Hepatic transcription factor activation and proinflammatory mediator production is attenuated by hypertonic saline and pentoxifylline resuscitation after hemorrhagic shock.
BACKGROUND
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).


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Deree
Jessica
J
Division of Trauma and Critical Care, Department of Surgery, University of California-San Diego, USA.
Loomis
William H
WH
Wolf
Paul
P
Coimbra
Raul
R
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010431:Pentoxifylline / Q000009:adverse effects* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation / Q000379:methods*; D012462:Saline Solution, Hypertonic / Q000009:adverse effects / Q000627:therapeutic use; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000209:etiology; D014157:Transcription Factors / Q000378:metabolism; D014665:Vasodilator Agents / Q000009:adverse effects* / Q000627:therapeutic use
D016207:Cytokines; D016328:NF-kappa B; D012462:Saline Solution, Hypertonic; D014157:Transcription Factors; D014665:Vasodilator Agents; D052247:Nitric Oxide Synthase Type II; D010431:Pentoxifylline