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Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice
BACKGROUND: Pulmonary fibrosis (PF) is a group of devastating and largely irreversible diseases. Phosphodiesterase (PDE) 4 is involved in the processes of remodeling and inflammation, which play key role in tissue fibrosis. The aim of the study was, therefore, to investigate the effect of PDE4 inhib...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881047/ https://www.ncbi.nlm.nih.gov/pubmed/20444277 http://dx.doi.org/10.1186/1471-2466-10-26 |
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author | Udalov, Sergey Dumitrascu, Rio Pullamsetti, Soni S Al-tamari, Hamza M Weissmann, Norbert Ghofrani, Hossein A Guenther, Andreas Voswinckel, Robert Seeger, Werner Grimminger, Friedrich Schermuly, Ralph T |
author_facet | Udalov, Sergey Dumitrascu, Rio Pullamsetti, Soni S Al-tamari, Hamza M Weissmann, Norbert Ghofrani, Hossein A Guenther, Andreas Voswinckel, Robert Seeger, Werner Grimminger, Friedrich Schermuly, Ralph T |
author_sort | Udalov, Sergey |
collection | PubMed |
description | BACKGROUND: Pulmonary fibrosis (PF) is a group of devastating and largely irreversible diseases. Phosphodiesterase (PDE) 4 is involved in the processes of remodeling and inflammation, which play key role in tissue fibrosis. The aim of the study was, therefore, to investigate the effect of PDE4 inhibition in experimental model of PF. METHODS: PF was induced in C57BL/6N mice by instillation of bleomycin. Pharmacological inhibition of PDE4 was achieved by using cilomilast, a selective PDE4 inhibitor. Changes in either lung inflammation or remodeling were evaluated at different stages of experimental PF. Lung inflammation was assessed by bronchoalveolar lavage fluid (BALF) differential cell count and reverse transcription quantitative polymerase chain reaction (RT-qPCR) for inflammatory cytokines. Changes in tissue remodeling were evaluated by pulmonary compliance measurement, quantified pathological examination, measurement of collagen deposition and RT-qPCR for late remodeling markers. Survival in all groups was analyzed as well. RESULTS: PDE4 inhibition significantly reduced the total number of alveolar inflammatory cells in BALF of mice with bleomycin-induced PF at early fibrosis stage (days 4 and 7). Number of macrophages and lymphocytes, but not neutrophils, was significantly reduced as well. Treatment decreased lung tumor necrosis factor (TNF)-α mRNA level and increased mRNA level of interleukin (IL)-6 but did not influence IL-1β. At later stage (days 14 and 24) cilomilast improved lung function, which was shown by increase in lung compliance. It also lowered fibrosis degree, as was shown by quantified pathological examination of Hematoxilin-Eosin stained lung sections. Cilomilast had no significant effect on the expression of late remodeling markers such as transforming growth factor (TGF)-β1 and collagen type Ia1 (COL(I)α1). However, it tended to restore the level of lung collagen, assessed by SIRCOL assay and Masson's trichrome staining, and to improve the overall survival. CONCLUSIONS: Selective PDE4 inhibition suppresses early inflammatory stage and attenuates the late stage of experimental pulmonary fibrosis. |
format | Text |
id | pubmed-2881047 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-28810472010-06-05 Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice Udalov, Sergey Dumitrascu, Rio Pullamsetti, Soni S Al-tamari, Hamza M Weissmann, Norbert Ghofrani, Hossein A Guenther, Andreas Voswinckel, Robert Seeger, Werner Grimminger, Friedrich Schermuly, Ralph T BMC Pulm Med Research article BACKGROUND: Pulmonary fibrosis (PF) is a group of devastating and largely irreversible diseases. Phosphodiesterase (PDE) 4 is involved in the processes of remodeling and inflammation, which play key role in tissue fibrosis. The aim of the study was, therefore, to investigate the effect of PDE4 inhibition in experimental model of PF. METHODS: PF was induced in C57BL/6N mice by instillation of bleomycin. Pharmacological inhibition of PDE4 was achieved by using cilomilast, a selective PDE4 inhibitor. Changes in either lung inflammation or remodeling were evaluated at different stages of experimental PF. Lung inflammation was assessed by bronchoalveolar lavage fluid (BALF) differential cell count and reverse transcription quantitative polymerase chain reaction (RT-qPCR) for inflammatory cytokines. Changes in tissue remodeling were evaluated by pulmonary compliance measurement, quantified pathological examination, measurement of collagen deposition and RT-qPCR for late remodeling markers. Survival in all groups was analyzed as well. RESULTS: PDE4 inhibition significantly reduced the total number of alveolar inflammatory cells in BALF of mice with bleomycin-induced PF at early fibrosis stage (days 4 and 7). Number of macrophages and lymphocytes, but not neutrophils, was significantly reduced as well. Treatment decreased lung tumor necrosis factor (TNF)-α mRNA level and increased mRNA level of interleukin (IL)-6 but did not influence IL-1β. At later stage (days 14 and 24) cilomilast improved lung function, which was shown by increase in lung compliance. It also lowered fibrosis degree, as was shown by quantified pathological examination of Hematoxilin-Eosin stained lung sections. Cilomilast had no significant effect on the expression of late remodeling markers such as transforming growth factor (TGF)-β1 and collagen type Ia1 (COL(I)α1). However, it tended to restore the level of lung collagen, assessed by SIRCOL assay and Masson's trichrome staining, and to improve the overall survival. CONCLUSIONS: Selective PDE4 inhibition suppresses early inflammatory stage and attenuates the late stage of experimental pulmonary fibrosis. BioMed Central 2010-05-05 /pmc/articles/PMC2881047/ /pubmed/20444277 http://dx.doi.org/10.1186/1471-2466-10-26 Text en Copyright ©2010 Udalov 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 article Udalov, Sergey Dumitrascu, Rio Pullamsetti, Soni S Al-tamari, Hamza M Weissmann, Norbert Ghofrani, Hossein A Guenther, Andreas Voswinckel, Robert Seeger, Werner Grimminger, Friedrich Schermuly, Ralph T Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice |
title | Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice |
title_full | Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice |
title_fullStr | Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice |
title_full_unstemmed | Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice |
title_short | Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice |
title_sort | effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice |
topic | Research article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881047/ https://www.ncbi.nlm.nih.gov/pubmed/20444277 http://dx.doi.org/10.1186/1471-2466-10-26 |
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