Related Experiment Video
Updated: May 22, 2025
Rapid Viscoelastic Characterization of Airway Mucus Using a Benchtop Rheometer
Published on: April 21, 2022
Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence
Maude A Liegeois1, Aileen Hsieh2,3, May Al-Fouadi2,3
1Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
Abstract:
BACKGROUNDMucus plugs form in acute asthma and persist in chronic disease. Although eosinophils are implicated in mechanisms of mucus pathology, many mechanistic details about mucus plug formation and persistence in asthma are unknown.METHODSUsing histology and spatial, single-cell proteomics, we characterized mucus-plugged airways from nontransplantable donor lungs of 14 patients with asthma (9 with fatal asthma and 5 with nonfatal asthma) and individuals acting as controls (10 with chronic obstructive pulmonary disease and 14 free of lung disease). Additionally, we used an airway epithelial cell-eosinophil (AEC-eosinophil) coculture model to explore how AEC mucus affects eosinophil degranulation.RESULTSAsthma mucus plugs were tethered to airways showing infiltration with innate lymphoid type 2 cells and hyperplasia of smooth muscle cells and MUC5AC-expressing goblet cells. Asthma mucus plugs were infiltrated with immune cells that were mostly dual positive for eosinophil peroxidase (EPX) and neutrophil elastase, suggesting that neutrophils internalize EPX from degranulating eosinophils. Indeed, eosinophils exposed to mucus from IL-13-activated AECs underwent CD11b- and glycan-dependent cytolytic degranulation. Dual-positive granulocytes varied in frequency in mucus plugs. Whereas paucigranulocytic plugs were MUC5AC rich, granulocytic plugs had a mix of MUC5AC, MUC5B, and extracellular DNA traps. Paucigranulocytic plugs occurred more frequently in (acute) fatal asthma and granulocytic plugs predominated in (chronic) nonfatal asthma.CONCLUSIONTogether, our data suggest that mucin-rich mucus plugs in fatal asthma form because of acute goblet cell degranulation in remodeled airways and that granulocytic mucus plugs in chronic asthma persist because of a sustaining niche characterized by epithelial cell-mucin-granulocyte cross-talk.FUNDINGNIH grants HL080414, HL107202, and AI077439.
Insights
Mucus plugs in fatal asthma stem from acute goblet cell degranulation, while chronic asthma plugs persist due to a persistent airway niche. This research clarifies mucus plug formation and persistence in asthma.
Area of Science:
- Pulmonology
- Immunology
- Cell Biology
Background:
- Mucus plugs are a hallmark of asthma, contributing to airway obstruction.
- The precise mechanisms of mucus plug formation and persistence, particularly involving eosinophils, remain incompletely understood.
- Understanding these processes is crucial for developing targeted therapies for asthma.
Purpose of the Study:
- To investigate the cellular and molecular characteristics of mucus plugs in asthma.
- To elucidate the role of airway epithelial cells and eosinophils in mucus plug formation and persistence.
- To differentiate the features of mucus plugs in fatal versus nonfatal asthma.
Main Methods:
- Histology and spatial, single-cell proteomics on donor lungs from asthma patients and controls.
- Airway epithelial cell-eosinophil coculture model to study mucus-induced eosinophil degranulation.
- Analysis of immune cell infiltration, goblet cell hyperplasia, and mucin composition.
Main Results:
- Asthma mucus plugs showed innate lymphoid type 2 cells, smooth muscle hyperplasia, and MUC5AC-expressing goblet cells.
- Immune cells in plugs were often dual-positive for eosinophil peroxidase and neutrophil elastase, suggesting neutrophil-eosinophil interactions.
- Eosinophils underwent cytolytic degranulation when exposed to mucus from activated airway epithelial cells.
- Paucigranulocytic plugs (rich in MUC5AC) were more common in fatal asthma, while granulocytic plugs (mixed mucins and DNA traps) predominated in nonfatal asthma.
Conclusions:
- Fatal asthma mucus plugs likely arise from acute goblet cell degranulation in remodeled airways.
- Chronic asthma mucus plugs may persist due to a niche involving epithelial cell-mucin-granulocyte crosstalk.
- These findings offer insights into distinct mechanisms driving mucus plugging in different asthma phenotypes.
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