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Genetic and pharmacologic inhibition of Tpl2 kinase is protective in a mouse model of ventilator-induced lung injury
BACKGROUND: Mechanical stress induced by injurious ventilation leads to pro-inflammatory cytokine production and lung injury. The extracellular-signal-regulated-kinase, ERK1/2, participates in the signaling pathways activated upon mechanical stress in the lungs to promote the inflammatory response....
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513004/ https://www.ncbi.nlm.nih.gov/pubmed/26266915 http://dx.doi.org/10.1186/2197-425X-2-15 |
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author | Kaniaris, Evangelos Vaporidi, Katerina Vergadi, Eleni Theodorakis, Emmanuel E Kondili, Eumorfia Lagoudaki, Eleni Tsatsanis, Christos Georgopoulos, Dimitris |
author_facet | Kaniaris, Evangelos Vaporidi, Katerina Vergadi, Eleni Theodorakis, Emmanuel E Kondili, Eumorfia Lagoudaki, Eleni Tsatsanis, Christos Georgopoulos, Dimitris |
author_sort | Kaniaris, Evangelos |
collection | PubMed |
description | BACKGROUND: Mechanical stress induced by injurious ventilation leads to pro-inflammatory cytokine production and lung injury. The extracellular-signal-regulated-kinase, ERK1/2, participates in the signaling pathways activated upon mechanical stress in the lungs to promote the inflammatory response. Tumor progression locus 2 (Tpl2) is a MAP3kinase that activates ERK1/2 upon cytokine or TLR signaling, to induce pro-inflammatory cytokine production. The role of Tpl2 in lung inflammation, and specifically in the one caused by mechanical stress has not been investigated. The aim of the study was to examine if genetic or pharmacologic inhibition of Tpl2 could ameliorate ventilator-induced lung injury. METHODS: Adult male wild-type and Tpl2-deficient mice were ventilated with normal or high tidal volume for 4 h. Additional wild-type mice were treated with a Tpl2 inhibitor either before or 30 min after initiation of high tidal ventilation. Non-ventilated mice of both genotypes served as controls. The development of lung injury was evaluated by measuring lung mechanics, arterial blood gases, concentrations of proteins, IL-6, and MIP-2 in bronchoalveolar lavage fluid (BALF) and by lung histology. Data were compared by Kruskal-Wallis non-parametric test and significance was defined as p < 0.05. RESULTS: Mechanical ventilation with normal tidal volume induced a mild increase of IL-6 in BALF in both strains. High tidal volume ventilation induced lung injury in wild-type mice, characterized by decreased lung compliance, increased concentrations of proteins, IL-6 and MIP-2 in BALF, and inflammatory cell infiltration on histology. All indices of lung injury were ameliorated in Tpl2-deficient mice. Wild-type mice treated with the Tpl2 inhibitor, either prior of after the initiation of high tidal volume ventilation were protected from the development of lung injury, as indicated by preserved lung compliance and lower BALF concentrations of proteins and IL-6, than similarly ventilated, untreated wild-type mice. CONCLUSIONS: Genetic and pharmacologic inhibition of Tpl2 is protective in a mouse model of ventilator-induced lung injury, ameliorating both high-permeability pulmonary edema and lung inflammation. |
format | Online Article Text |
id | pubmed-4513004 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-45130042015-07-27 Genetic and pharmacologic inhibition of Tpl2 kinase is protective in a mouse model of ventilator-induced lung injury Kaniaris, Evangelos Vaporidi, Katerina Vergadi, Eleni Theodorakis, Emmanuel E Kondili, Eumorfia Lagoudaki, Eleni Tsatsanis, Christos Georgopoulos, Dimitris Intensive Care Med Exp Research BACKGROUND: Mechanical stress induced by injurious ventilation leads to pro-inflammatory cytokine production and lung injury. The extracellular-signal-regulated-kinase, ERK1/2, participates in the signaling pathways activated upon mechanical stress in the lungs to promote the inflammatory response. Tumor progression locus 2 (Tpl2) is a MAP3kinase that activates ERK1/2 upon cytokine or TLR signaling, to induce pro-inflammatory cytokine production. The role of Tpl2 in lung inflammation, and specifically in the one caused by mechanical stress has not been investigated. The aim of the study was to examine if genetic or pharmacologic inhibition of Tpl2 could ameliorate ventilator-induced lung injury. METHODS: Adult male wild-type and Tpl2-deficient mice were ventilated with normal or high tidal volume for 4 h. Additional wild-type mice were treated with a Tpl2 inhibitor either before or 30 min after initiation of high tidal ventilation. Non-ventilated mice of both genotypes served as controls. The development of lung injury was evaluated by measuring lung mechanics, arterial blood gases, concentrations of proteins, IL-6, and MIP-2 in bronchoalveolar lavage fluid (BALF) and by lung histology. Data were compared by Kruskal-Wallis non-parametric test and significance was defined as p < 0.05. RESULTS: Mechanical ventilation with normal tidal volume induced a mild increase of IL-6 in BALF in both strains. High tidal volume ventilation induced lung injury in wild-type mice, characterized by decreased lung compliance, increased concentrations of proteins, IL-6 and MIP-2 in BALF, and inflammatory cell infiltration on histology. All indices of lung injury were ameliorated in Tpl2-deficient mice. Wild-type mice treated with the Tpl2 inhibitor, either prior of after the initiation of high tidal volume ventilation were protected from the development of lung injury, as indicated by preserved lung compliance and lower BALF concentrations of proteins and IL-6, than similarly ventilated, untreated wild-type mice. CONCLUSIONS: Genetic and pharmacologic inhibition of Tpl2 is protective in a mouse model of ventilator-induced lung injury, ameliorating both high-permeability pulmonary edema and lung inflammation. Springer International Publishing 2014-05-09 /pmc/articles/PMC4513004/ /pubmed/26266915 http://dx.doi.org/10.1186/2197-425X-2-15 Text en © Kaniaris et al.; licensee Springer. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. |
spellingShingle | Research Kaniaris, Evangelos Vaporidi, Katerina Vergadi, Eleni Theodorakis, Emmanuel E Kondili, Eumorfia Lagoudaki, Eleni Tsatsanis, Christos Georgopoulos, Dimitris Genetic and pharmacologic inhibition of Tpl2 kinase is protective in a mouse model of ventilator-induced lung injury |
title | Genetic and pharmacologic inhibition of Tpl2 kinase is protective in a mouse model of ventilator-induced lung injury |
title_full | Genetic and pharmacologic inhibition of Tpl2 kinase is protective in a mouse model of ventilator-induced lung injury |
title_fullStr | Genetic and pharmacologic inhibition of Tpl2 kinase is protective in a mouse model of ventilator-induced lung injury |
title_full_unstemmed | Genetic and pharmacologic inhibition of Tpl2 kinase is protective in a mouse model of ventilator-induced lung injury |
title_short | Genetic and pharmacologic inhibition of Tpl2 kinase is protective in a mouse model of ventilator-induced lung injury |
title_sort | genetic and pharmacologic inhibition of tpl2 kinase is protective in a mouse model of ventilator-induced lung injury |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513004/ https://www.ncbi.nlm.nih.gov/pubmed/26266915 http://dx.doi.org/10.1186/2197-425X-2-15 |
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