Abstract
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.
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