MARCKS protein is a potential target in a naturally occurring equine model of neutrophilic asthma
Bibliographic record
Abstract
BACKGROUND: Asthma is a chronic inflammatory airway disease that affects millions of people worldwide. Horses develop asthma spontaneously and serve as a relevant model for multiple phenotypes and endotypes of human asthma. In horses with equine asthma (EA), environmental organic dust triggers increased inflammatory cytokines, excess airway mucus, reversible bronchoconstriction, and airway inflammation. In horses with severe EA (sEA), lower airway inflammation is invariably neutrophilic, making sEA a potential model for severe neutrophilic asthma in humans. Alveolar macrophages (AM) and airway neutrophils contribute to lower airway inflammation and tissue damage through the release of cytokines and toxic mediators including reactive oxygen species. Previous work shows that the Myristoylated Alanine Rich C Kinase Substrate (MARCKS) protein is increased in activated macrophages and neutrophils and is an essential regulator of inflammatory functions in these cell types. We hypothesized that MARCKS protein would be increased in bronchoalveolar lavage (BAL) cells from horses with EA, and that in vitro inhibition of MARCKS with a specific inhibitor peptide known as MyristoylAted N-terminal Sequence (MANS), would diminish cytokine production and respiratory burst. METHODS: BAL cells from two populations of healthy and asthmatic horses were evaluated for cytology and MARCKS protein analysis. Isolated alveolar macrophages and peripheral blood neutrophils were stimulated with zymosan to evaluate MARCKS inhibition in cytokine secretion and respiratory burst. RESULTS: We found increased levels of normalized MARCKS protein in total BAL cells from horses with asthma compared to normal horses. MARCKS inhibition with the MANS peptide had no effect on zymosan-stimulated release of tumor necrosis factor alpha (TNFα) or interleukin-8 (IL-8) from alveolar macrophages but did attenuate zymosan-stimulated respiratory burst in both alveolar macrophages and peripheral blood neutrophils. CONCLUSIONS: These findings point to a possible role for MARCKS in the pathophysiology of neutrophilic equine asthma and support further investigation of MARCKS as a novel anti-inflammatory target for severe neutrophilic asthma.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".