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Simvastatin Posttreatment Controls Inflammation and Improves Bacterial Clearance in Experimental Sepsis

Sepsis is characterized by a life-threatening organ dysfunction caused by an unbalanced host response to microbe infection that can lead to death. Besides being currently the leading cause of death in intensive care units worldwide, sepsis can also induce long-term consequences among survivors, such...

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Autores principales: de Jesus Oliveira, Flora Magno, Gonçalves-de-Albuquerque, Cassiano Felippe, de Moraes, Isabel Matos Medeiros, Reis, Patrícia Alves, Rocha, Vinicius Novaes, Bozza, Patrícia Torres, Silva, Adriana Ribeiro, de Castro Faria Neto, Hugo Caire
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582071/
https://www.ncbi.nlm.nih.gov/pubmed/33110395
http://dx.doi.org/10.1155/2020/1839762
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author de Jesus Oliveira, Flora Magno
Gonçalves-de-Albuquerque, Cassiano Felippe
de Moraes, Isabel Matos Medeiros
Reis, Patrícia Alves
Rocha, Vinicius Novaes
Bozza, Patrícia Torres
Silva, Adriana Ribeiro
de Castro Faria Neto, Hugo Caire
author_facet de Jesus Oliveira, Flora Magno
Gonçalves-de-Albuquerque, Cassiano Felippe
de Moraes, Isabel Matos Medeiros
Reis, Patrícia Alves
Rocha, Vinicius Novaes
Bozza, Patrícia Torres
Silva, Adriana Ribeiro
de Castro Faria Neto, Hugo Caire
author_sort de Jesus Oliveira, Flora Magno
collection PubMed
description Sepsis is characterized by a life-threatening organ dysfunction caused by an unbalanced host response to microbe infection that can lead to death. Besides being currently the leading cause of death in intensive care units worldwide, sepsis can also induce long-term consequences among survivors, such as cognitive impairment. Statins (lipid-lowering drugs widely used to treat dyslipidemia) have been shown to possess pleiotropic anti-inflammatory and antimicrobial effects. These drugs act inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, the limiting step in cholesterol biosynthesis. In this work, we evaluated the therapeutic effects of simvastatin in an animal model of sepsis. In previous study from our group, statin pretreatment avoided cognitive damage and neuroinflammation in sepsis survivors. Herein, we focused on acute inflammation where sepsis was induced by cecal ligation and puncture (CLP), and the animals were treated with simvastatin (2 mg/kg) 6 h after surgery. We measured plasma biochemical markers of organ dysfunction, cell migration, cell activation, bacterial elimination, production of nitric oxide 24 h after CLP, survival rate for 7 days, and cognitive impairment 15 days after CLP. One single administration of simvastatin 6 h after CLP was able to prevent both liver and kidney dysfunction. In addition, this drug decreased cell accumulation in the peritoneum as well as the levels of TNF-α, MIF, IL-6, and IL-1β. Simvastatin diminished the number of bacterial colony forming units (CFU) and increased the production of nitric oxide production in the peritoneum. Simvastatin treatment increased survival for the first 24 h, but it did not alter survival rate at the end of 7 days. Our results showed that posttreatment with simvastatin hampered organ dysfunction, increased local production of nitric oxide, improved bacterial clearance, and modulated inflammation in a relevant model of sepsis.
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spelling pubmed-75820712020-10-26 Simvastatin Posttreatment Controls Inflammation and Improves Bacterial Clearance in Experimental Sepsis de Jesus Oliveira, Flora Magno Gonçalves-de-Albuquerque, Cassiano Felippe de Moraes, Isabel Matos Medeiros Reis, Patrícia Alves Rocha, Vinicius Novaes Bozza, Patrícia Torres Silva, Adriana Ribeiro de Castro Faria Neto, Hugo Caire Mediators Inflamm Research Article Sepsis is characterized by a life-threatening organ dysfunction caused by an unbalanced host response to microbe infection that can lead to death. Besides being currently the leading cause of death in intensive care units worldwide, sepsis can also induce long-term consequences among survivors, such as cognitive impairment. Statins (lipid-lowering drugs widely used to treat dyslipidemia) have been shown to possess pleiotropic anti-inflammatory and antimicrobial effects. These drugs act inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, the limiting step in cholesterol biosynthesis. In this work, we evaluated the therapeutic effects of simvastatin in an animal model of sepsis. In previous study from our group, statin pretreatment avoided cognitive damage and neuroinflammation in sepsis survivors. Herein, we focused on acute inflammation where sepsis was induced by cecal ligation and puncture (CLP), and the animals were treated with simvastatin (2 mg/kg) 6 h after surgery. We measured plasma biochemical markers of organ dysfunction, cell migration, cell activation, bacterial elimination, production of nitric oxide 24 h after CLP, survival rate for 7 days, and cognitive impairment 15 days after CLP. One single administration of simvastatin 6 h after CLP was able to prevent both liver and kidney dysfunction. In addition, this drug decreased cell accumulation in the peritoneum as well as the levels of TNF-α, MIF, IL-6, and IL-1β. Simvastatin diminished the number of bacterial colony forming units (CFU) and increased the production of nitric oxide production in the peritoneum. Simvastatin treatment increased survival for the first 24 h, but it did not alter survival rate at the end of 7 days. Our results showed that posttreatment with simvastatin hampered organ dysfunction, increased local production of nitric oxide, improved bacterial clearance, and modulated inflammation in a relevant model of sepsis. Hindawi 2020-10-14 /pmc/articles/PMC7582071/ /pubmed/33110395 http://dx.doi.org/10.1155/2020/1839762 Text en Copyright © 2020 Flora Magno de Jesus Oliveira et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
de Jesus Oliveira, Flora Magno
Gonçalves-de-Albuquerque, Cassiano Felippe
de Moraes, Isabel Matos Medeiros
Reis, Patrícia Alves
Rocha, Vinicius Novaes
Bozza, Patrícia Torres
Silva, Adriana Ribeiro
de Castro Faria Neto, Hugo Caire
Simvastatin Posttreatment Controls Inflammation and Improves Bacterial Clearance in Experimental Sepsis
title Simvastatin Posttreatment Controls Inflammation and Improves Bacterial Clearance in Experimental Sepsis
title_full Simvastatin Posttreatment Controls Inflammation and Improves Bacterial Clearance in Experimental Sepsis
title_fullStr Simvastatin Posttreatment Controls Inflammation and Improves Bacterial Clearance in Experimental Sepsis
title_full_unstemmed Simvastatin Posttreatment Controls Inflammation and Improves Bacterial Clearance in Experimental Sepsis
title_short Simvastatin Posttreatment Controls Inflammation and Improves Bacterial Clearance in Experimental Sepsis
title_sort simvastatin posttreatment controls inflammation and improves bacterial clearance in experimental sepsis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582071/
https://www.ncbi.nlm.nih.gov/pubmed/33110395
http://dx.doi.org/10.1155/2020/1839762
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