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Endotoxin-Induced Emphysema Exacerbation: A Novel Model of Chronic Obstructive Pulmonary Disease Exacerbations Causing Cardiopulmonary Impairment and Diaphragm Dysfunction

Chronic obstructive pulmonary disease (COPD) is a progressive disorder of the lung parenchyma which also involves extrapulmonary manifestations, such as cardiovascular impairment, diaphragm dysfunction, and frequent exacerbations. The development of animal models is important to elucidate the pathop...

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Autores principales: de Oliveira, Milena Vasconcellos, Rocha, Nazareth de Novaes, Santos, Raquel Souza, Rocco, Marcella Rieken Macedo, de Magalhães, Raquel Ferreira, Silva, Johnatas Dutra, Souza, Sergio Augusto Lopes, Capelozzi, Vera Luiza, Pelosi, Paolo, Silva, Pedro Leme, Rocco, Patricia Rieken Macedo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546905/
https://www.ncbi.nlm.nih.gov/pubmed/31191356
http://dx.doi.org/10.3389/fphys.2019.00664
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author de Oliveira, Milena Vasconcellos
Rocha, Nazareth de Novaes
Santos, Raquel Souza
Rocco, Marcella Rieken Macedo
de Magalhães, Raquel Ferreira
Silva, Johnatas Dutra
Souza, Sergio Augusto Lopes
Capelozzi, Vera Luiza
Pelosi, Paolo
Silva, Pedro Leme
Rocco, Patricia Rieken Macedo
author_facet de Oliveira, Milena Vasconcellos
Rocha, Nazareth de Novaes
Santos, Raquel Souza
Rocco, Marcella Rieken Macedo
de Magalhães, Raquel Ferreira
Silva, Johnatas Dutra
Souza, Sergio Augusto Lopes
Capelozzi, Vera Luiza
Pelosi, Paolo
Silva, Pedro Leme
Rocco, Patricia Rieken Macedo
author_sort de Oliveira, Milena Vasconcellos
collection PubMed
description Chronic obstructive pulmonary disease (COPD) is a progressive disorder of the lung parenchyma which also involves extrapulmonary manifestations, such as cardiovascular impairment, diaphragm dysfunction, and frequent exacerbations. The development of animal models is important to elucidate the pathophysiology of COPD exacerbations and enable analysis of possible therapeutic approaches. We aimed to characterize a model of acute emphysema exacerbation and evaluate its consequences on the lung, heart, and diaphragm. Twenty-four Wistar rats were randomly assigned into one of two groups: control (C) or emphysema (ELA). In ELA group, animals received four intratracheal instillations of pancreatic porcine elastase (PPE) at 1-week intervals. The C group received saline under the same protocol. Five weeks after the last instillation, C and ELA animals received saline (SAL) or E. coli lipopolysaccharide (LPS) (200 μg in 200 μl) intratracheally. Twenty-four hours after saline or endotoxin administration, arterial blood gases, lung inflammation and morphometry, collagen fiber content, and lung mechanics were analyzed. Echocardiography, diaphragm ultrasonography (US), and computed tomography (CT) of the chest were done. ELA-LPS animals, compared to ELA-SAL, exhibited decreased arterial oxygenation; increases in alveolar collapse (p < 0.0001), relative neutrophil counts (p = 0.007), levels of cytokine-induced neutrophil chemoattractant-1, interleukin (IL)-1β, tumor necrosis factor-α, IL-6, and vascular endothelial growth factor in lung tissue, collagen fiber deposition in alveolar septa, airways, and pulmonary vessel walls, and dynamic lung elastance (p < 0.0001); reduced pulmonary acceleration time/ejection time ratio, (an indirect index of pulmonary arterial hypertension); decreased diaphragm thickening fraction and excursion; and areas of emphysema associated with heterogeneous alveolar opacities on chest CT. In conclusion, we developed a model of endotoxin-induced emphysema exacerbation that affected not only the lungs but also the heart and diaphragm, thus resembling several features of human disease. This model of emphysema should allow preclinical testing of novel therapies with potential for translation into clinical practice.
