• Todd W Costantini, Jessica Deree, J O Martins, James G Putnam, Tercio de Campos, and Raul Coimbra.
• University of California San Diego School of Medicine, California, USA.
• Clinics (Sao Paulo). 2010 Jun 1;65(6):621-8.

IntroductionCombining the hemodynamic and immune benefits of hypertonic saline with the anti-inflammatory effects of the phosphodiesterase inhibitor pentoxifylline (HSPTX) as a hemorrhagic shock resuscitation strategy reduces lung injury when compared with the effects of Ringer's lactate (RL). We hypothesized that HSPTX exerts its anti-inflammatory effects by interfering with nuclear factor kappa B/cAMP response element-binding protein (NF-kappaB-CREB) competition for the coactivator CREB-binding protein (CBP) in lung tissue, thus affecting pro-inflammatory mediator production.MethodsMale Sprague-Dawley rats underwent 60 minutes of hemorrhagic shock to reach a mean arterial blood pressure of 35 mmHg followed by resuscitation with either RL or HSPTX (7.5% HS + 25 mg/kg PTX). After four hours, lung samples were collected. NF-kappaB activation was assessed by measuring the levels of phosphorylated cytoplasmic inhibitor of kappa B (I-kappaB) and nuclear NF-kappaB p65 by western blot. NF-kappaB and CREB DNA-binding activity were measured by electrophoretic mobility shift assay (EMSA). Competition between NF-kappaB and CREB for the coactivator CBP was determined by immunoprecipitation. Interleukin-8 (IL-8) levels in the lung were measured by ELISA.ResultsRL resuscitation produced significantly higher levels of lung IL-8 levels, I-kappaB phosphorylation, p65 phosphorylation, and NF-kappaB DNA binding compared with HSPTX. NF-kappaB-CBP-binding activity was similar in both groups, whereas CREB-CBP-binding activity was significantly increased with HSPTX. CREB-DNA binding-activity increased to a greater level with HSPTX compared with RL.DiscussionHSPTX decreases lung inflammation following hemorrhagic shock compared with conventional resuscitation using RL through attenuation of NF-kappaB signaling and increased CREB-DNA binding activity. HSPTX may have therapeutic potential in the attenuation of ischemia-reperfusion injury observed after severe hemorrhagic shock.

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