Department of Critical Care Medicine, Institute of Anesthesia and Critical Care, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Surg Res. 2013 Aug;183(2):710-9. doi: 10.1016/j.jss.2013.03.007. Epub 2013 Mar 26.
Hemorrhagic shock activates cellular stress signals and can lead to systemic inflammatory response, organ injury, and death. Mitogen-activated protein kinase (MAPK) acts as a sensor of tissue injury in models of ischemia-reperfusion injury. Lipoxins are endogenous lipid mediators with potent anti-inflammatory and pro-resolving actions. We hypothesized that BML-111 (a lipoxin A4-receptor agonist) attenuates hemorrhagic shock-induced acute lung injury (ALI) through inhibiting activation of the MAPK pathway.
We randomized Sprague-Dawley rats into four groups: sham, hemorrhagic shock-resuscitation (HS), HS plus BML-111 (BML-111), and HS plus BML-111 and BOC-2 (BOC-2). Two hours after resuscitation, we collected samples of lung. We obtained bronchoalveolar lavage fluid for neutrophil count. We performed optical microscopy to examine pathologic changes in lungs. Wet/dry ratios, myeloperoxidase expression, interleukin (IL)-1β and IL-6 levels in lung were measured. We evaluated MAPK activation and the DNA binding activity of activator protein-1 in lung.
Treatment with BML-111 reduced the lung damage and wet/dry ratio, neutrophil count in bronchoalveolar lavage fluid, expression of myeloperoxidase, and production of IL-1β and IL-6 in lung. Phosphorylation of MAPK was also decreased by BML-111 in lung. Furthermore, the DNA binding activity of activator protein-1 was blocked by BML-111. An antagonist of the lipoxin A4-receptor, BOC-2, reversed the protective effect of BML-111 on ALI induced by hemorrhagic shock.
This study indicates that BML-111 attenuated hemorrhagic shock-induced ALI via the MAPK/activator protein-1 signaling pathway. Therefore, BML-111 may have therapeutic potential for hemorrhagic shock-induced ALI.
失血性休克激活细胞应激信号，可导致全身炎症反应、器官损伤和死亡。丝裂原活化蛋白激酶（MAPK）在缺血再灌注损伤模型中作为组织损伤的传感器。脂氧素是具有强大抗炎和促解决作用的内源性脂质介质。我们假设 BML-111（一种脂氧素 A4 受体激动剂）通过抑制 MAPK 通路的激活来减轻失血性休克引起的急性肺损伤（ALI）。
我们将 Sprague-Dawley 大鼠随机分为四组：假手术组、失血性休克复苏组（HS）、HS 加 BML-111 组（BML-111）和 HS 加 BML-111 和 BOC-2 组（BOC-2）。复苏后 2 小时，我们收集肺样本。我们采集支气管肺泡灌洗液以计数中性粒细胞。我们进行光学显微镜检查以检查肺的病理变化。测量肺中的湿/干比、髓过氧化物酶表达、白细胞介素（IL）-1β 和 IL-6 水平。我们评估了 MAPK 激活和肺中激活蛋白-1 的 DNA 结合活性。
BML-111 治疗可减轻肺损伤和湿/干比、支气管肺泡灌洗液中的中性粒细胞计数、肺中髓过氧化物酶的表达以及 IL-1β 和 IL-6 的产生。MAPK 的磷酸化也被 BML-111 降低。此外，BML-111 阻断了激活蛋白-1 的 DNA 结合活性。脂氧素 A4 受体拮抗剂 BOC-2 逆转了 BML-111 对失血性休克引起的 ALI 的保护作用。
本研究表明，BML-111 通过 MAPK/激活蛋白-1 信号通路减轻失血性休克引起的 ALI。因此，BML-111 可能对失血性休克引起的 ALI 具有治疗潜力。
