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Research ArticlePulmonology
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10.1172/jci.insight.161487
1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
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Bueno, M.
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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
Find articles by Calyeca, J. in: JCI | PubMed | Google Scholar
1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
Find articles by Khaliullin, T. in: JCI | PubMed | Google Scholar
1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
Find articles by Miller, M. in: JCI | PubMed | Google Scholar
1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
Find articles by Rosas, L. in: JCI | PubMed | Google Scholar
1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
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Brands, J.
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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
Find articles by Baker, C. in: JCI | PubMed | Google Scholar
1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
Find articles by Nasser, A. in: JCI | PubMed | Google Scholar
1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
Find articles by Mathien, A. in: JCI | PubMed | Google Scholar
1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
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Sembrat, J.
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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
Find articles by Hahn, S. in: JCI | PubMed | Google Scholar
1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
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Salvatore, S.
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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
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Schopfer, F.
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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
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Rojas, M.
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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
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Sandner, P.
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1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
Find articles by Straub, A. in: JCI | PubMed | Google Scholar
1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
3Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
4Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5Department of Pharmacology and Chemical Biology,
6Pittsburgh Liver Research Center (PLRC), and
7Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
8Bayer Pharmaceuticals Wuppertal, Germany.
9Hannover Medical School, Hannover, Germany.
Address correspondence to: Ana L. Mora, 513 Davis Heart & Lung Research Institute, 473 W. 12th Ave., Columbus, Ohio 43210, USA. Phone: 614.685.9526; Email: Ana.Mora@osumc.edu. Or to: Adam C. Straub, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15261, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.
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Published February 7, 2023 - More info
Published in Volume 8, Issue 5 on March 8, 2023
AbstractType II alveolar epithelial cell (AECII) redox imbalance contributes to the pathogenesis of idiopathic pulmonary fibrosis (IPF), a deadly disease with 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 AECIIs. Deficiency of CYB5R3 in AECIIs led to sustained activation of the pro-fibrotic factor TGF-β1 and increased susceptibility to lung fibrosis. We further show that CYB5R3 is a critical regulator of ERK1/2 phosphorylation and the sGC/cGMP/protein kinase G axis that modulates activation of the 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 AECIIs. Taken together, these results show that CYB5R3 in AECIIs is required to maintain resilience after lung injury and fibrosis and that therapeutic manipulation of the sGC redox state could provide a basis for treating fibrotic conditions in the lung and beyond.
Graphical Abstract
Introduction
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and deadly disease with few and modest therapeutic options and a median survival of 3–4 years following diagnosis (1, 2). IPF is a disease of age: onset usually occurs at age 50 to 70 years, and most patients are older than 60 at the time of clinical presentation (3). While familial IPF has been linked to disordered telomerase activity and mutations in surfactant proteins, the etiology of many sporadic IPF cases and the mechanisms involved in the aging susceptibility to IPF are largely unknown (4, 5). The most accepted theory in IPF pathogenesis is an epithelial driven process triggered by injury of type II alveolar epithelial cells (AECIIs) that activates pro-fibrotic TGF-β1 signaling (6, 7). TGF-β1 activation leads to altered crosstalk with fibroblasts, myofibroblast activation, and excessive extracellular matrix (ECM) accumulation. While existing FDA-approved therapies slow the physiological progression of IPF, they have adverse effects and do not have an impact on mortality. It is universally appreciated that identification of novel pathways that regulate pro-fibrotic responses and development of the next generation of drugs are needed.
Alterations in reduction and oxidation (redox) homeostasis play a critical role in the pathogenesis of age-related diseases, such as IPF, and have been associated with increased oxidative stress in the lung. Accumulating evidence suggests that elevated expression and activity of NADPH oxidases (NOX enzymes) and mitochondrial dysfunction (8, 9) are critical contributing factors in different cell compartments of the lung. Furthermore, mitochondrial dysfunction (as a hallmark of aging) has been associated with alterations in the NAD+/NADH ratio, thus influencing the activity of several downstream proteins, including sirtuins, which can consume NAD+ and deplete cells from one of its main sources to restore cellular protection. Recent papers revealed dysfunctional NAD+ homeostasis with reduced expression of several NAD+ synthesis enzymes in IPF lungs (10, 11). Cytochrome b5 reductase 3 (CYB5R3) is a membrane-bound reductase that uses NADH as substrate and participates in reduction of several key redox molecules (12–14). Recently, we showed that in smooth muscle cells CYB5R3 can directly reduce oxidized heme in soluble guanylate cyclase (sGC), which is required for NO-stimulated 3′5′ cyclic guanosine monophosphate (cGMP) production (12, 15–17). While there is growing evidence for a critical role for CYB5R3 in the cardiovascular system and in aging (18–20), very little is known about the function of CYB5R3 in the context of physiological lung homeostasis and pathology, more specifically during fibrosis.
TGF-β, present in 3 isoforms (TGF-β1, 2, and 3), is a well-recognized pro-fibrotic factor in different organs (21). In the lung, TGF-β is produced by a variety of cell types, including activated alveolar epithelial cells. TGF-β effects in IPF pathogenesis include alveolar epithelial injury, activation of fibroblasts, myofibroblast transdifferentiation, excessive production of ECM, and inhibition of ECM degradation. Although it is known that oxidative stress promotes activation of TGF-β, the precise nature of the mediators regulating this process is not completely understood (8, 22). Considering that increased oxidative stress and redox imbalance in AECIIs are known components of IPF pathogenesis, we sought to investigate if CYB5R3 redox activity was altered in AECIIs from IPF lungs. Here, we demonstrate a potentially novel role for CYB5R3 in AECIIs controlling the TGF-β signaling pathway. In particular, we show that expression of CYB5R3 was diminished in AECIIs of IPF lungs,
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