{"doi":"10.1164/rccm.202111-2606oc","title":"Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease","abstract":"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-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.","journal":"American Journal of Respiratory and Critical Care Medicine","year":2022,"id":235838,"datarank":1.8632959321869724,"base_score":4.330733340286331,"endowment":4.330733340286331,"self_citation_contribution":0.6496100010429497,"citation_network_contribution":1.2136859311440227,"self_endowment_contribution":0.6496100010429497,"citer_contribution":1.2136859311440227,"corpus_percentile":null,"corpus_rank":null,"citation_count":75,"citer_count":68,"citers_with_citation_signal":45,"citers_with_endowment":45,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":105499,"name":"Takanori Asakura","orcid":"0000-0003-3122-6937","position":1,"is_corresponding":false},{"id":105497,"name":"Caitlin E. 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Askin","orcid":"0000-0002-4812-1704","position":19,"is_corresponding":false},{"id":107105,"name":"Camille Ehré","orcid":"0000-0002-0046-0096","position":20,"is_corresponding":false},{"id":72632,"name":"Scott H. Randell","orcid":"0000-0001-5351-2841","position":21,"is_corresponding":false},{"id":105529,"name":"Wanda K. O’Neal","orcid":"0000-0003-2412-5943","position":22,"is_corresponding":false},{"id":5952,"name":"Ralph S. Baric","orcid":"0000-0001-6827-8701","position":23,"is_corresponding":false},{"id":105530,"name":"Richard C. 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