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Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease.
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.
  • Kato T; Marsico Lung Institute.
  • Asakura T; Marsico Lung Institute.
  • Edwards CE; Department of Epidemiology.
  • Dang H; Marsico Lung Institute.
  • Mikami Y; Marsico Lung Institute.
  • Okuda K; Marsico Lung Institute.
  • Chen G; Marsico Lung Institute.
  • Sun L; Marsico Lung Institute.
  • Gilmore RC; Marsico Lung Institute.
  • Hawkins P; Marsico Lung Institute.
  • De la Cruz G; Pathology Services Core, Lineberger Comprehensive Cancer Center, and.
  • Cooley MR; Department of Epidemiology.
  • Bailey AB; Department of Epidemiology.
  • Hewitt SM; Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • Chertow DS; Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, Maryland; and.
  • Borczuk AC; Department of Pathology and Laboratory Medicine and.
  • Salvatore S; Department of Pathology and Laboratory Medicine and.
  • Martinez FJ; Pulmonary Critical Care Medicine, Weill Cornell Medicine, New York, New York.
  • Thorne LB; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  • Askin FB; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  • Ehre C; Marsico Lung Institute.
  • Randell SH; Marsico Lung Institute.
  • O'Neal WK; Marsico Lung Institute.
  • Baric RS; Department of Epidemiology.
  • Boucher RC; Marsico Lung Institute.
Am J Respir Crit Care Med ; 206(11): 1336-1352, 2022 Dec 01.
Article in English | MEDLINE | ID: covidwho-2231710
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/ß) 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Experimental Studies / Observational study Limits: Humans Language: English Journal: Am J Respir Crit Care Med Journal subject: Critical Care Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Experimental Studies / Observational study Limits: Humans Language: English Journal: Am J Respir Crit Care Med Journal subject: Critical Care Year: 2022 Document Type: Article