Mucus accumulation, MUC5B found in COVID-19 autopsy lungs
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Patients who died of COVID-19 had a high expression of MUC5B in their lungs and mucus accumulation in distal airways, according to a study published in American Journal of Respiratory and Critical Care Medicine.
“Airway mucus exhibits a protective role against viral acquisition, but excessive mucus secretion and accumulation in response to viral infections can produce airway mucus obstruction,” Takafumi Kato, MD, PhD, a research associate at Marsico Lung Institute at the University of North Carolina School of Medicine, and colleagues wrote. “Despite reports of excessive mucus in coronavirus disease (COVID-19) clinical settings, comprehensive characterizations of the regulation of mucin secretion and sites of mucus accumulation in COVID-19 lungs have not been reported.”
Kato and colleagues analyzed 61 COVID-19 autopsy lungs to identify how often mucus accumulates and the mechanisms that trigger mucin hypersecretion to better understand COVID-19 lung disease.
To observe mucus accumulation sites, mucin gene expression patterns and regulatory pathways, researchers utilized several tools, including Alcian blue and periodic acid-Schiff staining, immunohistochemical staining, RNA in situ hybridization (RNA-ISH) and spatial transcriptional profiling.
Additionally, researchers evaluated the kinetic, magnitude and mechanisms of mucin hypersecretion through models of human bronchial epithelial (HBE) cultures infected with SARS-CoV-2.
Of the total sample, 21 lungs had proximal airways and 15 lungs had distal airways that were sufficient for study via Alcian blue and periodic acid-Schiff staining. Researchers were able to conduct RNA-ISH on proximal airways of seven lung and distal airways of 14.
All airway regions of the autopsy lungs had higher concentrations of MUC5B, with MUC5AC expression showing a similar pattern that did not reach statistical significance, according to researchers. Researchers noted that these increased concentrations primarily occurred in the subacute/chronic disease phase that follows SARS-CoV-2 clearance.
When evaluating distal lungs, researchers observed that 14 (93%) lungs had MUC5B accumulation in both bronchioles and microcysts, an incidence that they called significantly greater than that occurring in healthy controls. These lungs also showed an accumulation of MUC5B in damaged alveolar spaces.
When evaluating HBE cell cultures, researchers found that SARS-CoV-2 titers peaked at day 3 after inoculation and was suppressed or eliminated by day 14, whereas MUC5B and MUC5AC gene expression peaked after 7 to 14 days, which researchers wrote signals the subacute to chronic phases.
The HBE cultures infected with SARS-CoV-2 also demonstrated expression of epidermal growth factor receptor (EGFR) ligands and inflammatory cytokines (eg, IL 1-alpha/beta) that are associated with mucin gene regulation.
Based on these findings, researchers evaluated the cells lines to see if targeting these pathways would reduce mucin induction. They found a significant reduction of mucin gene expression in virus-infected cultures at days 3 to 7 using the EGFR tyrosine kinase inhibitor gefitinib or EGFR monoclonal antibody cetuximab (Erbitux, Lilly). Also, using dexamethasone between days 3 and 14 after inoculation significantly reduced MUC5B and MUC5AC RNA and protein expression at 14 days.
“Mucolytic agents, EGFR/IL-1 receptor antagonists, and/or corticosteroids may be beneficial at targeted intervals for the treatment of the airway muco-obstructive component of COVID-19 lung disease,” Kato and colleagues wrote.
This study by Kato and colleagues adds to the literature indicating that studies on COVID-19 have provided important insights on not just this infection, but for other diseases as well, according to an accompanying editorial by Burton F. Dickey, MD and Jichao Chen, PhD, from the department of pulmonary medicine at the University of Texas MD Anderson Cancer Center, and R. Strokes Peebles, MD, from the division of allergy, pulmonary and critical care medicine at Vanderbilt University Medical Center.
“In summary, COVID-19 has only been with us a short while; yet, it is now perhaps the best-studied human viral pneumonia,” Dickey, Chen and Peebles wrote. “Further analysis of similarities with and differences from other viral pneumonias should provide us new insight into cellular and molecular mechanisms of lung immunity, injury, and repair to guide diagnosis and treatment.”