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The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis

BACKGROUND: Reactive oxygen species and tissue remodeling regulators, such as metalloproteinases (MMPs) and their inhibitors (TIMPs), are thought to be involved in the development of pulmonary fibrosis. We investigated these factors in the fibrotic response to bleomycin of p47(phox )-/- (KO) mice, d...

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Autores principales: Manoury, Boris, Nenan, Soazig, Leclerc, Olivier, Guenon, Isabelle, Boichot, Elisabeth, Planquois, Jean-Michel, Bertrand, Claude P, Lagente, Vincent
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2005
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC548519/
https://www.ncbi.nlm.nih.gov/pubmed/15663794
http://dx.doi.org/10.1186/1465-9921-6-11
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author Manoury, Boris
Nenan, Soazig
Leclerc, Olivier
Guenon, Isabelle
Boichot, Elisabeth
Planquois, Jean-Michel
Bertrand, Claude P
Lagente, Vincent
author_facet Manoury, Boris
Nenan, Soazig
Leclerc, Olivier
Guenon, Isabelle
Boichot, Elisabeth
Planquois, Jean-Michel
Bertrand, Claude P
Lagente, Vincent
author_sort Manoury, Boris
collection PubMed
description BACKGROUND: Reactive oxygen species and tissue remodeling regulators, such as metalloproteinases (MMPs) and their inhibitors (TIMPs), are thought to be involved in the development of pulmonary fibrosis. We investigated these factors in the fibrotic response to bleomycin of p47(phox )-/- (KO) mice, deficient for ROS production through the NADPH-oxidase pathway. METHODS: Mice are administered by intranasal instillation of 0.1 mg bleomycin. Either 24 h or 14 days after, mice were anesthetized and underwent either bronchoalveolar lavage (BAL) or lung removal. RESULTS: BAL cells from bleomycin treated WT mice showed enhanced ROS production after PMA stimulation, whereas no change was observed with BAL cells from p47(phox )-/- mice. At day 1, the bleomycin-induced acute inflammatory response (increased neutrophil count and MMP-9 activity in the BAL fluid) was strikingly greater in KO than wild-type (WT) mice, while IL-6 levels increased significantly more in the latter. Hydroxyproline assays in the lung tissue 14 days after bleomycin administration revealed the absence of collagen deposition in the lungs of the KO mice, which had significantly lower hydroxyproline levels than the WT mice. The MMP-9/TIMP-1 ratio did not change at day 1 after bleomycin administration in WT mice, but increased significantly in the KO mice. By day 14, the ratio fell significantly from baseline in both strains, but more in the WT than KO strains. CONCLUSIONS: These results suggest that NADPH-oxidase-derived ROS are essential to the development of pulmonary fibrosis. The absence of collagen deposition in KO mice seems to be associated with an elevated MMP-9/TIMP-1 ratio in the lungs. This finding highlights the importance of metalloproteinases and protease/anti-protease imbalances in pulmonary fibrosis.
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spelling pubmed-5485192005-02-11 The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis Manoury, Boris Nenan, Soazig Leclerc, Olivier Guenon, Isabelle Boichot, Elisabeth Planquois, Jean-Michel Bertrand, Claude P Lagente, Vincent Respir Res Research BACKGROUND: Reactive oxygen species and tissue remodeling regulators, such as metalloproteinases (MMPs) and their inhibitors (TIMPs), are thought to be involved in the development of pulmonary fibrosis. We investigated these factors in the fibrotic response to bleomycin of p47(phox )-/- (KO) mice, deficient for ROS production through the NADPH-oxidase pathway. METHODS: Mice are administered by intranasal instillation of 0.1 mg bleomycin. Either 24 h or 14 days after, mice were anesthetized and underwent either bronchoalveolar lavage (BAL) or lung removal. RESULTS: BAL cells from bleomycin treated WT mice showed enhanced ROS production after PMA stimulation, whereas no change was observed with BAL cells from p47(phox )-/- mice. At day 1, the bleomycin-induced acute inflammatory response (increased neutrophil count and MMP-9 activity in the BAL fluid) was strikingly greater in KO than wild-type (WT) mice, while IL-6 levels increased significantly more in the latter. Hydroxyproline assays in the lung tissue 14 days after bleomycin administration revealed the absence of collagen deposition in the lungs of the KO mice, which had significantly lower hydroxyproline levels than the WT mice. The MMP-9/TIMP-1 ratio did not change at day 1 after bleomycin administration in WT mice, but increased significantly in the KO mice. By day 14, the ratio fell significantly from baseline in both strains, but more in the WT than KO strains. CONCLUSIONS: These results suggest that NADPH-oxidase-derived ROS are essential to the development of pulmonary fibrosis. The absence of collagen deposition in KO mice seems to be associated with an elevated MMP-9/TIMP-1 ratio in the lungs. This finding highlights the importance of metalloproteinases and protease/anti-protease imbalances in pulmonary fibrosis. BioMed Central 2005 2005-01-21 /pmc/articles/PMC548519/ /pubmed/15663794 http://dx.doi.org/10.1186/1465-9921-6-11 Text en Copyright © 2005 Manoury et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 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 cited.
spellingShingle Research
Manoury, Boris
Nenan, Soazig
Leclerc, Olivier
Guenon, Isabelle
Boichot, Elisabeth
Planquois, Jean-Michel
Bertrand, Claude P
Lagente, Vincent
The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis
title The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis
title_full The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis
title_fullStr The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis
title_full_unstemmed The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis
title_short The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis
title_sort absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC548519/
https://www.ncbi.nlm.nih.gov/pubmed/15663794
http://dx.doi.org/10.1186/1465-9921-6-11
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