The fibronectin-targeting PEG-FUD imaging probe shows enhanced uptake during fibrogenesis in experimental lung fibrosis
Abstract Progressive forms of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), are deadly disorders lacking non-invasive biomarkers for assessment of early disease activity, which presents a major obstacle in disease management. Excessive extracellular matrix (ECM) depositi...
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2025-01-01
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| Series: | Respiratory Research |
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| Online Access: | https://doi.org/10.1186/s12931-025-03107-x |
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| author | Thomas J. Harr Nikesh Gupta Babita Rahar Kristen Stott Yadira Medina-Guevara Metti K. Gari Angie T. Oler Ivy Sohee McDermott Hye Jin Lee Morteza Rasoulianboroujeni Ashley M. Weichmann Amir Forati Kelsey Holbert Trevor S. Langel Kade W. Coulter Brian M. Burkel Bianca R. Tomasini-Johansson Suzanne M. Ponik Jonathan W. Engle Reinier Hernandez Glen S. Kwon Nathan Sandbo Ksenija Bernau |
| author_facet | Thomas J. Harr Nikesh Gupta Babita Rahar Kristen Stott Yadira Medina-Guevara Metti K. Gari Angie T. Oler Ivy Sohee McDermott Hye Jin Lee Morteza Rasoulianboroujeni Ashley M. Weichmann Amir Forati Kelsey Holbert Trevor S. Langel Kade W. Coulter Brian M. Burkel Bianca R. Tomasini-Johansson Suzanne M. Ponik Jonathan W. Engle Reinier Hernandez Glen S. Kwon Nathan Sandbo Ksenija Bernau |
| author_sort | Thomas J. Harr |
| collection | DOAJ |
| description | Abstract Progressive forms of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), are deadly disorders lacking non-invasive biomarkers for assessment of early disease activity, which presents a major obstacle in disease management. Excessive extracellular matrix (ECM) deposition is a hallmark of these disorders, with fibronectin being an abundant ECM glycoprotein that is highly upregulated in early fibrosis and serves as a scaffold for the deposition of other matrix proteins. Due to its role in active fibrosis, we are targeting fibronectin as a biomarker of early lung fibrosis disease activity via the PEGylated fibronectin-binding polypeptide (PEG-FUD). In this work, we demonstrate the binding of PEG-FUD to the fibrotic lung throughout the course of bleomycin-induced murine model of pulmonary fibrosis. We first analyzed the binding of radiolabeled PEG-FUD following direct incubation to precision cut lung slices from mice at different stages of experimental lung fibrosis. Then, we administered fluorescently labeled PEG-FUD subcutaneously to mice over the course of bleomycin-induced pulmonary fibrosis and assessed peptide uptake 24 h later through ex vivo tissue imaging. Using both methods, we found that peptide targeting to the fibrotic lung is increased during the fibrogenic phase of the single dose bleomycin lung fibrosis model (days 7 and 14 post-bleomycin). At these timepoints we found a correlative relationship between peptide uptake and fibrotic burden. These data suggest that PEG-FUD targets fibronectin associated with active fibrogenesis in this model, making it a promising candidate for a clinically translatable molecular imaging probe to non-invasively determine pulmonary fibrosis disease activity, enabling accelerated therapeutic decision-making. |
| format | Article |
| id | doaj-art-48305e26b875482996c4b746c41cc7be |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Respiratory Research |
| spelling | doaj-art-48305e26b875482996c4b746c41cc7be2025-01-26T12:49:02ZengBMCRespiratory Research1465-993X2025-01-0126111710.1186/s12931-025-03107-xThe fibronectin-targeting PEG-FUD imaging probe shows enhanced uptake during fibrogenesis in experimental lung fibrosisThomas J. Harr0Nikesh Gupta1Babita Rahar2Kristen Stott3Yadira Medina-Guevara4Metti K. Gari5Angie T. Oler6Ivy Sohee McDermott7Hye Jin Lee8Morteza Rasoulianboroujeni9Ashley M. Weichmann10Amir Forati11Kelsey Holbert12Trevor S. Langel13Kade W. Coulter14Brian M. Burkel15Bianca R. Tomasini-Johansson16Suzanne M. Ponik17Jonathan W. Engle18Reinier Hernandez19Glen S. Kwon20Nathan Sandbo21Ksenija Bernau22Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonPharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-MadisonDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Medical