Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease.
The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of th...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3614979?pdf=render |
| _version_ | 1819075726502002688 |
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| author | Ruoqi Peng Sriram Sridhar Gaurav Tyagi Jonathan E Phillips Rosario Garrido Paul Harris Lisa Burns Lorena Renteria John Woods Leena Chen John Allard Palanikumar Ravindran Hans Bitter Zhenmin Liang Cory M Hogaboam Chris Kitson David C Budd Jay S Fine Carla M T Bauer Christopher S Stevenson |
| author_facet | Ruoqi Peng Sriram Sridhar Gaurav Tyagi Jonathan E Phillips Rosario Garrido Paul Harris Lisa Burns Lorena Renteria John Woods Leena Chen John Allard Palanikumar Ravindran Hans Bitter Zhenmin Liang Cory M Hogaboam Chris Kitson David C Budd Jay S Fine Carla M T Bauer Christopher S Stevenson |
| author_sort | Ruoqi Peng |
| collection | DOAJ |
| description | The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFβ was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease. |
| first_indexed | 2024-12-21T18:29:59Z |
| format | Article |
| id | doaj.art-f1de7e184b004255ba62f718b13adc00 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T18:29:59Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-f1de7e184b004255ba62f718b13adc002022-12-21T18:54:18ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0184e5934810.1371/journal.pone.0059348Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease.Ruoqi PengSriram SridharGaurav TyagiJonathan E PhillipsRosario GarridoPaul HarrisLisa BurnsLorena RenteriaJohn WoodsLeena ChenJohn AllardPalanikumar RavindranHans BitterZhenmin LiangCory M HogaboamChris KitsonDavid C BuddJay S FineCarla M T BauerChristopher S StevensonThe preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFβ was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.http://europepmc.org/articles/PMC3614979?pdf=render |
| spellingShingle | Ruoqi Peng Sriram Sridhar Gaurav Tyagi Jonathan E Phillips Rosario Garrido Paul Harris Lisa Burns Lorena Renteria John Woods Leena Chen John Allard Palanikumar Ravindran Hans Bitter Zhenmin Liang Cory M Hogaboam Chris Kitson David C Budd Jay S Fine Carla M T Bauer Christopher S Stevenson Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease. PLoS ONE |
| title | Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease. |
| title_full | Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease. |
| title_fullStr | Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease. |
| title_full_unstemmed | Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease. |
| title_short | Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease. |
| title_sort | bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis a model for active disease |
| url | http://europepmc.org/articles/PMC3614979?pdf=render |
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