Ozturk Erdogan, Demirbilek Semra, Begec Zekine, Surucu Murat, Fadillioglu Ersin, Kirimlioglu Hale, Ersoy M Ozcan
Department of Anesthesiology and Reanimation, Faculty of Medicine, Turgut Ozal Medical Center, Inonu University, 44315, Malatya, Turkey.
Pediatr Surg Int. 2008 Aug;24(8):899-905. doi: 10.1007/s00383-008-2184-y. Epub 2008 May 31.
The organ that is affected first and most severely in intraabdominal sepsis is the lung. Oxygen radicals and active neutrophils in the lung are important sources for severe pulmonary inflammation leading to acute lung injury (ALI)/acute respiratory distress syndrome. The aim of this study was to investigate the effects of leflunomide, an immunomodulatory agent, on oxidant/antioxidant status with nitric oxide (NO) level and myeloperoxidase (MPO) activity in rats with sepsis-induced ALI. Fifty male Wistar albino rats were divided into five groups: control, sham, sepsis, leflunomide (10 mg/kg, intragastrically for two doses with an 8 h interval prior to the experiment) and sepsis + leflunomide. After the animals were anesthetized with ketamine and xylazine, the abdominal cavity was opened and ligated just below the ileocaecal valve with 3-0 silk. The antimesentric surface of the cecum was perforated and the cecum was gently compressed until fecal matter was extruded to induce sepsis. None of the rats received antibiotics during the experimental procedures. The experiment was ended 24 h after cecal ligation puncture (CLP) with the cervical dislocation under anesthesia. The lung tissues were removed for analysis of biochemical parameters and light microscopic investigation. The lung superoxide dismutase (SOD), catalase and glutathione peroxidase activities were decreased in the sepsis group as compared to the group control, sham, leflunomide and sepsis + leflunomide (P < 0.05), and SOD activity were significantly higher in group sepsis + leflunomide than sham, control, leflunomide and sepsis group (P < 0.05). The lung MPO, malondialdehyde (MDA), protein carbonyl and NO levels were higher in the sepsis group when compared to group control, sham, leflunomide and sepsis + leflunomide (P < 0.05), and MPO, MDA and NO levels were higher in the sepsis + leflunomide group than in the sham, control and leflunomide group (P < 0.05). The light microscopic evaluation showed that pulmonary architecture was preserved, and infiltration of neutrophil and edema decreased in sepsis + leflunomide group. The grade of alveolar damage was significantly decreased in sepsis + leflunomide group in comparison with sepsis group (P < 0.05). Our findings suggested that leflunomide attenuated the lung injury after CLP-induced sepsis by inhibition of neutrophils accumulation and increasing endogenous antioxidant capacity.
在腹腔内脓毒症中，最先且最严重受影响的器官是肺。肺中的氧自由基和活性中性粒细胞是导致严重肺部炎症进而引发急性肺损伤（ALI）/急性呼吸窘迫综合征的重要来源。本研究旨在探讨免疫调节剂来氟米特对脓毒症诱导的ALI大鼠氧化/抗氧化状态、一氧化氮（NO）水平及髓过氧化物酶（MPO）活性的影响。将50只雄性Wistar白化大鼠分为五组：对照组、假手术组、脓毒症组、来氟米特组（10 mg/kg，实验前经胃内给药，分两剂，间隔8小时）和脓毒症+来氟米特组。用氯胺酮和赛拉嗪对动物进行麻醉后，打开腹腔，在回盲瓣下方用3-0丝线结扎。在盲肠的系膜对侧表面穿孔，轻轻挤压盲肠直到挤出粪便以诱导脓毒症。在实验过程中，所有大鼠均未接受抗生素治疗。在盲肠结扎穿刺（CLP）后24小时，在麻醉下通过颈椎脱臼结束实验。取出肺组织用于生化参数分析和光镜检查。与对照组、假手术组、来氟米特组和脓毒症+来氟米特组相比，脓毒症组肺组织中超氧化物歧化酶（SOD）、过氧化氢酶和谷胱甘肽过氧化物酶活性降低（P<0.05），脓毒症+来氟米特组的SOD活性显著高于假手术组、对照组、来氟米特组和脓毒症组（P<0.05）。与对照组、假手术组、来氟米特组和脓毒症+来氟米特组相比，脓毒症组肺组织中MPO、丙二醛（MDA）、蛋白质羰基和NO水平更高（P<0.05），脓毒症+来氟米特组的MPO、MDA和NO水平高于假手术组、对照组和来氟米特组（P<0.05）。光镜评估显示，脓毒症+来氟米特组肺组织结构得以保留，中性粒细胞浸润和水肿减少。与脓毒症组相比，脓毒症+来氟米特组肺泡损伤程度显著降低（P<0.05）。我们的研究结果表明，来氟米特通过抑制中性粒细胞聚集和提高内源性抗氧化能力减轻CLP诱导的脓毒症后的肺损伤。
