Phosphorylation-dependent modulation of CFTR macromolecular signalling complex activity by cigarette smoke condensate in airway epithelia
Bibliographic record
Abstract
Genetic and acquired loss-of-function defect of the cystic fibrosis transmembrane conductance regulator (CFTR) compromise airway surface liquid homeostasis and mucociliary clearance (MCC), culminating in recurrent lung inflammation/infection. While chronic cigarette smoke (CS), CS extract (CSE; water-soluble compounds) and CS condensate (CSC; particulate, organic fraction) exposure inhibit CFTR activity at transcriptional, biochemical, and functional levels, the acute impact of CSC remains incompletely understood. We report that CSC transiently activates CFTR chloride secretion in airway epithelia. The comparable CFTR phospho-occupancy after CSC- and forskolin-exposure, determined by affinity-enriched tandem mass spectrometry and pharmacology, suggest that localised cAMP-dependent protein kinase (PKA) stimulation by CSC causes the channel opening. Due to the inhibition of the MRP4/ABCC4, a cAMP-exporter confined to the CFTR macromolecular signalling-complex, PKA activation is accomplished by the subcompartmentalised elevation of cytosolic cAMP. In line, MRP4 inhibition results in CFTR activation and phospho-occupancy similar to that by forskolin. In contrast, acute CSC exposure reversibly inhibits the phosphorylated CFTR both in vivo and in phospholipid bilayers, without altering its cell surface density and phospho-occupancy. We propose that components of CSC elicit both a transient protective CFTR activation, as well as subsequent channel block in airway epithelia, contributing to the subacute MCC defect in acquired CF lung diseases.
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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 | 0.000 | 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) | 0.001 | 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".