Distinct Cellular and Molecular Features of Asthma Mucus Plugs Provide Clues About the Mechanisms of Their Formation and Persistence
Bibliographic record
Abstract
Abstract RATIONALE: The rational design of needed treatments for airway mucus plugging in asthma requires better understanding of the mechanisms that underlie rapid mucus plug formation in asthma exacerbations and their persistence in chronic asthma. METHODS: Lung tissue sections from lung disease-free controls (n=8) and asthma patients who died from asthma (fatal asthma, n=9) or from non-asthma causes (non-fatal asthma, n=5), were assessed by histology and spatial, single-cell proteomics (imaging mass cytometry [IMC]) to characterize the landscape of mucins, structural cells and immune cells in mucus plugged airways. RESULTS: Mucus plugs were detectable in fatal (acute) and non-fatal (chronic) cases of asthma (Fig. 1A). Using IMC, we identified mucins and determined the single-cell composition of mucus plugs and the airways in which they occurred (Fig. 1B). Compared to unplugged airways, we found that mucus plugged airways had a greater number of epithelial cells and smooth muscle cells (all p values <0.05). The mucus plugs were infiltrated with immune cells that were mostly dual positive for markers of eosinophils and neutrophils (Fig. 1C), and these granulocytes were infrequent in some plugs and abundant in others (Fig. 1D). By using the median number of infiltrating granulocytes to classify mucus plugs as pauci-granulocytic or granulocytic, we found that pauci-granulocytic plugs had a higher MUC5AC content than granulocytic plugs (Fig. 1E) whereas granulocytic plugs had higher numbers of extracellular DNA traps (Histone H3 extracellular immunostaining, P<0.05). Notably, the frequency of pauci-granulocytic plugs was higher in acute (fatal) asthma than in chronic (non-fatal) asthma, whereas the frequency of granulocytic plugs was higher in chronic asthma than in acute asthma (Fig. 1F, p<0.01). CONLUSION: Mucus plugs in asthma occur in acute and chronic disease.The acute mucus plugs are relatively acellular and MUC5AC-rich whereas the chronic mucus plugs are more frequently infiltrated with granulocytes and DNA traps. We speculate that chronic mucus plugs may arise from lack of resolution of acute plugs. These data and concepts provide a framework for tackling mucus plug pathology that supports treatments that target airway remodeling and mucin gene dysregulation as well as those that target the biological pathways that drive granulocyte trafficking to mucus plugs in the airway lumen and the formation of extracellular DNA traps.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".