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- Title
Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease.
- Authors
Kato, Takafumi; Asakura, Takanori; Edwards, Caitlin E.; Dang, Hong; Mikami, Yu; Okuda, Kenichi; Chen, Gang; Sun, Ling; Gilmore, Rodney C.; Hawkins, Padraig; De la Cruz, Gabriela; Cooley, Michelle R.; Bailey, Alexis B.; Hewitt, Stephen M.; Chertow, Daniel S.; Borczuk, Alain C.; Salvatore, Steven; Martinez, Fernando J.; Thorne, Leigh B.; Askin, Frederic B.
- Abstract
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-1a/b) 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.
- Publication
American Journal of Respiratory & Critical Care Medicine, 2022, Vol 206, Issue 11, p1336
- ISSN
1073-449X
- Publication type
Article
- DOI
10.1164/rccm.202111-2606oc