Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease
Rationale: The incidence and sites of mucus accumulation and molecular regulation of mucin gene expression in coronavirus (COVID-19) lung disease have not been reported. Objectives: To characterize the incidence of mucus accumulation and the mechanisms mediating mucin hypersecretion in COVID-19 lung disease. Methods: Airway mucus and mucins were evaluated in COVID-19 autopsy lungs by Alcian blue and periodic acid-Schiff staining, immunohistochemical staining, RNA in situ hybridization, and spatial transcriptional profiling. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected human bronchial epithelial (HBE) cultures were used to investigate mechanisms of SARS-CoV-2-induced mucin expression and synthesis and test candidate countermeasures. Measurements and Main Results: MUC5B and variably MUC5AC RNA concentrations were increased throughout all airway regions of COVID-19 autopsy lungs, notably in the subacute/chronic disease phase after SARS-CoV-2 clearance. In the distal lung, MUC5B-dominated mucus plugging was observed in 90% of subjects with COVID-19 in both morphologically identified bronchioles and microcysts, and MUC5B accumulated in damaged alveolar spaces. SARS-CoV-2-infected HBE cultures exhibited peak titers 3 days after inoculation, whereas induction of MUC5B/MUC5AC peaked 7-14 days after inoculation. SARS-CoV-2 infection of HBE cultures induced expression of epidermal growth factor receptor (EGFR) ligands and inflammatory cytokines (e.g., IL-1α/β) associated with mucin gene regulation. Inhibiting EGFR/IL-1R pathways or administration of dexamethasone reduced SARS-CoV-2-induced mucin expression. Conclusions: SARS-CoV-2 infection is associated with a high prevalence of distal airspace mucus accumulation and increased MUC5B expression in COVID-19 autopsy lungs. HBE culture studies identified roles for EGFR and IL-1R signaling in mucin gene regulation after SARS-CoV-2 infection. These data suggest that time-sensitive mucolytic agents, specific pathway inhibitors, or corticosteroid administration may be therapeutic for COVID-19 lung disease.
| Errataetall: |
CommentIn: Am J Respir Crit Care Med. 2022 Dec 1;206(11):1304-1306. - PMID 35830305 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:206 |
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| Enthalten in: |
American journal of respiratory and critical care medicine - 206(2022), 11 vom: 01. Dez., Seite 1336-1352 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kato, Takafumi [VerfasserIn] |
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| Links: |
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| Themen: |
63231-63-0 |
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| Anmerkungen: |
Date Completed 02.12.2022 Date Revised 06.11.2023 published: Print CommentIn: Am J Respir Crit Care Med. 2022 Dec 1;206(11):1304-1306. - PMID 35830305 Citation Status MEDLINE |
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| doi: |
10.1164/rccm.202111-2606OC |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM34336901X |
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| 100 | 1 | |a Kato, Takafumi |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease |
| 264 | 1 | |c 2022 | |
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| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 02.12.2022 | ||
| 500 | |a Date Revised 06.11.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a CommentIn: Am J Respir Crit Care Med. 2022 Dec 1;206(11):1304-1306. - PMID 35830305 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Rationale: The incidence and sites of mucus accumulation and molecular regulation of mucin gene expression in coronavirus (COVID-19) lung disease have not been reported. Objectives: To characterize the incidence of mucus accumulation and the mechanisms mediating mucin hypersecretion in COVID-19 lung disease. Methods: Airway mucus and mucins were evaluated in COVID-19 autopsy lungs by Alcian blue and periodic acid-Schiff staining, immunohistochemical staining, RNA in situ hybridization, and spatial transcriptional profiling. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected human bronchial epithelial (HBE) cultures were used to investigate mechanisms of SARS-CoV-2-induced mucin expression and synthesis and test candidate countermeasures. Measurements and Main Results: MUC5B and variably MUC5AC RNA concentrations were increased throughout all airway regions of COVID-19 autopsy lungs, notably in the subacute/chronic disease phase after SARS-CoV-2 clearance. In the distal lung, MUC5B-dominated mucus plugging was observed in 90% of subjects with COVID-19 in both morphologically identified bronchioles and microcysts, and MUC5B accumulated in damaged alveolar spaces. SARS-CoV-2-infected HBE cultures exhibited peak titers 3 days after inoculation, whereas induction of MUC5B/MUC5AC peaked 7-14 days after inoculation. SARS-CoV-2 infection of HBE cultures induced expression of epidermal growth factor receptor (EGFR) ligands and inflammatory cytokines (e.g., IL-1α/β) associated with mucin gene regulation. Inhibiting EGFR/IL-1R pathways or administration of dexamethasone reduced SARS-CoV-2-induced mucin expression. Conclusions: SARS-CoV-2 infection is associated with a high prevalence of distal airspace mucus accumulation and increased MUC5B expression in COVID-19 autopsy lungs. HBE culture studies identified roles for EGFR and IL-1R signaling in mucin gene regulation after SARS-CoV-2 infection. These data suggest that time-sensitive mucolytic agents, specific pathway inhibitors, or corticosteroid administration may be therapeutic for COVID-19 lung disease | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a COVID-19 | |
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| 700 | 1 | |a Asakura, Takanori |e verfasserin |4 aut | |
| 700 | 1 | |a Edwards, Caitlin E |e verfasserin |4 aut | |
| 700 | 1 | |a Dang, Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Mikami, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Okuda, Kenichi |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Gang |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Gilmore, Rodney C |e verfasserin |4 aut | |
| 700 | 1 | |a Hawkins, Padraig |e verfasserin |4 aut | |
| 700 | 1 | |a De la Cruz, Gabriela |e verfasserin |4 aut | |
| 700 | 1 | |a Cooley, Michelle R |e verfasserin |4 aut | |
| 700 | 1 | |a Bailey, Alexis B |e verfasserin |4 aut | |
| 700 | 1 | |a Hewitt, Stephen M |e verfasserin |4 aut | |
| 700 | 1 | |a Chertow, Daniel S |e verfasserin |4 aut | |
| 700 | 1 | |a Borczuk, Alain C |e verfasserin |4 aut | |
| 700 | 1 | |a Salvatore, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Martinez, Fernando J |e verfasserin |4 aut | |
| 700 | 1 | |a Thorne, Leigh B |e verfasserin |4 aut | |
| 700 | 1 | |a Askin, Frederic B |e verfasserin |4 aut | |
| 700 | 1 | |a Ehre, Camille |e verfasserin |4 aut | |
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