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A Novel Fluid Resuscitation Strategy Modulates Pulmonary Transcription Factor Activation in a Murine Model of Hemorrhagic Shock
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...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898548/ https://www.ncbi.nlm.nih.gov/pubmed/20613939 http://dx.doi.org/10.1590/S1807-59322010000600010 |
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author | Costantini, Todd W. Deree, Jessica Martins, J.O. Putnam, James G. de Campos, Tercio Coimbra, Raul |
author_facet | Costantini, Todd W. Deree, Jessica Martins, J.O. Putnam, James G. de Campos, Tercio Coimbra, Raul |
author_sort | Costantini, Todd W. |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2898548 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo |
record_format | MEDLINE/PubMed |
spelling | pubmed-28985482010-07-07 A Novel Fluid Resuscitation Strategy Modulates Pulmonary Transcription Factor Activation in a Murine Model of Hemorrhagic Shock Costantini, Todd W. Deree, Jessica Martins, J.O. Putnam, James G. de Campos, Tercio Coimbra, Raul Clinics (Sao Paulo) Basic Research 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. Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo 2010-06 /pmc/articles/PMC2898548/ /pubmed/20613939 http://dx.doi.org/10.1590/S1807-59322010000600010 Text en Copyright © 2010 Hospital das Clínicas da FMUSP http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Basic Research Costantini, Todd W. Deree, Jessica Martins, J.O. Putnam, James G. de Campos, Tercio Coimbra, Raul A Novel Fluid Resuscitation Strategy Modulates Pulmonary Transcription Factor Activation in a Murine Model of Hemorrhagic Shock |
title | A Novel Fluid Resuscitation Strategy Modulates Pulmonary Transcription Factor Activation in a Murine Model of Hemorrhagic Shock |
title_full | A Novel Fluid Resuscitation Strategy Modulates Pulmonary Transcription Factor Activation in a Murine Model of Hemorrhagic Shock |
title_fullStr | A Novel Fluid Resuscitation Strategy Modulates Pulmonary Transcription Factor Activation in a Murine Model of Hemorrhagic Shock |
title_full_unstemmed | A Novel Fluid Resuscitation Strategy Modulates Pulmonary Transcription Factor Activation in a Murine Model of Hemorrhagic Shock |
title_short | A Novel Fluid Resuscitation Strategy Modulates Pulmonary Transcription Factor Activation in a Murine Model of Hemorrhagic Shock |
title_sort | novel fluid resuscitation strategy modulates pulmonary transcription factor activation in a murine model of hemorrhagic shock |
topic | Basic Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898548/ https://www.ncbi.nlm.nih.gov/pubmed/20613939 http://dx.doi.org/10.1590/S1807-59322010000600010 |
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