TRPV4 and Ca <sup>2+</sup> downregulate ENaC expression and activity following a loss of barrier integrity in alveolar epithelial cells
Bibliographic record
Abstract
The epithelial Na channel (ENaC) plays an essential role in lung physiology by modulating the amount of liquid lining the respiratory epithelium. This is crucial at birth for removing foetal liquid from the lung and for edema clearance during lung injury in adulthood. We reported that ENaC is expressed in alveolar epithelial cells and that pro‐inflammatory conditions such as TNFα, TGF‐β and LPS decrease its expression and function in alveolar epithelial cells in primary culture. We tested here how breaking epithelial integrity would affect ENaC expression and function. We found that mechanical wounding (MW) or disruption of tight junction by treating the cells with a 5 min EDTA treatment, induces a ~40–60% decrease of α,β and γENaC mRNA expression. ENaC short‐circuit current ( I sc ) recorded in Ussing chamber was decreased by 80% at 6h following MW and EDTA treatment and was correlated to αENaC mRNA expression (R=0,8379). BAPTA‐AM pre‐treatment abolishes the effect of MW or EDTA on αENaC mRNA, suggesting that [Ca 2+ ] i is important for this modulation. Inhibition of TRPV4 a mechano‐sensitive cationic channel that drives Ca 2+ in the cytoplasm with HC‐067047 (HC0) almost inhibited completely αENAC mRNA downregulation. Activation of TRPV4 with GSK‐1016790A (GSK), a specific TRPV4 agonist, downregulates αENAC mRNA and has a major impact on the I sc response of alveolar epithelial cells. The treatment elicits a rapid, but transient, Ca 2+ dependent drop of the current followed by a return to the baseline that is amiloride‐insensitive. TRPV4 current activated by GSK and inhibited by HCO was also confirmed by patch clamp in cell attach configuration. By Ca 2+ fluorescence microscopy with Fluo3‐AM, we found that GSK increases [Ca 2+ ] i and that MW generates a Ca 2+ wave that spreads from the margin of the scratch to the whole epithelium. Altogether our results suggest that mechanical stress induced by MW or loss of tight junction by activating TRPV4 could increase [Ca 2+ ] i and elicit a Ca 2+ wave that could affect ENaC expression and function away from the site of injury. These data are important to better understand how intercellular Ca 2+ signalling could have consequence on lung liquid clearance in injured lungs.
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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) | 0.001 | 0.001 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".