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)...
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| Format: | Article |
| Language: | English |
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Elsevier España
2010-01-01
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| Series: | Clinics |
| Subjects: | |
| Online Access: | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1807-59322010000600010 |
| _version_ | 1818120270039220224 |
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| author | Todd W. Costantini Jessica Deree J.O. Martins James G. Putnam Tercio de Campos Raul Coimbra |
| author_facet | Todd W. Costantini Jessica Deree J.O. Martins James G. Putnam Tercio de Campos Raul Coimbra |
| author_sort | Todd W. Costantini |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-11T05:23:25Z |
| format | Article |
| id | doaj.art-88fb3f2e793b41e483a49b63f3c3116d |
| institution | Directory Open Access Journal |
| issn | 1807-5932 1980-5322 |
| language | English |
| last_indexed | 2024-12-11T05:23:25Z |
| publishDate | 2010-01-01 |
| publisher | Elsevier España |
| record_format | Article |
| series | Clinics |
| spelling | doaj.art-88fb3f2e793b41e483a49b63f3c3116d2022-12-22T01:19:38ZengElsevier EspañaClinics1807-59321980-53222010-01-0165662162810.1590/S1807-59322010000600010A novel fluid resuscitation strategy modulates pulmonary transcription factor activation in a murine model of hemorrhagic shockTodd W. CostantiniJessica DereeJ.O. MartinsJames G. PutnamTercio de CamposRaul CoimbraINTRODUCTION: 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.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1807-59322010000600010Hypertonic salinePentoxifyllineNF-κBCREBCREB-binding protein |
| spellingShingle | Todd W. Costantini Jessica Deree J.O. Martins James G. Putnam Tercio de Campos Raul Coimbra A novel fluid resuscitation strategy modulates pulmonary transcription factor activation in a murine model of hemorrhagic shock Clinics Hypertonic saline Pentoxifylline NF-κB CREB CREB-binding protein |
| 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 | Hypertonic saline Pentoxifylline NF-κB CREB CREB-binding protein |
| url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1807-59322010000600010 |
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