Ca <sup>2+</sup> entry via transient receptor potential vanilloid channel 4 mediates ventilation‐induced lung vascular barrier failure (1176.3)
Bibliographic record
Abstract
Study objective : High tidal volume ventilation causes lung vascular barrier failure, yet underlying mechanisms are unclear. Here, we tested whether endothelial Ca 2+ influx via mechanosensitive TRPV4 may contribute to stretch‐induced pulmonary hyperpermeability in vivo and ex vivo . Next, we probed for the role of putative upstream (serum/glucocorticoid‐regulated kinase (SGK) 1) and downstream (Ca 2+ ‐activated K + channels) regulators of TRPV4 in this scenario. Methods : Mice were ventilated for 2 h with low (7 ml/kg) and high (20 ml/kg) tidal volumes (LV T /HV T ) in vivo. Isolated‐perfused lungs were inflated with 5 or 15 cmH 2 O (L PIP /H PIP ) and [Ca 2+ ] i was quantified by real‐time imaging with or without pharmacological inhibition of SGK1, TRPV4 or Ca 2+ ‐activated K + channels. Results : TRPV4 deficiency or inhibition by HC‐067047 protected from HV T ‐induced lung injury in vivo , and attenuated the endothelial Ca 2+ response to H PIP ex vivo . Involvement of SGK1 and Ca 2+ ‐activated K + channels was evident as reduced lung hyperpermeability in HV T mice following inhibition by GSK650394 (SGK1), apamin or charybdotoxin. Conclusions : Activation of TRPV4 by HV T mediates endothelial Ca 2+ influx and promotes lung injury and barrier failure via a signaling pathway that involves both SGK1 and Ca 2+ ‐activated K + channels, which may present new targets for the prevention or treatment of stretch‐induced vascular pathologies. Grant Funding Source : Supported by an operational grant of the Deutsche Forschungsgemeinschaft to W.M.K.
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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 | 0.001 | 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".