A Novel Fluid Resuscitation Strategy Modulates Pulmonary Transcription Factor Activation in a Murine Model of Hemorrhagic Shock

Abstract

INTRODUCTION:Combining 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-κB-CREB) competition for the coactivator CREB-binding protein (CBP) in lung tissue, thus affecting pro-inflammatory mediator production.METHODS:Male 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-κB activation was assessed by measuring the levels of phosphorylated cytoplasmic inhibitor of kappa B (I-κB) and nuclear NF-κB p65 by western blot. NF-κB and CREB DNA-binding activity were measured by electrophoretic mobility shift assay (EMSA). Competition between NF-κB and CREB for the coactivator CBP was determined by immunoprecipitation. Interleukin-8 (IL-8) levels in the lung were measured by ELISA.RESULTS:RL resuscitation produced significantly higher levels of lung IL-8 levels, I-κB phosphorylation, p65 phosphorylation, and NF-κB DNA binding compared with HSPTX. NF-κB-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.DISCUSSION:HSPTX decreases lung inflammation following hemorrhagic shock compared with conventional resuscitation using RL through attenuation of NF-κB signaling and increased CREB-DNA binding activity. HSPTX may have therapeutic potential in the attenuation of ischemia-reperfusion injury observed after severe hemorrhagic shock.

Effects of Different Resuscitation Fluids on Pulmonary Expression of Aquaporin1 and Aquaporin5 in a Rat Model of Uncontrolled Hemorrhagic Shock and Infection

“…The animals were randomly divided into five groups (n = 12 per group), to receive following treatments: (1) sham operation group (group C), only received cannulation and observation; (2) no fluid resuscitation in the “prehospital phase” group (group NF); (3) lactated Ringer’s solution group (group LR), resuscitated with lactate Ringer’s solution in a 3∶1 ratio to the shed blood volume during the “prehospital phase”; (4) 7.5% hypertonic saline group (group HTS), resuscitated with a bolus dose of 4 ml/kg [12] of 7.5% hypertonic saline during the “prehospital phase”; (5)Hydroxylethyl starch group (group HES), resuscitated with Hydroxylethyl starch (Voluven, mean molecular weight 130 kDa; degree of substitution, 0.4, Fresenius Kabi) in a volume equal to the shed blood volume during the “prehospital phase”.All the resuscitation fluids were given immediately after the tail cut.…”

Hypertonic saline for treatment of shock: have we looked for everything?

“…They later showed that the hypertonic saline-pentoxifylline (vs. conventional lactated Ringers resuscitation) modulates pulmonary transcription factor activation and reduces lung injury. 44 An equivalent conclusion, indicating superiority of the hypertonic saline-pentoxifylline strategy, was reached by Cruz et al, 45 regarding cardiovascular performance and gastric mucosal oxygenation. As previously noted, Lu et al 23 examined the effects of small volume resuscitation and report that it showed itself to be more effective than normal saline in reducing immunologic disorders and promoting a more balanced profile of T-lymphocyte subpopulations regulating networks.…”

Pesquisas em pneumologia recentemente publicadas em revistas brasileiras

“…In a murine model of hemorrhagic shock, Costantini et al (60) evaluated the use of hypertonic saline, which has hemodynamic and immune benefits, in combination with the phosphodiesterase inhibitor pentoxifylline, which has anti-inflammatory effects, as a hemorrhagic shock resuscitation strategy. The authors found that the use of that combination resulted in less lung injury than did the use of Ringer's lactate.…”