Deree Jessica, de Campos Tercio, Shenvi Edna, Loomis William H, Hoyt David B, Coimbra Raul
Department of Surgery, Division of Trauma and Surgical Critical Care, University of California School of Medicine, CA, USA.
J Trauma. 2007 Apr;62(4):818-27; discussion 827-8. doi: 10.1097/TA.0b013e31802d9745.
We have previously demonstrated that postshock resuscitation with Hypertonic saline and Pentoxifylline (HSPTX) attenuates pulmonary and histologic gut injury when compared with Ringer's lactate (RL). In this study, we hypothesized that the decrease in gut injury observed with HSPTX is associated with the attenuation of inducible nitric oxide synthase (iNOS) activity and production of ileal proinflammatory mediators after hemorrhagic shock.
In a rat model of hemorrhagic shock, resuscitation was conducted with RL (32 mL/kg; n = 7) or HSPTX (4 mL/kg 7.5% NaCl + PTX 25 mg/kg; n = 7). Sham animals that did not undergo shock were also studied. Four hours after resuscitation, the terminal ileum was collected for evaluation of nitrite, tumor necrosis factor (TNF)-alpha, Interleukin (IL)-6, and cytokine-induced neutrophil chemoattractant (CINC) by enzyme immunoassay. Heme oxygenase-1 (HO-1), iNOS, cytoplasmic inhibitor of kappa B (Ikappa B) phosphorylation, and nuclear factor (NF)kappa B p65 nuclear translocation were determined by Western blot.
HSPTX resuscitation resulted in a 49% decrease in iNOS when compared with RL (p < 0.05). Similar results were obtained when examining nitrite (882 +/- 59 vs. 1,435 +/- 177 micromol/L; p < 0.01), and HO-1 content (p < 0.05). RL resuscitation resulted in markedly higher levels of TNF-alpha (83 +/- 27 vs. 9 +/- 5 pg/mL; p < 0.01), IL-6 (329 +/- 58 vs. 118 +/- 43 pg/mL; p < 0.05), and CINC (0.43 +/- .06 vs. 0.19 +/- .08 ng/mL; p < 0.05) than HSPTX. The increase in cytokines observed with RL was also associated with an increase in I-kappaB phosphorylation (p < 0.01) and NF-kappaB p65 nuclear translocation (p < 0.001).
The attenuation in gut injury after postshock resuscitation with HSPTX is associated with downregulation of iNOS activity and subsequent proinflammatory mediator synthesis. HSPTX has the potential to be a superior resuscitation fluid with significant immunomodulatory properties.
我们之前已经证明，与乳酸林格液（RL）相比，高渗盐水和己酮可可碱（HSPTX）进行休克后复苏可减轻肺部和肠道组织损伤。在本研究中，我们假设HSPTX观察到的肠道损伤减轻与出血性休克后诱导型一氧化氮合酶（iNOS）活性降低以及回肠促炎介质的产生减少有关。
在大鼠出血性休克模型中，用RL（32 mL/kg；n = 7）或HSPTX（4 mL/kg 7.5% NaCl + PTX 25 mg/kg；n = 7）进行复苏。也对未经历休克的假手术动物进行了研究。复苏后4小时，收集末端回肠，通过酶免疫测定法评估亚硝酸盐、肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6和细胞因子诱导的中性粒细胞趋化因子（CINC）。通过蛋白质印迹法测定血红素加氧酶-1（HO-1）、iNOS、细胞质κB抑制蛋白（Ikappa B）磷酸化和核因子（NF）κB p65核转位。
与RL相比，HSPTX复苏导致iNOS降低49%（p < 0.05）。检查亚硝酸盐（882±59对1,435±177 μmol/L；p < 0.01）和HO-1含量（p < 0.05）时也获得了类似结果。RL复苏导致TNF-α（83±27对9±5 pg/mL；p < 0.01）、IL-6（329±58对118±43 pg/mL；p < 0.05）和CINC（0.43±0.06对0.19±0.08 ng/mL；p < 0.05）水平明显高于HSPTX。RL观察到的细胞因子增加也与I-κB磷酸化增加（p < 0.01）和NF-κB p65核转位增加（p < 0.001）有关。
HSPTX进行休克后复苏后肠道损伤的减轻与iNOS活性下调及随后促炎介质合成减少有关。HSPTX有可能成为具有显著免疫调节特性的优质复苏液。
