小时后，所有动物的内毒素血症、IL-1β和IL-6水平相似。A、B、C组的平均白细胞计数分别为5631.1、2638.9和8169.3个细胞/微升（组间P值<0.0001）；TNF-α水平分别为77.3、107.2和26.1pg/ml（组间P值<0.0001）。用沙利度胺预处理人单核细胞可阻止TNF-α和IL-1β的分泌，但不能阻止IL-6的分泌。结论是，沙利度胺通过防止发展为脓毒症并降低TNF-α的产生水平发挥了相当大的抗炎作用，因此值得在脓毒症治疗研究中进一步评估。
