Hsu Jun-Te, Kan Wen-Hong, Hsieh Chi-Hsun, Choudhry Mashkoor A, Bland Kirby I, Chaudry Irshad H
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Surgery. 2009 Feb;145(2):226-34. doi: 10.1016/j.surg.2008.10.008. Epub 2008 Dec 23.
Extracellular signal-regulated protein kinase (ERK) is known to be involved in pro-inflammatory and chemotactic events in response to injury. The aim of this study is to elucidate whether ERK plays any role in 17beta-estradiol (E2)-mediated attenuation of lung injury and pro-inflammatory mediators after trauma-hemorrhage.
Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure approximately 40 mm Hg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle (cyclodextrin), E2 (1 mg/kg body weight [BW]), or the ERK inhibitor PD98059 (2 mg/kg BW). At 2 h after sham operation or trauma-hemorrhage, various parameters were measured.
Trauma-hemorrhage led to a significant increase in lung ERK phosphorylation, which was associated with increased lung myeloperoxidase activity, wet-to-dry weight ratio, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, intercellular adhesion molecule (ICAM)-1, cytokine-induced neutrophil chemoattractant (CINC)-1, and macrophage inflammatory protein-2 levels. Circulatory IL-6, TNF-alpha, and lactate levels were also increased after trauma-hemorrhage compared with shams. Administration of E2 or ERK inhibitor PD98059 after trauma-hemorrhage attenuated the trauma-hemorrhage-induced increase in lung injury markers, ERK phosphorylation and cytokines/chemokines, ICAM-1 production, as well as circulatory cytokines and lactate levels.
These results collectively suggest that the salutary effects of E2 on the lung after trauma-hemorrhage are mediated via an ERK pathway and subsequent downregulation of pro-inflammatory mediator production.
已知细胞外信号调节蛋白激酶（ERK）参与损伤后的促炎和趋化事件。本研究的目的是阐明ERK在创伤性出血后17β-雌二醇（E2）介导的肺损伤和促炎介质的减轻中是否发挥任何作用。
雄性Sprague-Dawley大鼠经历创伤性出血（平均血压约40 mmHg，持续90分钟），随后进行液体复苏。在复苏开始时，大鼠接受载体（环糊精）、E2（1 mg/kg体重[BW]）或ERK抑制剂PD98059（2 mg/kg BW）治疗。在假手术或创伤性出血后2小时，测量各种参数。
创伤性出血导致肺ERK磷酸化显著增加，这与肺髓过氧化物酶活性、湿重与干重比、白细胞介素（IL）-6、肿瘤坏死因子（TNF）-α、细胞间黏附分子（ICAM）-1、细胞因子诱导的中性粒细胞趋化因子（CINC）-1和巨噬细胞炎性蛋白-2水平升高有关。与假手术组相比，创伤性出血后循环中的IL-6、TNF-α和乳酸水平也升高。创伤性出血后给予E2或ERK抑制剂PD98059可减轻创伤性出血诱导的肺损伤标志物、ERK磷酸化和细胞因子/趋化因子、ICAM-1产生以及循环细胞因子和乳酸水平的增加。
这些结果共同表明，E2对创伤性出血后肺的有益作用是通过ERK途径介导的，并随后下调促炎介质的产生。
