摘要
目的探讨模拟睡眠呼吸暂停综合征(sleep apnea syndrome,SAS)的慢性间断性缺氧(chronic intermittent hypoxia,CIH)对小鼠肝脏组织结构、超微结构、肝功能、细胞色素P450(cytochrome p-450,CYP450)及小鼠离体肝细胞对茶碱代谢的影响。
方法将32只健康雄性C57BL6J小鼠随机分为以下四组：空气模拟对照组、CIH组、抗痨药物组和CIH+抗痨药物组,进行12周的CIH模型实验。实验结束前两周,抗痨药物组、CIH+抗痨药物组分别给予利福平加异烟肼灌胃。检测血清转氨酶浓度,观察肝组织病理变化,电子显微镜观察肝脏超微结构改变,检测肝微粒体悬液总CYP450浓度,分离肝细胞与15mg/ml浓度茶碱共培养,4小时后检测培养上清液茶碱浓度。
结果(1)血清谷草转氨酶浓度在各组间差异均无统计学意义：空气对照组(19.0±9.4IU/L),CIH组(19.1±17.9IU/L),抗痨药物组(9.6±2.1IU/L),CIH+抗痨药物组(13.3±4.7IU/L)(P>0.05)；血清谷丙转氨酶浓度在各组间差异均无统计学意义：空气对照组(65.4±27.0IU/L),CIH组(58.0±24.3IU/L),抗痨药物组(41.1±17.7IU/L),CIH+抗痨药物组(47.8±11.6IU/L)(P>0.05)。(2)CIH可引起肝细胞空泡变性。电镜下,CIH可引起少量肝细胞水肿,部分粗面内质网模糊,窦周隙少量胶原纤维增生；CIH可加重抗痨药物的肝超微结构损害：表现为肝细胞结构模糊、水肿、坏死,损伤线粒体,加剧胶原纤维增生,部分毛细胆管消失。(3)CIH组肝微粒体悬液总CYP450含量(0.83±0.088nmol/mg蛋白)低于空气对照组(1.13±0.21nmol/mg蛋白)(P=0.00I)；CIH+抗痨药物组肝微粒体悬液总CYP450含量(0.83±0.08nmol/mg蛋白)低于空气对照组(P=0.001)及抗痨药物组(1.19±0.20nmol/mg蛋白)(P=0.000)；CIH组肝微粒体悬液总CYP450含量与CIH加抗痨药物组差异无统计学意义(P>0.05)；抗痨药物组肝微粒体悬液总CYP450含量与对照组差异无统计学意义(P>0.05)。(4)两因素两水平析因设计方差分析显示：CIH可降低肝细胞对茶碱的清除(F=71.6,P=0.000)；抗痨药物可促进茶碱的清除(F=17,7,P=0.000)；CIH与抗痨药物对茶碱清除影响存在交互作用(F=689.4,P=0.000)。
结论：(1)模拟SAS的CIH可引起小鼠肝组织结构损害,并可加重抗痨药物所造成的肝脏超微结构的损害。(2)CIH可抑制小鼠肝脏CYP450的表达。(3)CIH可降低小鼠肝细胞对茶碱的清除率。CIH与抗痨药物对茶碱清除率的影响存在交互作用,两者并存时明显降低茶碱的清除率。
Objective:To explore the effect of chronic intermittent hypoxia (CIH) on hepatic histological feature and hepatic function, including theophylline metabolism, in mice.
Methods:32 male C57BL6J mice were divided into four groups, which were air control group, CIH group, anti-tuberculosis group, and CIH plus anti-tuberculosis group. Total 12 weeks CIH experiment was performed. 2 weeks before sacrifice, mice of anti-tuberculosis group and CIH plus anti-tuberculosis group were treated with rifampicin (25mg/kg/d) and isoniazid (10mg/kg/d) intragastrically, and saline as for control. Serum alanine aminotransferase and aspartate aminotransferase level were detected. Hepatic histological features were observed and hepa-tocyte ultra-structure was observed through electron microscope. Total cytochrome p-450 (CYP450) concentrations of hepatic microsomes were measured. Hepatocytes were isolated and incubated with 15mg/ml theophylline. After hepatocytes were incubated with theophylline for 4 hours, the theophylline concentration in supernatant of hepatocytes were measured.
