Caveolin-1-derived peptide limits development of pulmonary fibrosis
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works..
Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with a median 5-year survival of ~20%. Current U.S. Food and Drug Administration-approved pharmacotherapies slow progression of IPF, providing hope that even more effective treatments can be developed. Alveolar epithelial progenitor type II cell (AEC) apoptosis and proliferation, and accumulation of activated myofibroblasts or fibrotic lung fibroblasts (fLfs) contribute to the progression of IPF. Full-length caveolin-1 scaffolding domain peptide (CSP; amino acids 82 to 101 of Cav1: DGIWKASFTTFTVTKYWFYR) inhibits AEC apoptosis and fLf activation and expansion and attenuates PF in bleomycin (BLM)-induced lung injury in mice. Like full-length CSP, a seven-amino acid deletion fragment of CSP, CSP7 (FTTFTVT), demonstrated antifibrotic effects in murine models of lung fibrosis. When CSP7 was administered during the fibrotic phase in three preclinical models [single-dose BLM, repeated-dose BLM, and adenovirus expressing constitutively active transforming growth factor-β1 (Ad-TGF-β1)-induced established PF], CSP7 reduced extracellular matrix (ECM) markers characteristic of PF, increased AEC survival, and improved lung function. CSP7 is amenable to both systemic (intraperitoneal) or direct lung delivery in a nebulized or dry powder form. Furthermore, CSP7 treatment of end-stage human IPF lung tissue explants attenuated ECM production and promoted AEC survival. Ames testing for mutagenicity and in vitro human peripheral blood lymphocyte and in vivo mouse micronucleus transformation assays indicated that CSP7 is not carcinogenic. Together, these findings support the further development of CSP7 as an antifibrotic treatment for patients with IPF or other interstitial lung diseases.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Science translational medicine - 11(2019), 522 vom: 11. Dez. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Marudamuthu, Amarnath Satheesh [VerfasserIn] |
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| Links: |
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| Themen: |
11056-06-7 |
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| Anmerkungen: |
Date Completed 11.09.2020 Date Revised 11.09.2020 published: Print Citation Status MEDLINE |
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| doi: |
10.1126/scitranslmed.aat2848 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM304282510 |
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| 500 | |a published: Print | ||
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| 520 | |a Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. | ||
| 520 | |a Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with a median 5-year survival of ~20%. Current U.S. Food and Drug Administration-approved pharmacotherapies slow progression of IPF, providing hope that even more effective treatments can be developed. Alveolar epithelial progenitor type II cell (AEC) apoptosis and proliferation, and accumulation of activated myofibroblasts or fibrotic lung fibroblasts (fLfs) contribute to the progression of IPF. Full-length caveolin-1 scaffolding domain peptide (CSP; amino acids 82 to 101 of Cav1: DGIWKASFTTFTVTKYWFYR) inhibits AEC apoptosis and fLf activation and expansion and attenuates PF in bleomycin (BLM)-induced lung injury in mice. Like full-length CSP, a seven-amino acid deletion fragment of CSP, CSP7 (FTTFTVT), demonstrated antifibrotic effects in murine models of lung fibrosis. When CSP7 was administered during the fibrotic phase in three preclinical models [single-dose BLM, repeated-dose BLM, and adenovirus expressing constitutively active transforming growth factor-β1 (Ad-TGF-β1)-induced established PF], CSP7 reduced extracellular matrix (ECM) markers characteristic of PF, increased AEC survival, and improved lung function. CSP7 is amenable to both systemic (intraperitoneal) or direct lung delivery in a nebulized or dry powder form. Furthermore, CSP7 treatment of end-stage human IPF lung tissue explants attenuated ECM production and promoted AEC survival. Ames testing for mutagenicity and in vitro human peripheral blood lymphocyte and in vivo mouse micronucleus transformation assays indicated that CSP7 is not carcinogenic. Together, these findings support the further development of CSP7 as an antifibrotic treatment for patients with IPF or other interstitial lung diseases | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Fan, Liang |e verfasserin |4 aut | |
| 700 | 1 | |a Radhakrishnan, Vijay |e verfasserin |4 aut | |
| 700 | 1 | |a MacKenzie, BreAnne |e verfasserin |4 aut | |
| 700 | 1 | |a Maier, Esther |e verfasserin |4 aut | |
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| 700 | 1 | |a Tiwari, Nivedita |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yajie |e verfasserin |4 aut | |
| 700 | 1 | |a Watts, Alan B |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Robert O |c 3rd |e verfasserin |4 aut | |
| 700 | 1 | |a Criner, Gerald J |e verfasserin |4 aut | |
| 700 | 1 | |a Bolla, Sudhir |e verfasserin |4 aut | |
| 700 | 1 | |a Marchetti, Nathaniel |e verfasserin |4 aut | |
| 700 | 1 | |a Idell, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Shetty, Sreerama |e verfasserin |4 aut | |
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