Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease

• Published in: American journal of respiratory and critical care medicine 2022-12, Vol.206 (11), p.1336-1352
• Main 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, Ehre, Camille, Randell, Scott H, O'Neal, Wanda K, Baric, Ralph S, Boucher, Richard C
• Format: Article
• Language: English
• Subjects: Autopsies; Body fluids; COVID-19; ErbB Receptors; Humans; Lung - metabolism; Lung diseases; Mucin 5AC - genetics; Mucin-5B - genetics; Mucus - metabolism; Original; Pathogenesis; Prevalence; RNA - metabolism; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Steroids
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.202111-2606OC

The incidence and sites of mucus accumulation and molecular regulation of mucin gene expression in coronavirus (COVID-19) lung disease have not been reported. To characterize the incidence of mucus accumulation and the mechanisms mediating mucin hypersecretion in COVID-19 lung disease. Airway mucus and mucins were evaluated in COVID-19 autopsy lungs by Alcian blue and periodic acid-Schiff staining, immunohistochemical staining, RNA 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. 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. 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.