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Resolution of Pulmonary Fibrosis by a Caveolin-1-Derived Peptide
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A2221 - Resolution of Pulmonary Fibrosis by a Caveolin-1-Derived Peptide
Author Block: L. Fan1, V. Gopu1, N. Tiwari1, A. Marudamuthu1, S. Shetty1, Y. Bhandary1, M. Nagaraja1, V. Radhakrishnan1, A. B. Watts2, R. Williams III2, S. Idell1, S. Shetty1; 1Cellular and Molecular Biology, UT health science center at Tyler, Tyler, TX, United States, 2The University of Texas at Austin, Austin, TX, United States.
INTRODUCTION: Human idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with a median five-year survival of about 20%. Recent pharmacotherapy has been shown to slow progression of the disease, providing hope that an even more effective treatment can be developed. METHODS: Human and mouse nLfs and fLfs (IPF) were treated with 10 μM caveolin-1 scaffolding peptide (CSP) or its deletion or mutation fragments or control peptide (CP) in vitro. Wild-type (WT) mice were exposed to single dose of bleomycin (BLM). Fourteen days later treated with CSP or CSP7 or CP by intraperitoneal injection for seven days. All mice were evaluated for changes in PF on day 21. WT mice with Ad-TGF-β1- or repeated dose BLM-induced established PF were treated with vehicle or CSP or CSP7 or CP daily for the next 14 days and their lungs were analyzed for PF. WT mice with BLM-induced established PF were also exposed to CSP7 using inhalation system for one week and evaluated for PF.RESULTS: We found that CSP and its seven amino acid deletion fragment CSP7 inhibits alveolar epithelial cell (AEC) apoptosis, fLf expansion and BLM-induced established PF in mice. CSP7 is well-tolerated, resolves PF improves lung function in all three pre-clinical models of established PF and is amenable to systemic or local; airway delivery. Further, CSP7 treatment of IPF lung tissues ex vivo inhibits collagen 1 and alpha-smooth muscle actin expression, and attenuates AEC apoptosis. There were no detectable effects in normal lung tissues. Nebulization of formulated CSP7 significantly reduced total lung weight, total hydroxyproline and soluble collagen content in whole lung tissues, which are otherwise increased in mice with single dose BLM-induced PF. CSP7 also markedly reduced ECM deposition in the lung tissues by histologic analyses. These observations underscore the potential of CSP7 to resolve fibrotic lung diseases including IPF. CONCLUSION: Our findings demonstrate that CSP7 enhances AEC viability via a novel mechanism of action involving p53, while concurrently slowing the expansion of activated fLfs. This peptide blocks progression of PF, likewise involving changes in fLf p53. The intervention appears to be well-tolerated and offers a novel, well-tolerated and potentially more effective therapeutic candidate for the treatment of IPF or other interstitial lung diseases.
Author Block: L. Fan1, V. Gopu1, N. Tiwari1, A. Marudamuthu1, S. Shetty1, Y. Bhandary1, M. Nagaraja1, V. Radhakrishnan1, A. B. Watts2, R. Williams III2, S. Idell1, S. Shetty1; 1Cellular and Molecular Biology, UT health science center at Tyler, Tyler, TX, United States, 2The University of Texas at Austin, Austin, TX, United States.
INTRODUCTION: Human idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with a median five-year survival of about 20%. Recent pharmacotherapy has been shown to slow progression of the disease, providing hope that an even more effective treatment can be developed. METHODS: Human and mouse nLfs and fLfs (IPF) were treated with 10 μM caveolin-1 scaffolding peptide (CSP) or its deletion or mutation fragments or control peptide (CP) in vitro. Wild-type (WT) mice were exposed to single dose of bleomycin (BLM). Fourteen days later treated with CSP or CSP7 or CP by intraperitoneal injection for seven days. All mice were evaluated for changes in PF on day 21. WT mice with Ad-TGF-β1- or repeated dose BLM-induced established PF were treated with vehicle or CSP or CSP7 or CP daily for the next 14 days and their lungs were analyzed for PF. WT mice with BLM-induced established PF were also exposed to CSP7 using inhalation system for one week and evaluated for PF.RESULTS: We found that CSP and its seven amino acid deletion fragment CSP7 inhibits alveolar epithelial cell (AEC) apoptosis, fLf expansion and BLM-induced established PF in mice. CSP7 is well-tolerated, resolves PF improves lung function in all three pre-clinical models of established PF and is amenable to systemic or local; airway delivery. Further, CSP7 treatment of IPF lung tissues ex vivo inhibits collagen 1 and alpha-smooth muscle actin expression, and attenuates AEC apoptosis. There were no detectable effects in normal lung tissues. Nebulization of formulated CSP7 significantly reduced total lung weight, total hydroxyproline and soluble collagen content in whole lung tissues, which are otherwise increased in mice with single dose BLM-induced PF. CSP7 also markedly reduced ECM deposition in the lung tissues by histologic analyses. These observations underscore the potential of CSP7 to resolve fibrotic lung diseases including IPF. CONCLUSION: Our findings demonstrate that CSP7 enhances AEC viability via a novel mechanism of action involving p53, while concurrently slowing the expansion of activated fLfs. This peptide blocks progression of PF, likewise involving changes in fLf p53. The intervention appears to be well-tolerated and offers a novel, well-tolerated and potentially more effective therapeutic candidate for the treatment of IPF or other interstitial lung diseases.
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