Bicarbonate‐dependent chloride transport drives fluid secretion by the human airway epithelial cell line Calu‐3
Bibliographic record
Abstract
Key points The mechanisms of anion and fluid transport by airway submucosal glands are not well understood and may differ from those in surface epithelium. The Calu‐3 cell line is often used as a model for submucosal gland serous cells and has cAMP‐stimulated fluid secretion; however, it does not actively transport chloride under short‐circuit conditions. In this study we show that fluid secretion requires chloride, bicarbonate and sodium, that chloride is the predominant anion in Calu‐3 secretions, and that a large fraction of the basolateral chloride loading during cAMP stimulation occurs by Cl−/HCO3−exchange. The results suggest a novel cellular model for anion and fluid secretion by Calu‐3 and submucosal gland acinar cells Abstract Anion and fluid secretion are both defective in cystic fibrosis (CF); however, the transport mechanisms are not well understood. In this study, Cl−and HCO3−secretion was measured using genetically matched CF transmembrane conductance regulator (CFTR)‐deficient and CFTR‐expressing cell lines derived from the human airway epithelial cell line Calu‐3. Forskolin stimulated the short‐circuit current (Isc) across voltage‐clamped monolayers, and also increased the equivalent short‐circuit current (Ieq) calculated under open‐circuit conditions.Iscwas equivalent to the HCO3−net flux measured using the pH‐stat technique, whereasIeqwas the sum of the Cl−and HCO3−net fluxes.Ieqand HCO3−fluxes were increased by bafilomycin and ZnCl2, suggesting that some secreted HCO3−is neutralized by parallel electrogenic H+secretion.Ieqand fluid secretion were dependent on the presence of both Na+and HCO3−. The carbonic anhydrase inhibitor acetazolamide abolished forskolin stimulation ofIeqand HCO3−secretion, suggesting that HCO3−transport under these conditions requires catalysed synthesis of carbonic acid. Cl−was the predominant anion in secretions under all conditions studied and thus drives most of the fluid transport. Nevertheless, 50–70% of Cl−and fluid transport was bumetanide‐insensitive, suggesting basolateral Cl−loading by a sodium–potassium–chloride cotransporter 1 (NKCC1)‐independent mechanism. Imposing a transepithelial HCO3−gradient across basolaterally permeabilized Calu‐3 cells sustained a forskolin‐stimulated current, which was sensitive to CFTR inhibitors and drastically reduced in CFTR‐deficient cells. Net HCO3−secretion was increased by bilateral Cl−removal and therefore did not require apical Cl−/HCO3−exchange. The results suggest a model in which most HCO3−is recycled basolaterally by exchange with Cl−, and the resulting HCO3−‐dependent Cl−transport provides an osmotic driving force for fluid secretion.
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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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".