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

  • Am J Respir Crit Care Med. 2022 Jul 11. doi: 10.1164/rccm.202111-2606OC.
Takafumi Kato  1 ,  Takanori Asakura  1 ,  Caitlin E Edwards  2 ,  Hong Dang  1 ,  Yu Mikami  1 ,  Kenichi Okuda  1 ,  Gang Chen  1 ,  Ling Sun  1 ,  Rodney C Gilmore  1 ,  Padraig Hawkins  1 ,  Gabriela De la Cruz  3 ,  Michelle R Cooley  2 ,  Alexis B Bailey  2 ,  Stephen M Hewitt  4 ,  Daniel S Chertow  5 ,  Alain C Borczuk  6 ,  Steven Salvatore  7 ,  Fernando J Martinez  8 ,  Leigh B Thorne  9 ,  Frederic B Askin  9 ,  Camille Ehre  1 ,  Scott H Randell  1 ,  Wanda K O'Neal  10 ,  Ralph S Baric  2 ,  Richard C Boucher  11 ,  NIH COVID-19 Autopsy Consortium
Affiliations
  • 1. University of North Carolina at Chapel Hill School of Medicine, 6797, Marsico Lung Institute, Chapel Hill, North Carolina, United States.
  • 2. University of North Carolina at Chapel Hill School of Medicine, 6797, Department of Epidemiology, Chapel Hill, North Carolina, United States.
  • 3. University of North Carolina at Chapel Hill School of Medicine, 6797, Pathology Services Core, Chapel Hill, North Carolina, United States.
  • 4. National Cancer Institute, 3421, Center for Cancer Research, Bethesda, Maryland, United States.
  • 5. NIH Clinical Center, 24481, Critical Care Medicine Department, Bethesda, Maryland, United States.
  • 6. Weill Cornell Medicine, 12295, Anatomic Pathology, New York, New York, United States.
  • 7. Weill Cornell Medicine, 12295, Pathology and Laboratory Medicine , New York, New York, United States.
  • 8. Weill Cornell Medicine, 12295, Pulmonary Critical Care Medicine, New York, New York, United States.
  • 9. University of North Carolina at Chapel Hill School of Medicine, 6797, Department of Pathology and Laboratory Medicine, Chapel Hill, North Carolina, United States.
  • 10. University of North Carolina at Chapel Hill, 2331, Marsico Lung Institute/Cystic Fibrosis Research Center, Chapel Hill, North Carolina, United States.
  • 11. University of North Carolina at Chapel Hill School of Medicine, 6797, Marsico Lung Institute, Chapel Hill, North Carolina, United States; [email protected].
PMID: 35816430 DOI: 10.1164/rccm.202111-2606OC
Abstract

Rationale: The incidence and sites of mucus accumulation, and molecular regulation of Mucin gene expression, in COVID-19 lung disease have not been reported.

Objectives: Characterize 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 AB-PAS and immunohistochemical staining, RNA in situ hybridization, and spatial transcriptional profiling. SARS-CoV-2-infected human bronchial epithelial (HBE) cultures were utilized 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 levels were increased throughout all airway regions of COVID-19 autopsy lungs, notably in the sub-acute/chronic disease phase following SARS-CoV-2 clearance. In the distal lung, MUC5B-dominated mucus plugging was observed in 90% of COVID-19 subjects 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 post inoculation, whereas induction of MUC5B/MUC5AC peaked 7-14 days post inoculation. SARS-CoV-2 Infection of HBE cultures induced expression of EGFR ligands and inflammatory cytokines (e.g., IL-1α/β) associated with Mucin gene regulation. Inhibiting EGFR/IL-1R pathways, or dexamethasone administration, 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 post 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. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords
Airway mucins; COVID-19; Epidermal growth factor receptor; Interleukin-1 receptor; SARS-CoV-2.
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