Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration.
Current evidence indicates that dysregulation of the host inflammatory response to infectious agents is central to the mortality of patients with sepsis. Strategies to block inflammatory mediators such as PAF have been investigated as adjuvant therapies for sepsis. PAF-AH, the enzyme responsible for...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3771912?pdf=render |
| _version_ | 1819183194422902784 |
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| author | Mariana G A Teixeira-da-Cunha Rachel N Gomes Nathassia Roehrs Fernando A Bozza Stephen M Prescott Diana Stafforini Guy A Zimmerman Patricia T Bozza Hugo C Castro-Faria-Neto |
| author_facet | Mariana G A Teixeira-da-Cunha Rachel N Gomes Nathassia Roehrs Fernando A Bozza Stephen M Prescott Diana Stafforini Guy A Zimmerman Patricia T Bozza Hugo C Castro-Faria-Neto |
| author_sort | Mariana G A Teixeira-da-Cunha |
| collection | DOAJ |
| description | Current evidence indicates that dysregulation of the host inflammatory response to infectious agents is central to the mortality of patients with sepsis. Strategies to block inflammatory mediators such as PAF have been investigated as adjuvant therapies for sepsis. PAF-AH, the enzyme responsible for PAF degradation, showed positive results in pre-clinical studies and phase II clinical trials, but the results of a phase III study were disappointing. In this study, we investigated the potential protective mechanism of PAF-AH in sepsis using the murine model of cecal ligation and puncture (CLP). Treatment with rPAF-AH increased peritoneal fluid levels of the anti-inflammatory mediators MCP-1/CCL2 after CLP. The numbers of bacteria (CFU) in the peritoneal cavity were decreased in the rPAF-AH-treated group, indicating more efficient bacterial clearance after rPAF-AH treatment. Interestingly, we observed increased levels of nitric oxide (NO) after PAF-AH administration, and rPAF-AH treatment did not decrease CFU numbers either in iNOS-deficient mice or in CCR2-deficient mice. We concluded that administration of exogenous rPAF-AH reduced inflammatory injury, altered cytokine levels and favored bacterial clearance with a clear impact on mortality through modulation of MCP-1/CCL2 and NO levels in a clinically relevant sepsis model. |
| first_indexed | 2024-12-22T22:58:09Z |
| format | Article |
| id | doaj.art-b8cf7ee3c90241fa98b772576b2811a1 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T22:58:09Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b8cf7ee3c90241fa98b772576b2811a12022-12-21T18:09:46ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0189e7456710.1371/journal.pone.0074567Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration.Mariana G A Teixeira-da-CunhaRachel N GomesNathassia RoehrsFernando A BozzaStephen M PrescottDiana StafforiniGuy A ZimmermanPatricia T BozzaHugo C Castro-Faria-NetoCurrent evidence indicates that dysregulation of the host inflammatory response to infectious agents is central to the mortality of patients with sepsis. Strategies to block inflammatory mediators such as PAF have been investigated as adjuvant therapies for sepsis. PAF-AH, the enzyme responsible for PAF degradation, showed positive results in pre-clinical studies and phase II clinical trials, but the results of a phase III study were disappointing. In this study, we investigated the potential protective mechanism of PAF-AH in sepsis using the murine model of cecal ligation and puncture (CLP). Treatment with rPAF-AH increased peritoneal fluid levels of the anti-inflammatory mediators MCP-1/CCL2 after CLP. The numbers of bacteria (CFU) in the peritoneal cavity were decreased in the rPAF-AH-treated group, indicating more efficient bacterial clearance after rPAF-AH treatment. Interestingly, we observed increased levels of nitric oxide (NO) after PAF-AH administration, and rPAF-AH treatment did not decrease CFU numbers either in iNOS-deficient mice or in CCR2-deficient mice. We concluded that administration of exogenous rPAF-AH reduced inflammatory injury, altered cytokine levels and favored bacterial clearance with a clear impact on mortality through modulation of MCP-1/CCL2 and NO levels in a clinically relevant sepsis model.http://europepmc.org/articles/PMC3771912?pdf=render |
| spellingShingle | Mariana G A Teixeira-da-Cunha Rachel N Gomes Nathassia Roehrs Fernando A Bozza Stephen M Prescott Diana Stafforini Guy A Zimmerman Patricia T Bozza Hugo C Castro-Faria-Neto Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration. PLoS ONE |
| title | Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration. |
| title_full | Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration. |
| title_fullStr | Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration. |
| title_full_unstemmed | Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration. |
| title_short | Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration. |
| title_sort | bacterial clearance is improved in septic mice by platelet activating factor acetylhydrolase paf ah administration |
| url | http://europepmc.org/articles/PMC3771912?pdf=render |
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