Research Institute of General Pathology and Pathophysiology, Moscow, Russia.
Biogerontology. 2010 Apr;11(2):229-43. doi: 10.1007/s10522-009-9242-2. Epub 2009 Jul 26.
There is now a large body of evidence suggesting that the decline in ovarian function with menopause is associated with spontaneous increases in pro-inflammatory cytokines. On the other hand, oxidative stress has been implicated in the pathogenesis of several alterations due to menopause, and can arise through the increased production of lipid peroxides (LPO) and/or a deficiency of antioxidant defense. The aim of the present study was to investigate the effect of aging and ovariectomy on various physiological parameters related to inflammation and oxidative stress in livers obtained from old female rats and the influence of chronic exogenous administration of estrogens, phytoestrogens and growth hormone on these. Thirty-six female Wistar rats of 22 months of age were used in the present study. Twelve of them remained intact, and the other 24 had been ovariectomized at 12 months of age. Intact animals were divided into two groups and treated for 10 weeks with GH or saline, and ovariectomized animals were divided into four groups and treated for the same time with GH, estrogens, phytoestrogens or saline. A group of 2 month old intact female rats was used as young control. Protein expression of iNOS, HO-1, IL-6, TNFalpha, and IL-1beta were determined by Western blot analysis. The levels of NO( x ), LPO, TNFalpha, IL-1beta, IL-6 and IL-10 were determined in different fractions of the liver. Levels of LPO in the liver homogenates as well as iNOS protein expression and NO( x ) levels were increased in old rats as compared to young animals; this effect was more evident in ovariectomized animals. Pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6 were significantly increased and anti-inflammatory IL-10 decreased during ageing and after ovariectomy. Aging also significantly increased expression of HO-1 protein and ovariectomized rats showed an additional increase. Hormonal administration to the ovariectomized groups decreased NO( x ), LPO levels and pro-inflammatory cytokines as compared with untreated rats. Significant rise in IL-10 and reductions in the iNOS, IL-6, TNFalpha and IL-1beta proteins expression were also found. Oxidative stress and inflammation induced during aging in the liver are more marked in castrated than in intact old females. Administration of the different hormonal replacement therapies was able to inhibit the induction of pro-inflammatory cytokines and iNOS, decreased the levels of oxidative stress markers and had therapeutic potential in the prevention of liver injury.
现在有大量证据表明，绝经后卵巢功能下降与自发性促炎细胞因子增加有关。另一方面，氧化应激与绝经后多种改变的发病机制有关，可通过增加脂质过氧化物 (LPO) 的产生和/或抗氧化防御的缺乏而产生。本研究旨在探讨衰老和卵巢切除术对老年雌性大鼠肝脏中与炎症和氧化应激相关的各种生理参数的影响，以及慢性外源性给予雌激素、植物雌激素和生长激素对这些参数的影响。本研究使用了 36 只 22 月龄的雌性 Wistar 大鼠。其中 12 只为完整组，其余 24 只为 12 月龄时卵巢切除术组。完整组动物分为两组，分别用 GH 或生理盐水处理 10 周，卵巢切除术组动物分为四组，用 GH、雌激素、植物雌激素或生理盐水处理 10 周。一组 2 月龄完整的雌性大鼠作为年轻对照组。通过 Western blot 分析测定 iNOS、HO-1、IL-6、TNFalpha 和 IL-1beta 的蛋白表达。测定肝不同部位的 NO(x)、LPO、TNFalpha、IL-1beta、IL-6 和 IL-10 水平。与年轻动物相比，老年大鼠的 LPO 水平、肝匀浆中 iNOS 蛋白表达和 NO(x)水平升高，卵巢切除术大鼠的这种效应更为明显。随着衰老和卵巢切除，促炎细胞因子 TNFalpha、IL-1beta 和 IL-6 显著增加，抗炎细胞因子 IL-10 减少。衰老还显著增加了 HO-1 蛋白的表达，卵巢切除术大鼠的表达进一步增加。与未治疗组相比，给予卵巢切除组激素治疗可降低 NO(x)、LPO 水平和促炎细胞因子。还发现 IL-10 显著升高，iNOS、IL-6、TNFalpha 和 IL-1beta 蛋白表达减少。与完整的老年雌性大鼠相比，卵巢切除大鼠肝脏中的氧化应激和炎症在衰老过程中更为明显。给予不同的激素替代疗法能够抑制促炎细胞因子和 iNOS 的诱导，降低氧化应激标志物的水平，在预防肝损伤方面具有治疗潜力。
