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ResearchIn-Press PreviewPulmonology Open Access | 10.1172/jci.insight.161487

CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling

Marta Bueno,1 Jazmin Calyeca,2 Timur Khaliullin,2 Megan Miller,3 Diana Álvarez,4 Lorena Rosas,2 Judith Brands,3 Christian M. Baker,4 Amro Nasser,4 Stephanie Shulkowski,4 August Mathien,4 Nneoma O, Uzoukwu,4 John Sembrat,1 Brenton G. Mays,3 Kaitlin Fiedler,3 Scott A. Hahn,3 Sonia R. Salvatore,6 Francisco J. Schopfer,6 Mauricio Rojas,2 Peter Sandner,7 Adam Straub,6 and Ana L. Mora2

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Bueno, M. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Calyeca, J. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Álvarez, D. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Rosas, L. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Brands, J. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Baker, C. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Shulkowski, S. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Mathien, A. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Uzoukwu, N. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Sembrat, J. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Mays, B. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Fiedler, K. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Hahn, S. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Salvatore, S. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Schopfer, F. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Rojas, M. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Sandner, P. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Straub, A. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

2Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, United States of America

3Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States of America

4Aging Institute, Department of Medicine, University of Pittsburgh, PITTSBURGH, United States of America

5Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America

6Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

7Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal, Germany

Find articles by Mora, A. in: JCI | PubMed | Google Scholar

Published February 7, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.161487.
Copyright © 2023, Bueno et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 7, 2023 - Version history
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Abstract

Type II alveolar epithelial cell (AECII) redox imbalance contributes to the pathogenesis of idiopathic pulmonary fibrosis (IPF) – a deadly disease with restricted and limited treatment options. Here, we show that expression of membrane-bound cytochrome B5 reductase 3 (CYB5R3), an enzyme critical for maintaining cellular redox homeostasis and soluble guanylate cyclase (sGC) heme iron redox state, is diminished in IPF AECII. Deficiency of CYB5R3 in AECII leads to sustained activation of the profibrotic factor TGF-β1 and increased susceptibility to lung fibrosis. We further show that CYB5R3 is a critical regulator of ERK1/2 phosphorylation and sGC-cGMP-protein kinase G axis that modulates activation of TGF-β1 signaling pathway. We demonstrate that sGC agonists (BAY 41-8543 and BAY 54-6544) are effective in reducing the pulmonary fibrotic outcomes of in vivo deficiency of CYB5R3 in AECII. Taken together, these results establish that CYB5R3 in AECII is required to maintain resilience against lung injury and fibrosis, and that therapeutic manipulation of sGC redox state could provide a basis for treating fibrotic conditions in the lung and beyond.

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  • Version 1 (February 7, 2023): In-Press Preview
  • Version 2 (March 8, 2023): Electronic publication
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