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spelling pubmed-65469052019-06-12 Endotoxin-Induced Emphysema Exacerbation: A Novel Model of Chronic Obstructive Pulmonary Disease Exacerbations Causing Cardiopulmonary Impairment and Diaphragm Dysfunction de Oliveira, Milena Vasconcellos Rocha, Nazareth de Novaes Santos, Raquel Souza Rocco, Marcella Rieken Macedo de Magalhães, Raquel Ferreira Silva, Johnatas Dutra Souza, Sergio Augusto Lopes Capelozzi, Vera Luiza Pelosi, Paolo Silva, Pedro Leme Rocco, Patricia Rieken Macedo Front Physiol Physiology Chronic obstructive pulmonary disease (COPD) is a progressive disorder of the lung parenchyma which also involves extrapulmonary manifestations, such as cardiovascular impairment, diaphragm dysfunction, and frequent exacerbations. The development of animal models is important to elucidate the pathophysiology of COPD exacerbations and enable analysis of possible therapeutic approaches. We aimed to characterize a model of acute emphysema exacerbation and evaluate its consequences on the lung, heart, and diaphragm. Twenty-four Wistar rats were randomly assigned into one of two groups: control (C) or emphysema (ELA). In ELA group, animals received four intratracheal instillations of pancreatic porcine elastase (PPE) at 1-week intervals. The C group received saline under the same protocol. Five weeks after the last instillation, C and ELA animals received saline (SAL) or E. coli lipopolysaccharide (LPS) (200 μg in 200 μl) intratracheally. Twenty-four hours after saline or endotoxin administration, arterial blood gases, lung inflammation and morphometry, collagen fiber content, and lung mechanics were analyzed. Echocardiography, diaphragm ultrasonography (US), and computed tomography (CT) of the chest were done. ELA-LPS animals, compared to ELA-SAL, exhibited decreased arterial oxygenation; increases in alveolar collapse (p < 0.0001), relative neutrophil counts (p = 0.007), levels of cytokine-induced neutrophil chemoattractant-1, interleukin (IL)-1β, tumor necrosis factor-α, IL-6, and vascular endothelial growth factor in lung tissue, collagen fiber deposition in alveolar septa, airways, and pulmonary vessel walls, and dynamic lung elastance (p < 0.0001); reduced pulmonary acceleration time/ejection time ratio, (an indirect index of pulmonary arterial hypertension); decreased diaphragm thickening fraction and excursion; and areas of emphysema associated with heterogeneous alveolar opacities on chest CT. In conclusion, we developed a model of endotoxin-induced emphysema exacerbation that affected not only the lungs but also the heart and diaphragm, thus resembling several features of human disease. This model of emphysema should allow preclinical testing of novel therapies with potential for translation into clinical practice. Frontiers Media S.A. 2019-05-28 /pmc/articles/PMC6546905/ /pubmed/31191356 http://dx.doi.org/10.3389/fphys.2019.00664 Text en Copyright © 2019 Oliveira, Rocha, Santos, Rocco, Magalhães, Silva, Souza, Capelozzi, Pelosi, Silva and Rocco. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
de Oliveira, Milena Vasconcellos
Rocha, Nazareth de Novaes
Santos, Raquel Souza
Rocco, Marcella Rieken Macedo
de Magalhães, Raquel Ferreira
Silva, Johnatas Dutra
Souza, Sergio Augusto Lopes
Capelozzi, Vera Luiza
Pelosi, Paolo
Silva, Pedro Leme
Rocco, Patricia Rieken Macedo
Endotoxin-Induced Emphysema Exacerbation: A Novel Model of Chronic Obstructive Pulmonary Disease Exacerbations Causing Cardiopulmonary Impairment and Diaphragm Dysfunction
title Endotoxin-Induced Emphysema Exacerbation: A Novel Model of Chronic Obstructive Pulmonary Disease Exacerbations Causing Cardiopulmonary Impairment and Diaphragm Dysfunction
title_full Endotoxin-Induced Emphysema Exacerbation: A Novel Model of Chronic Obstructive Pulmonary Disease Exacerbations Causing Cardiopulmonary Impairment and Diaphragm Dysfunction
title_fullStr Endotoxin-Induced Emphysema Exacerbation: A Novel Model of Chronic Obstructive Pulmonary Disease Exacerbations Causing Cardiopulmonary Impairment and Diaphragm Dysfunction
title_full_unstemmed Endotoxin-Induced Emphysema Exacerbation: A Novel Model of Chronic Obstructive Pulmonary Disease Exacerbations Causing Cardiopulmonary Impairment and Diaphragm Dysfunction
title_short Endotoxin-Induced Emphysema Exacerbation: A Novel Model of Chronic Obstructive Pulmonary Disease Exacerbations Causing Cardiopulmonary Impairment and Diaphragm Dysfunction
title_sort endotoxin-induced emphysema exacerbation: a novel model of chronic obstructive pulmonary disease exacerbations causing cardiopulmonary impairment and diaphragm dysfunction
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546905/
https://www.ncbi.nlm.nih.gov/pubmed/31191356
http://dx.doi.org/10.3389/fphys.2019.00664
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