The competition between lung NF‐kB and CREB for the co‐activator CPB is affected by the resuscitation strategy in hemorrhagic shock.

Abstract

A novel resuscitation fluid (HSPTX) combining the low volume benefits of hypertonic saline and the anti-inflammatory effects of phosphodiesterase inhibition with pentoxifylline (PTX) attenuates lung injury compared to Ringer's lactate (RL). We hypothesized that HSPTX acts by interfering with NF-κB - CREB competition for the co-activator CBP in lung tissue, thus affecting inflammatory mediator production. A pressure-driven model of controlled hemorrhage (mean arterial pressure 35±5 mm Hg) was used. Rats were resuscitated after 1 hour with RL or HSPTX. Lung tissue and bronchoalveolar lavage fluid (BAL) were collected at 4 hours. HSPTX markedly decreased BAL IL-8 levels (ELISA), NF-κb p65 phosphorylation (Western Blotting), NF-κB DNA binding (EMSA), and I-κB phosphorylation and increased CREB phosphorylation at ser 133 and CREB DNA binding. p65-CBP binding levels were similar in both treatment groups whereas CREB-CPB binding was significantly increased in HSPTX-treated animals. RL activates the NF-κB cascade in the lung following hemorrhagic shock and increases pro-inflammatory mediator production and tissue injury. NF-κB and CREB compete for the co-activator CBP and HSPTX treatment favors CREB-CBP binding. HSPTX attenuates lung injury likely by decreasing NF-κB and increasing CREB activation, affecting the transcriptional machinery and decreasing pro-inflammatory mediator synthesis. HSPTX is a superior resuscitation strategy.