大鼠肝脏缺血再灌注损伤中的性别差异与内皮细胞一氧化氮合酶衍生的一氧化氮有关。
Gender differences in hepatic ischemic reperfusion injury in rats are associated with endothelial cell nitric oxide synthase-derived nitric oxide.
作者信息
Lü Ping, Liu Fang, Wang Chun-You, Chen Dao-Da, Yao Zhong, Tian Yuan, Zhang Jing-Hui, Wu Yi-Hua
机构信息
Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
出版信息
World J Gastroenterol. 2005 Jun 14;11(22):3441-5. doi: 10.3748/wjg.v11.i22.3441.
AIM
This study was designed to examine the hypothesis that gender differences in I/R injury are associated with endothelial cell nitric oxide synthase (eNOS)-derived nitric oxide (NO).
METHODS
Wistar rats were randomized into seven experimental groups (12 animals per group). Except for the sham operated groups, all rats were subjected to total liver ischemia for 40 min followed by reperfusion. All experimental groups received different treatments 45 min before the laparotomy. For each group, half of the animals (six) were used to investigate the survival; blood samples and liver tissues were obtained in the remaining six animals after 3 h of reperfusion to assess serum NO, alanine aminotransferase (ALT) and TNF-alpha levels, liver tissue malondialdehyde (MDA) content, and severity of hepatic I/R injury.
RESULTS
Basal serum NO levels in female sham operated (FS) group were nearly 1.5-fold of male sham operated (MS) group (66.7+/-11.0 micromol/L vs 45.3+/-10.1 micromol/L, P<0.01). Although serum NO levels decreased significantly after hepatic I/R (P<0.01, vs sham operated groups), they were still significantly higher in female rat (F) group than in male rat (M) group (47.8+/-8.6 micromol/L vs 23.8+/-4.7 micromol/L, P<0.01). Serum ALT and TNF-alpha levels, and liver tissue MDA content were significantly lower in F group than in M group (370.5+/-46.4 U/L, 0.99+/-0.11 microg/L and 0.57+/-0.10 micromol/g vs 668.7+/-78.7 U/L, 1.71+/-0.18 microg/L and 0.86+/-0.11 micromol/g, respectively, P<0.01). I/R induced significant injury to the liver both in M and F groups (P<0.01 vs sham operated groups). But the degree of hepatocyte injury was significantly milder in F group than in M group (P<0.05 and P<0.01). The median survival time was six days in F group and one day in M group. The overall survival rate was significantly higher in F group than in M group (P<0.05). When compared with male rats pretreated with saline (M group), pretreatment of male rats with 17-beta-estradiol (E2) (M+E2 group) significantly increased serum NO levels and significantly decreased serum ALT and TNF-alpha levels, and liver tissue MDA content after I/R (P<0.01). The degree of hepatocyte injury was significantly decreased and the overall survival rate was significantly improved in M+E2 group than in M group (P<0.01 and P<0.05). The NOS inhibitor N(w) -nitro-L-arginine methyl ester (L-NAME) treatment could completely abolish the protective effects of estrogen in both male and female rats.
CONCLUSION
The protective effects afforded to female rats subjected to hepatic I/R are associated with eNOS-derived NO.
目的
本研究旨在检验以下假设，即缺血/再灌注（I/R）损伤中的性别差异与内皮细胞一氧化氮合酶（eNOS）衍生的一氧化氮（NO）有关。
方法
将Wistar大鼠随机分为七个实验组（每组12只动物）。除假手术组外，所有大鼠均经历40分钟的全肝缺血，随后进行再灌注。所有实验组在剖腹术前45分钟接受不同处理。对于每组，一半动物（六只）用于研究存活率；在再灌注3小时后，从其余六只动物中采集血样和肝组织，以评估血清NO、丙氨酸转氨酶（ALT）和肿瘤坏死因子-α（TNF-α）水平、肝组织丙二醛（MDA）含量以及肝I/R损伤的严重程度。
结果
雌性假手术（FS）组的基础血清NO水平几乎是雄性假手术（MS）组的1.5倍（66.7±11.0微摩尔/升对45.3±10.1微摩尔/升，P<0.01）。尽管肝I/R后血清NO水平显著降低（P<0.01，与假手术组相比），但雌性大鼠（F）组的血清NO水平仍显著高于雄性大鼠（M）组（47.8±8.6微摩尔/升对23.8±4.7微摩尔/升，P<0.01）。F组的血清ALT和TNF-α水平以及肝组织MDA含量显著低于M组（分别为370.5±46.4 U/L、0.99±0.11微克/升和0.57±0.10微摩尔/克对668.7±78.7 U/L、1.71±0.18微克/升和0.86±0.11微摩尔/克，P<0.01）。I/R在M组和F组均对肝脏造成了显著损伤（与假手术组相比，P<0.01）。但F组的肝细胞损伤程度明显轻于M组（P<0.05和P<0.01）。F组的中位存活时间为6天，M组为1天。F组的总体存活率显著高于M组（P<0.05）。与用盐水预处理的雄性大鼠（M组）相比，用17-β-雌二醇（E2）预处理雄性大鼠（M+E2组）可显著提高I/R后的血清NO水平，并显著降低血清ALT和TNF-α水平以及肝组织MDA含量（P<0.01）。M+E2组的肝细胞损伤程度显著降低，总体存活率显著高于M组（P<0.01和P<0.05）。一氧化氮合酶抑制剂N（ω）-硝基-L-精氨酸甲酯（L-NAME）处理可完全消除雌激素对雄性和雌性大鼠的保护作用。
结论
给予雌性大鼠肝I/R的保护作用与eNOS衍生的NO有关。
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