Results:There was no difference among serum aspartate aminotrans-ferase levels of air control group (19.0±9.4IU/L), CIH group (19.1±17.9IU/L), anti-tuberculosis group (9.6±2.1IU/L) and CIH plus anti-tuberculosis group (13.3±4.7IU/L) (P>0.05). There was no difference among serum alanine aminotransferase levels of air control group (65.4±27.0IU/L), CIH group (58.0±24.3IU/L), anti-tubercu-losis group (41.1±17,7IU/L) and CIH plus anti-tuberculosis group (47.8±11.6IU/L) (P>0.05). Mice exposed to CIH caused vacuolar degeneration in liver. Mice exposed to CIH showed cellular edema, fuzzy rough endoplasmic reticulum in hepatocytes, and a little collagen fiber hyperplasia in hepatic disse space. CIH plus anti-tuberculosis could intensify the ultra-structure lesion, which showed fuzzy cellular structures, cellular edema, hepatocytes necrosis, mitochondrial lesion, intensified collagen fiber hyperplasia in hepatic disse space, and abolition of part of cholangioles. Total cytochrome CYP450 concentration of hepatic microsomes of CIH group (0.83±0.08nmol/mgprotein) was lower than that of air control group (1.13±0.21nmol/mgprotein) (P=0.001). Total CYP450 concentration of hepatic microsomes of CIH plus anti-tuberculosis group (0.83±0.08nmol/mgprotein) was lower that of air control group (P=0.001) and that of anti-tuberculosis group (1.19±0.20nmol/mgprotein) (P=0.000). There was no difference between total CYP450 concentra-tion of CIH group and that of CIH plus anti-tuberculosis group(P>0.05). There was no difference between total CYP450 concentration of CIH plus anti-tuberculosis group and that of air control group (P>0.05). CIH could reduce theophylline metabolism by mouse hepatocytes (F=71.6, P=0.000). Anti-tuberculosis could enhance theophylline metabolism by hepatocytes (F=17.7, P=0.000). There was interaction between CIH and anti-tuberculosis on theophylline metabolism (F=689.4, P=0.000).
Conclusion:CIH could cause histological feature lesion in mouse liver. CIH could intensify liver ultra-structure lesion caused by anti-tuberculosis drugs. CIH could affect theophylline metabolism through affect CYP450 expression in mouse liver. There was interactive effect between CIH and anti-tuberculosis drugs on theophylline metabolism.
引文
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1. Korcarz CE, Gepner AD, Peppard PE, Young TB, Stein JH. The effects of sleep-disordered breathing on arterial stiffness are modulated by age. Sleep.2010 Aug 1; 33(8):1081-5.
2. Johnson KG, Johnson DC. Obstructive sleep apnea is a risk factor for stroke and atrial fibrillation. Chest.2010 Jul; 138(1):239.
3. Trombetta IC, Somers VK, Maki-Nunes C, Drager LF, Toschi-Dias E, Alves MJ, Fraga RF, Rondon MU, Bechara MG, Lorenzi-Filho G, Negrao CE. Consequences of comorbid sleep apnea in the metabolic syndrome--implications for cardiovascular risk. Sleep.2010 Sep 1; 33 (9):1193-9.
4. Henrion J, Colin L, Schapira M, Heller FR。 Hypoxic hepatitis caused by severe hypoxemia from obstructive sleep apnea. J Clin Gastroenterol. 1997 Jun;24(4):245-9.
5. Eric R. Kallwitz, MD,* James Herdegen, MD,* James Madura, MD, Sriram Jakate, MD, z and Scott J. Cotler, MD. Liver Enzymes and Histology in Obese Patients ith Obstructive Sleep Apnea. J Clin Gastroenterol 2007:41:918-921.
6. Tanne F, Gagnadoux F, Chazouilleres O, Fleury B, Wendum D, Lasnier E, Lebeau B, Poupon R, Serfaty L. Chronic Liver Injury During Obstructive Sleep Apnea. HEPATOLOGY 2005:41:1290-1296.
7. Pauline J.1; Jean-Marc Sabatel; Dominique Maillard2; Simon Msika3; Charlotte Mechler4; Severine Ledoux2; Florence Harnois1; Benoit Coffinl. Relationship between Obstructive Sleep Apnea and Liver Abnormalities in Morbidly Obese Patients:A Prospective Study. Obesity Surgery,17,478-485.
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9. Stijn L. Verhulst & Sarah Jacobs & Liselotte Aerts & Nancy Schrauwen & Dominique Haentjens & Raoul P. Rooman & Luc Van Gaal & Wilfried A. De Backer & Kristine N. Desager. Sleep-disordered breathing:a new risk factor of suspected fatty liver disease in overweight children and adolescents? Sleep Breath.2009 May;13(2):207-10.
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12. Koichiro Tatsumi, Toshiji Saibara. Effects of obstructive sleep apnea syndrome on hepatic steatosis and nonalcoholic steatohepatitis. Hepatol Res.2005 Oct;33(2):100-4.
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