Sener Göksel, Sakarcan Abdullah, Sehirli Ozer, Ekşioğlu-Demiralp Emel, Sener Emre, Ercan Feriha, Gedik Nursal, Yeğen Berrak C
Marmara University, School of Pharmacy, Department of Pharmacology, Tibbiye Cad., 34668 Istanbul, Turkey.
Prostaglandins Other Lipid Mediat. 2007 Jun;83(4):257-67. doi: 10.1016/j.prostaglandins.2007.01.013. Epub 2007 Jan 20.
Chronic renal failure (CRF) is associated with oxidative stress that promotes production of reactive oxygen species and cytokine release. We aimed to investigate the possible protective effect of montelukast, a CysLT1 receptor antagonist, against oxidative damage in a rat model of CRF, induced by 5/6 reduction of renal mass. Male Wistar albino rats were randomly assigned to either the CRF group or the sham-operated control group, which received saline or montelukast (10mg/kg, i.p.) for 4 weeks. At the end of the 4 weeks, rats were decapitated and trunk blood was collected. Creatinine, blood urea nitrogen and lactate dehydrogenase (LDH) activity were measured in the serum samples, while leukotriene B(4), TNF-alpha, IL-1 beta, IL-6, total antioxidant capacity (AOC) and leukocyte apoptosis were assayed in plasma samples. Kidney, lung, heart and brain tissue samples were taken for the determination of tissue malondialdehyde (MDA), glutathione (GSH) levels, and myeloperoxidase (MPO) activity. Oxidant-induced tissue fibrosis was determined by tissue collagen contents, and the extent of tissue injuries was analyzed microscopically. CRF caused significant decreases in tissue GSH and plasma AOC, which were accompanied with significant increases in MDA levels, MPO activities, and collagen contents of all the studied tissues, while the circulating levels of the pro-inflammatory mediators, LDH activity, creatinine and BUN were elevated. Montelukast treatment reversed all these biochemical indices, as well as histopathological alterations induced by CRF. Similarly, flow cytometric measurements revealed that leukocyte apoptosis was increased in CRF group, while montelukast reversed this effect. In conclusion, CRF-induced oxidative tissue injury occurs via the activation of pro-inflammatory mediators and by neutrophil infiltration into tissues, and that protective effects of montelukast on CRF-induced injury can be attributed to its ability to inhibit neutrophil infiltration and apoptosis, to balance oxidant-antioxidant status and to regulate the generation of pro-inflammatory mediators.
慢性肾衰竭（CRF）与氧化应激相关，氧化应激会促进活性氧的产生和细胞因子的释放。我们旨在研究半胱氨酰白三烯1（CysLT1）受体拮抗剂孟鲁司特对肾大部切除诱导的CRF大鼠模型氧化损伤的可能保护作用。雄性Wistar白化大鼠被随机分为CRF组或假手术对照组，分别接受生理盐水或孟鲁司特（10mg/kg，腹腔注射），持续4周。4周结束时，大鼠断头并采集躯干血。测定血清样本中的肌酐、血尿素氮和乳酸脱氢酶（LDH）活性，同时测定血浆样本中的白三烯B4、肿瘤坏死因子-α、白细胞介素-1β、白细胞介素-6、总抗氧化能力（AOC）和白细胞凋亡。采集肾脏、肺、心脏和脑组织样本，测定组织丙二醛（MDA）、谷胱甘肽（GSH）水平和髓过氧化物酶（MPO）活性。通过组织胶原蛋白含量测定氧化诱导的组织纤维化，并通过显微镜分析组织损伤程度。CRF导致组织GSH和血浆AOC显著降低，同时所有研究组织的MDA水平、MPO活性和胶原蛋白含量显著增加，而促炎介质的循环水平、LDH活性、肌酐和尿素氮升高。孟鲁司特治疗逆转了所有这些生化指标以及CRF诱导的组织病理学改变。同样，流式细胞术测量显示CRF组白细胞凋亡增加，而孟鲁司特逆转了这种效应。总之，CRF诱导的氧化组织损伤是通过促炎介质的激活和中性粒细胞浸润到组织中发生的，孟鲁司特对CRF诱导损伤的保护作用可归因于其抑制中性粒细胞浸润和凋亡、平衡氧化-抗氧化状态以及调节促炎介质生成的能力。
