Deree Jessica, Loomis William H, Wolf Paul, Coimbra Raul
Division of Trauma and Critical Care, Department of Surgery, University of California-San Diego, USA.
J Trauma. 2008 May;64(5):1230-8; discussion 1238-9. doi: 10.1097/TA.0b013e31816a4391.
Fluid resuscitation can contribute to postshock inflammation and the development of end organ injury. We have previously observed an attenuation in pulmonary and ileal inflammation when hypertonic saline and pentoxifylline (HSPTX) were concomitantly administered after hemorrhage. We hypothesized that the attenuation in hepatic injury observed with HSPTX is associated with the reduction of transcription factor activation and proinflammatory mediator production when compared with Ringer's lactate (RL).
Male Sprague-Dawley rats were resuscitated with racemic RL (32 mL/kg) or HSPTX (4 mL/kg 7.5% NaCl + PTX 25 mg/kg) and killed at 4 hours and 24 hours after resuscitation. Liver injury was determined by histology and serum aminotransferases. Nitrite, tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 were measured with enzyme-linked immunosorbent assay. High mobility group box 1, inducible nitric oxide synthase, nuclear factor (NF)-kappaB phosphorylation, and signal transducers and activators of transcription-3 phosphorylation were determined by Western blot. Transcription factor activation was verified with Electrophoretic Mobility Shift Assay.
RL resuscitation led to significant increases all measured parameters when compared with control. In contrast, HSPTX did not induce elevations in histologic liver injury or alanine aminotransferase levels. HSPTX attenuated inducible nitric oxide synthase by 23% (p < 0.01), nitrite by 25% (p < 0.05), tumor necrosis factor-alpha by 25% (p < 0.05), IL-1 by 63% (p < 0.01), IL-6 by 35% (p < 0.05), and high mobility group box 1 by 39% (p < 0.05) when compared with RL. HSPTX reduced IkappaB-alpha phosphorylation by 34% (p < 0.05), NF-kappaB p65 phosphorylation by 75% (p < 0.01), and signal transducers and activators of transcription-3 phosphorylation by 52% (p < 0.01).
The reduction in liver injury observed with HSPTX resuscitation after hemorrhage is associated with attenuation transcription factor activation and proinflammatory mediators. HSPTX has the potential to be a superior resuscitation fluid with significant immunomodulatory properties.
液体复苏可导致休克后炎症反应及终末器官损伤的发生。我们之前观察到，出血后同时给予高渗盐水和己酮可可碱（HSPTX）时，肺部和回肠炎症反应减轻。我们推测，与乳酸林格液（RL）相比，HSPTX所观察到的肝损伤减轻与转录因子激活及促炎介质生成减少有关。
将雄性Sprague-Dawley大鼠用消旋RL（32 mL/kg）或HSPTX（4 mL/kg 7.5%氯化钠 + 己酮可可碱25 mg/kg）进行复苏，并在复苏后4小时和24小时处死。通过组织学和血清转氨酶测定肝损伤情况。采用酶联免疫吸附测定法检测亚硝酸盐、肿瘤坏死因子-α、白细胞介素（IL）-1β和IL-6。通过蛋白质免疫印迹法测定高迁移率族蛋白B1、诱导型一氧化氮合酶、核因子（NF）-κB磷酸化以及信号转导和转录激活因子-3磷酸化。通过电泳迁移率变动分析验证转录因子激活情况。
与对照组相比，RL复苏导致所有测量参数显著升高。相比之下，HSPTX未引起肝组织学损伤或丙氨酸转氨酶水平升高。与RL相比，HSPTX使诱导型一氧化氮合酶降低23%（p < 0.01），亚硝酸盐降低25%（p < 0.05），肿瘤坏死因子-α降低25%（p < 0.05），IL-1降低63%（p < 0.01），IL-6降低35%（p < 0.05），高迁移率族蛋白B1降低39%（p < 0.05）。HSPTX使IκB-α磷酸化降低34%（p < 0.05），NF-κB p65磷酸化降低75%（p < 0.01），信号转导和转录激活因子-3磷酸化降低52%（p < 0.01）。
出血后HSPTX复苏所观察到的肝损伤减轻与转录因子激活及促炎介质的减弱有关。HSPTX有可能成为一种具有显著免疫调节特性的优质复苏液。
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