Szalay László, Shimizu Tomoharu, Schwacha Martin G, Choudhry Mashkoor A, Rue Loring W, Bland Kirby I, Chaudry Irshad H
Center for Surgical Research, Univ. of Alabama at Birmingham, 1670 University Blvd., Volker Hall, Rm. G094, Birmingham, AL 35294-0019, USA.
Am J Physiol Heart Circ Physiol. 2005 Jul;289(1):H92-8. doi: 10.1152/ajpheart.01247.2004. Epub 2005 Feb 25.
A growing body of evidence indicates that heme degradation products may counteract the deleterious consequences of hypoxia and/or ischemia-reperfusion injury. Because heme oxygenase (HO)-1 induction after adverse circulatory conditions is known to be protective, and because females in the proestrus cycle (with high estrogen) have better hepatic function and less hepatic damage than males after trauma-hemorrhage, we hypothesized that estrogen administration in males after trauma-hemorrhage will upregulate HO activity and protect the organs against dysfunction and injury. To test this hypothesis, male Sprague-Dawley rats underwent 5-cm laparotomy and hemorrhagic shock (35-40 mmHg for 93 +/- 2 min), followed by resuscitation with four times the shed blood volume in the form of Ringer lactate. 17beta-Estradiol and/or the specific HO enzyme inhibitor chromium mesoporphyrin (CrMP) were administered at the end of resuscitation, and the animals were killed 24 h thereafter. Trauma-hemorrhage reduced cardiac output, myocardial contractility, and serum albumin levels. Portal pressure and serum alanine aminotransferase levels were markedly increased under those conditions. These parameters were significantly improved in the 17beta-estradiol-treated rats. Estradiol treatment also induced increased HO-1 mRNA expression, HO-1 protein levels, and HO enzymatic activity in cardiac and hepatic tissue compared with vehicle-treated trauma-hemorrhage rats. Administration of the HO inhibitor CrMP prevented the estradiol-induced attenuation of shock-induced organ dysfunction and damage. Thus the salutary effects of estradiol administration on organ function after trauma-hemorrhage are mediated in part via upregulation of HO-1 expression and activity.
越来越多的证据表明，血红素降解产物可能会抵消缺氧和/或缺血再灌注损伤的有害后果。由于已知在不良循环条件下诱导血红素加氧酶（HO）-1具有保护作用，并且由于处于发情前期（雌激素水平高）的雌性比创伤性出血后的雄性具有更好的肝功能和更少的肝损伤，我们推测创伤性出血后给雄性大鼠施用雌激素会上调HO活性，并保护器官免受功能障碍和损伤。为了验证这一假设，对雄性Sprague-Dawley大鼠进行5厘米的剖腹手术和失血性休克（35-40 mmHg，持续93±2分钟），然后以乳酸林格液的形式用失血量四倍的液体进行复苏。在复苏结束时给予17β-雌二醇和/或特异性HO酶抑制剂中卟啉铬（CrMP），并在24小时后处死动物。创伤性出血降低了心输出量、心肌收缩力和血清白蛋白水平。在这些条件下，门静脉压力和血清丙氨酸转氨酶水平显著升高。在17β-雌二醇治疗的大鼠中，这些参数得到了显著改善。与载体处理的创伤性出血大鼠相比，雌二醇治疗还诱导心脏和肝脏组织中HO-1 mRNA表达、HO-1蛋白水平和HO酶活性增加。施用HO抑制剂CrMP可防止雌二醇诱导的休克诱导的器官功能障碍和损伤的减轻。因此，创伤性出血后施用雌二醇对器官功能的有益作用部分是通过上调HO-1的表达和活性来介导的。
