Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction

The National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP)

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)997-1009
Number of pages13
JournalJournal of Clinical Investigation
Volume128
Issue number3
DOIs
StatePublished - Mar 1 2018

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Eosinophilia
Mucus
Asthma
Eosinophil Peroxidase
Forced Expiratory Volume
Eosinophils
Oxidants
Multidetector Computed Tomography
Sulfhydryl Compounds
Lung
Cysteine
Hydrogels
Sputum
Bromides
Chronic Obstructive Pulmonary Disease
Gels

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

The National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP) (2018). Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. Journal of Clinical Investigation, 128(3), 997-1009. https://doi.org/10.1172/JCI95693
The National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP). / Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 3. pp. 997-1009.
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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.",
author = "{The National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP)} and Dunican, {Eleanor M.} and Elicker, {Brett M.} and Gierada, {David S.} and Nagle, {Scott K.} and Schiebler, {Mark L.} and Newell, {John D.} and Raymond, {Wilfred W.} and Lachowicz-Scroggins, {Marrah E.} and {Di Maio}, Selena and Hoffman, {Eric A.} and Mario Castro and Fain, {Sean B.} and Jarjour, {Nizar N.} and Elliot Israel and Levy, {Bruce D.} and Erzurum, {Serpil C.} and Wenzel, {Sally E.} and Meyers, {Deborah A.} and Bleecker, {Eugene R.} and Phillips, {Brenda R.} and Mauger, {David T.} and Gordon, {Erin D.} and Woodruff, {Prescott G.} and Peters, {Michael C.} and Fahy, {John V.} and Patricia Noel and Robert Smith",
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The National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP) 2018, 'Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction', Journal of Clinical Investigation, vol. 128, no. 3, pp. 997-1009. https://doi.org/10.1172/JCI95693

Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. / The National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP).

In: Journal of Clinical Investigation, Vol. 128, No. 3, 01.03.2018, p. 997-1009.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction

AU - The National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP)

AU - Dunican, Eleanor M.

AU - Elicker, Brett M.

AU - Gierada, David S.

AU - Nagle, Scott K.

AU - Schiebler, Mark L.

AU - Newell, John D.

AU - Raymond, Wilfred W.

AU - Lachowicz-Scroggins, Marrah E.

AU - Di Maio, Selena

AU - Hoffman, Eric A.

AU - Castro, Mario

AU - Fain, Sean B.

AU - Jarjour, Nizar N.

AU - Israel, Elliot

AU - Levy, Bruce D.

AU - Erzurum, Serpil C.

AU - Wenzel, Sally E.

AU - Meyers, Deborah A.

AU - Bleecker, Eugene R.

AU - Phillips, Brenda R.

AU - Mauger, David T.

AU - Gordon, Erin D.

AU - Woodruff, Prescott G.

AU - Peters, Michael C.

AU - Fahy, John V.

AU - Noel, Patricia

AU - Smith, Robert

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

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The National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP). Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. Journal of Clinical Investigation. 2018 Mar 1;128(3):997-1009. https://doi.org/10.1172/JCI95693