Flutamide protects against trauma-hemorrhage-induced liver injury via attenuation of the inflammatory response, oxidative stress, and apopotosis
Flutamide protects against trauma-hemorrhage-induced liver injury via attenuation of the inflammatory response, oxidative stress, and apopotosis
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DOI：
10.1152/japplphysiol.00012.2008
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发表时间：
2008-08-01
影响因子：
3.3
通讯作者：
Chaudry, Irshad H.
中科院分区：
文献类型：
--
作者：
Kan, Wen-Hong;Hsieh, Chi-Hsun;Chaudry, Irshad H.
尽管研究表明，创伤性出血后使用睾酮受体拮抗剂氟他胺可改善肝脏、心血管和免疫功能，但产生这些有益作用的确切细胞/分子机制在很大程度上仍不清楚。为了研究这一点，雄性C3H/HeN小鼠接受中线剖腹手术和失血性休克（35 +/- 5 mmHg，持续约90分钟），然后用乳酸林格液复苏。复苏开始时皮下给予氟他胺（25mg /kg）或对照药，2 h后处死动物。通过血浆α -谷胱甘肽s -转移酶浓度、肝髓过氧化物酶活性和硝基酪氨酸形成来评估肝损伤。肝脏丙二醛和4-羟基醛（脂质过氧化指标）、细胞DNA断裂、诱导型一氧化氮合酶和缺氧诱导因子-1 α的表达也进行了评估。细胞因子（tnf - α、IL-6）和趋化因子（角化细胞来源的趋化因子和单核细胞趋化蛋白-1）水平通过细胞头阵列检测。结果表明，创伤性出血后给予氟他胺可减轻肝损伤，这与α -谷胱甘肽s -转移酶、髓过氧化物酶活性、硝基酪氨酸形成、脂质过氧化和细胞因子/趋化因子（全身、肝组织和细胞内细胞因子/趋化因子）水平降低有关。在此条件下，细胞凋亡、肝细胞缺氧诱导因子-1 α和诱导型一氧化氮合酶的表达也有所下降。因此，外伤性出血后给予氟他胺通过减少炎症、细胞氧化应激和细胞凋亡来保护肝脏免受损伤。
Although studies have shown that administration of testosterone receptor antagonist, flutamide, following trauma-hemorrhage, improves hepatic, cardiovascular, and immune functions, the precise cellular/molecular mechanisms responsible for producing these salutary effects remain largely unknown. To study this, male C3H/HeN mice were subjected to a midline laparotomy and hemorrhagic shock (35 +/- 5 mmHg for similar to 90 min), followed by resuscitation with Ringer lactate. Flutamide (25 mg/kg) or vehicle was administered subcutaneously at the onset of resuscitation, and animals were killed 2 h thereafter. Hepatic injury was assessed by plasma alpha-glutathione S-transferase concentration, liver myeloperoxidase activity, and nitrotyrosine formation. Hepatic malondialdehyde and 4-hydroxyalkenals ( lipid peroxidation indicators), cellular DNA fragmentation, and the expression of inducible nitric oxide synthase and hypoxia-inducible factor-1 alpha were also evaluated. Cytokines (TNF-alpha, IL-6) and chemokines (keratinocyte-derived chemokine and monocyte chemoattractant protein-1) levels were determined by cytometric bead array. The results indicate that flutamide administration after trauma-hemorrhage reduced liver injury, which was associated with decreased levels of alpha-glutathione S-transferase, myeloperoxidase activity, nitrotyrosine formation, lipid peroxidation, and cytokines/chemokines (systemic, liver tissue, and intracellular cytokines/chemokines). Cellular apoptosis, hepatocyte hypoxia-inducible factor-1 alpha, and inducible nitric oxide synthase expression were also decreased under such conditions. Thus administration of flutamide following trauma-hemorrhage protects against liver injury via reduced inflammation, cellular oxidative stress, and apoptosis.