Observational Study
. 2018 Mar 1;128(3):997-1009.
doi: 10.1172/JCI95693. Epub 2018 Feb 5.
Eleanor M Dunican 1 ,Brett M Elicker 2 ,David S Gierada 3 ,Scott K Nagle 4 ,Mark L Schiebler 4 ,John D Newell 5 ,Wilfred W Raymond 1 ,Marrah E Lachowicz-Scroggins 1 ,Selena Di Maio 1 ,Eric A Hoffman 5 ,Mario Castro 6 ,Sean B Fain 4 ,Nizar N Jarjour 7 ,Elliot Israel 8 ,Bruce D Levy 8 ,Serpil C Erzurum 9 ,Sally E Wenzel 10 ,Deborah A Meyers 11 ,Eugene R Bleecker 11 ,Brenda R Phillips 12 ,David T Mauger 12 ,Erin D Gordon 1 ,Prescott G Woodruff 1 ,Michael C Peters 1 ,John V Fahy 1 ;National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP)
Affiliations
Affiliations
- 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine and Cardiovascular Research Institute, and.
- 2 Department of Radiology and Biomedical Imaging, UCSF, San Francisco, California, USA.
- 3 Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.
- 4 Department of Medical Physics and Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
- 5 Division of Cardiovascular and Pulmonary Imaging, Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
- 6 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, Missouri, USA.
- 7 Allergy, Pulmonary and Critical Care Medicine Division, University of Wisconsin School of Medicine, Madison, Wisconsin, USA.
- 8 Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
- 9 Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
- 10 Pulmonary, Allergy and Critical Care Medicine Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
- 11 Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- 12 Division of Biostatistics and Bioinformatics, Department of Public Health Sciences, Penn State University, Hershey, Pennsylvania, USA.
- PMID: 29400693
- PMCID: PMC5824874
- DOI: 10.1172/JCI95693
Observational Study
Eleanor M Dunicanet al. J Clin Invest. .
. 2018 Mar 1;128(3):997-1009.
doi: 10.1172/JCI95693. Epub 2018 Feb 5.
Authors
Eleanor M Dunican 1 ,Brett M Elicker 2 ,David S Gierada 3 ,Scott K Nagle 4 ,Mark L Schiebler 4 ,John D Newell 5 ,Wilfred W Raymond 1 ,Marrah E Lachowicz-Scroggins 1 ,Selena Di Maio 1 ,Eric A Hoffman 5 ,Mario Castro 6 ,Sean B Fain 4 ,Nizar N Jarjour 7 ,Elliot Israel 8 ,Bruce D Levy 8 ,Serpil C Erzurum 9 ,Sally E Wenzel 10 ,Deborah A Meyers 11 ,Eugene R Bleecker 11 ,Brenda R Phillips 12 ,David T Mauger 12 ,Erin D Gordon 1 ,Prescott G Woodruff 1 ,Michael C Peters 1 ,John V Fahy 1 ;National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP)
Affiliations
- 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine and Cardiovascular Research Institute, and.
- 2 Department of Radiology and Biomedical Imaging, UCSF, San Francisco, California, USA.
- 3 Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.
- 4 Department of Medical Physics and Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
- 5 Division of Cardiovascular and Pulmonary Imaging, Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
- 6 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, Missouri, USA.
- 7 Allergy, Pulmonary and Critical Care Medicine Division, University of Wisconsin School of Medicine, Madison, Wisconsin, USA.
- 8 Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
- 9 Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
- 10 Pulmonary, Allergy and Critical Care Medicine Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
- 11 Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- 12 Division of Biostatistics and Bioinformatics, Department of Public Health Sciences, Penn State University, Hershey, Pennsylvania, USA.
- PMID: 29400693
- PMCID: PMC5824874
- DOI: 10.1172/JCI95693
Abstract
Background: The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown.
Methods: In clinical studies, we developed and applied a bronchopulmonary segment-based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation.
Results: Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in ≥ 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%-80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels.
Conclusion: Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma.
Trial registration: Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915.
Funding: NIH grants P01 HL107201, R01 HL080414, U10 HL109146, U10 HL109164, U10 HL109172, U10 HL109086, U10 HL109250, U10 HL109168, U10 HL109257, U10 HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428.
Keywords: Asthma; Cytokines; Pulmonology; Th2 response.
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Conflict of interest statement
Figures
Figure 1. Consort diagram of CT substudy.
Figure 1. Consort diagram of CT substudy.
Flow chart shows the number of asthma patients…
Figure 2. Development and distribution of the…
Figure 2. Development and distribution of the CT mucus score in asthma patients and healthy…
Figure 3. Relationship between bronchiectasis and mucus…
Figure 3. Relationship between bronchiectasis and mucus plugging.
( A ) Frequency distribution of bronchiectasis…
Figure 4. Mucus plugging is associated with…
Figure 4. Mucus plugging is associated with low lung function.
( A ) Spirometric measures…
Figure 5. Persistent airflow obstruction is seen…
Figure 5. Persistent airflow obstruction is seen in subjects with high mucus scores after treatment…
Figure 6. High mucus score is associated…
Figure 6. High mucus score is associated with markers of type 2 inflammation.
( A…
Figure 7. Eosinophil products are associated with…
Figure 7. Eosinophil products are associated with mucus plugging.
( A ) The sputum eosinophil…
See this image and copyright information in PMC
Comment in
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All plugged up - noninvasive mucus score to assess airway dysfunction in asthma.
Georas SN. Georas SN. J Clin Invest. 2018 Mar 1;128(3):906-909. doi: 10.1172/JCI99726. Epub 2018 Feb 5. J Clin Invest. 2018. PMID: 29400694 Free PMC article.
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