Caveolin-1-Derived Peptide Reduces ER Stress and Enhances Gelatinolytic Activity in IPF Fibroblasts
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by an excess deposition of extracellular matrix in the pulmonary interstitium. Caveolin-1 scaffolding domain peptide (CSP) has been found to mitigate pulmonary fibrosis in several animal models. However, its pathophysiological role...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/6/3316 |
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| author | Satoshi Komatsu Liang Fan Steven Idell Sreerama Shetty Mitsuo Ikebe |
| author_facet | Satoshi Komatsu Liang Fan Steven Idell Sreerama Shetty Mitsuo Ikebe |
| author_sort | Satoshi Komatsu |
| collection | DOAJ |
| description | Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by an excess deposition of extracellular matrix in the pulmonary interstitium. Caveolin-1 scaffolding domain peptide (CSP) has been found to mitigate pulmonary fibrosis in several animal models. However, its pathophysiological role in IPF is obscure, and it remains critical to understand the mechanism by which CSP protects against pulmonary fibrosis. We first studied the delivery of CSP into cells and found that it is internalized and accumulated in the Endoplasmic Reticulum (ER). Furthermore, CSP reduced ER stress via suppression of inositol requiring enzyme1α (IRE1α) in transforming growth factor β (TGFβ)-treated human IPF lung fibroblasts (hIPF-Lfs). Moreover, we found that CSP enhanced the gelatinolytic activity of TGFβ-treated hIPF-Lfs. The IRE1α inhibitor; 4µ8C also augmented the gelatinolytic activity of TGFβ-treated hIPF-Lfs, supporting the concept that CSP induced inhibition of the IRE1α pathway. Furthermore, CSP significantly elevated expression of MMPs in TGFβ-treated hIPF-Lfs, but conversely decreased the secretion of collagen 1. Similar results were observed in two preclinical murine models of PF, bleomycin (BLM)- and adenovirus expressing constitutively active TGFβ (Ad-TGFβ)-induced PF. Our findings provide new insights into the mechanism by which lung fibroblasts contribute to CSP dependent protection against lung fibrosis. |
| first_indexed | 2024-03-09T19:41:28Z |
| format | Article |
| id | doaj.art-7bed99aba4564b9aa89d93b03be7be49 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T19:41:28Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7bed99aba4564b9aa89d93b03be7be492023-11-24T01:37:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01236331610.3390/ijms23063316Caveolin-1-Derived Peptide Reduces ER Stress and Enhances Gelatinolytic Activity in IPF FibroblastsSatoshi Komatsu0Liang Fan1Steven Idell2Sreerama Shetty3Mitsuo Ikebe4Department of Cellular and Molecular Biology, The University of Texas at Tyler Health Science Center, Tyler, TX 75708, USADepartment of Cellular and Molecular Biology, The University of Texas at Tyler Health Science Center, Tyler, TX 75708, USADepartment of Cellular and Molecular Biology, The University of Texas at Tyler Health Science Center, Tyler, TX 75708, USADepartment of Cellular and Molecular Biology, The University of Texas at Tyler Health Science Center, Tyler, TX 75708, USADepartment of Cellular and Molecular Biology, The University of Texas at Tyler Health Science Center, Tyler, TX 75708, USAIdiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by an excess deposition of extracellular matrix in the pulmonary interstitium. Caveolin-1 scaffolding domain peptide (CSP) has been found to mitigate pulmonary fibrosis in several animal models. However, its pathophysiological role in IPF is obscure, and it remains critical to understand the mechanism by which CSP protects against pulmonary fibrosis. We first studied the delivery of CSP into cells and found that it is internalized and accumulated in the Endoplasmic Reticulum (ER). Furthermore, CSP reduced ER stress via suppression of inositol requiring enzyme1α (IRE1α) in transforming growth factor β (TGFβ)-treated human IPF lung fibroblasts (hIPF-Lfs). Moreover, we found that CSP enhanced the gelatinolytic activity of TGFβ-treated hIPF-Lfs. The IRE1α inhibitor; 4µ8C also augmented the gelatinolytic activity of TGFβ-treated hIPF-Lfs, supporting the concept that CSP induced inhibition of the IRE1α pathway. Furthermore, CSP significantly elevated expression of MMPs in TGFβ-treated hIPF-Lfs, but conversely decreased the secretion of collagen 1. Similar results were observed in two preclinical murine models of PF, bleomycin (BLM)- and adenovirus expressing constitutively active TGFβ (Ad-TGFβ)-induced PF. Our findings provide new insights into the mechanism by which lung fibroblasts contribute to CSP dependent protection against lung fibrosis.https://www.mdpi.com/1422-0067/23/6/3316idiopathic pulmonary fibrosisendoplasmic reticulum stresscaveolin-1 scaffolding domain peptidematrix metalloproteinases |
| spellingShingle | Satoshi Komatsu Liang Fan Steven Idell Sreerama Shetty Mitsuo Ikebe Caveolin-1-Derived Peptide Reduces ER Stress and Enhances Gelatinolytic Activity in IPF Fibroblasts International Journal of Molecular Sciences idiopathic pulmonary fibrosis endoplasmic reticulum stress caveolin-1 scaffolding domain peptide matrix metalloproteinases |
| title | Caveolin-1-Derived Peptide Reduces ER Stress and Enhances Gelatinolytic Activity in IPF Fibroblasts |
| title_full | Caveolin-1-Derived Peptide Reduces ER Stress and Enhances Gelatinolytic Activity in IPF Fibroblasts |
| title_fullStr | Caveolin-1-Derived Peptide Reduces ER Stress and Enhances Gelatinolytic Activity in IPF Fibroblasts |
| title_full_unstemmed | Caveolin-1-Derived Peptide Reduces ER Stress and Enhances Gelatinolytic Activity in IPF Fibroblasts |
| title_short | Caveolin-1-Derived Peptide Reduces ER Stress and Enhances Gelatinolytic Activity in IPF Fibroblasts |
| title_sort | caveolin 1 derived peptide reduces er stress and enhances gelatinolytic activity in ipf fibroblasts |
| topic | idiopathic pulmonary fibrosis endoplasmic reticulum stress caveolin-1 scaffolding domain peptide matrix metalloproteinases |
| url | https://www.mdpi.com/1422-0067/23/6/3316 |
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