Physics, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin-MadisonDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonPharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-MadisonPharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-MadisonUniversity of Wisconsin Carbone Cancer Center, University of Wisconsin-MadisonDepartment of Medicine, School of Medicine and Public Health, University of Wisconsin- MadisonDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin-MadisonDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Medical Physics, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Medical Physics, School of Medicine and Public Health, University of Wisconsin-MadisonPharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-MadisonDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-MadisonAbstract Progressive forms of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), are deadly disorders lacking non-invasive biomarkers for assessment of early disease activity, which presents a major obstacle in disease management. Excessive extracellular matrix (ECM) deposition is a hallmark of these disorders, with fibronectin being an abundant ECM glycoprotein that is highly upregulated in early fibrosis and serves as a scaffold for the deposition of other matrix proteins. Due to its role in active fibrosis, we are targeting fibronectin as a biomarker of early lung fibrosis disease activity via the PEGylated fibronectin-binding polypeptide (PEG-FUD). In this work, we demonstrate the binding of PEG-FUD to the fibrotic lung throughout the course of bleomycin-induced murine model of pulmonary fibrosis. We first analyzed the binding of radiolabeled PEG-FUD following direct incubation to precision cut lung slices from mice at different stages of experimental lung fibrosis. Then, we administered fluorescently labeled PEG-FUD subcutaneously to mice over the course of bleomycin-induced pulmonary fibrosis and assessed peptide uptake 24 h later through ex vivo tissue imaging. Using both methods, we found that peptide targeting to the fibrotic lung is increased during the fibrogenic phase of the single dose bleomycin lung fibrosis model (days 7 and 14 post-bleomycin). At these timepoints we found a correlative relationship between peptide uptake and fibrotic burden. These data suggest that PEG-FUD targets fibronectin associated with active fibrogenesis in this model, making it a promising candidate for a clinically translatable molecular imaging probe to non-invasively determine pulmonary fibrosis disease activity, enabling accelerated therapeutic decision-making.https://doi.org/10.1186/s12931-025-03107-xRecombinant peptidePulmonary fibrosisImagingNon-invasive biomarkerFibronectin |
| spellingShingle | Thomas J. Harr Nikesh Gupta Babita Rahar Kristen Stott Yadira Medina-Guevara Metti K. Gari Angie T. Oler Ivy Sohee McDermott Hye Jin Lee Morteza Rasoulianboroujeni Ashley M. Weichmann Amir Forati Kelsey Holbert Trevor S. Langel Kade W. Coulter Brian M. Burkel Bianca R. Tomasini-Johansson Suzanne M. Ponik Jonathan W. Engle Reinier Hernandez Glen S. Kwon Nathan Sandbo Ksenija Bernau The fibronectin-targeting PEG-FUD imaging probe shows enhanced uptake during fibrogenesis in experimental lung fibrosis Respiratory Research Recombinant peptide Pulmonary fibrosis Imaging Non-invasive biomarker Fibronectin |
| title | The fibronectin-targeting PEG-FUD imaging probe shows enhanced uptake during fibrogenesis in experimental lung fibrosis |
| title_full | The fibronectin-targeting PEG-FUD imaging probe shows enhanced uptake during fibrogenesis in experimental lung fibrosis |
| title_fullStr | The fibronectin-targeting PEG-FUD imaging probe shows enhanced uptake during fibrogenesis in experimental lung fibrosis |
| title_full_unstemmed | The fibronectin-targeting PEG-FUD imaging probe shows enhanced uptake during fibrogenesis in experimental lung fibrosis |
| title_short | The fibronectin-targeting PEG-FUD imaging probe shows enhanced uptake during fibrogenesis in experimental lung fibrosis |
| title_sort | fibronectin targeting peg fud imaging probe shows enhanced uptake during fibrogenesis in experimental lung fibrosis |
| topic | Recombinant peptide Pulmonary fibrosis Imaging Non-invasive biomarker Fibronectin |
| url | https://doi.org/10.1186/s12931-025-03107-x |
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