A novel actor in mechanotransduction: transient receptor potential cation channel vanilloid (TRPV) 1 in ventilator‐induced lung injury (VILI)
Bibliographic record
Abstract
Study objective Mechanical ventilation can damage the lung by causing endothelial barrier failure, edema formation and lung injury. Yet, the exact mechanisms underlying the mechanotransduction at the microvascular barrier are still unclear. In previous work, we had identified a critical role of the endothelial Ca 2+ channel transient receptor potential vanilloid 4 (TRPV4) in endothelial barrier failure subsequent to mechanical overventilation. Here, we assessed the relevance of TRPV1 as novel regulator in VILI in vivo , and probed for its contribution to TRPV4‐induced Ca 2+ signalling in vivo , ex vivo and in vitro . Methods Wild type, TRPV4‐ or TRPV1‐deficient mice were ventilated for 2 h with low (7 mL/kg) and high (20 mL/kg) tidal volumes (LV T /HV T ) in vivo. Endothelial [Ca 2+ ] i in isolated‐perfused lungs, inflated with 5 or 15 cmH 2 O, and in human pulmonary microvascular endothelial cells (HPMVECs) was quantified by real‐time imaging with or without pharmacological inhibition of TRPV1 and TRPV4, or after activation of TRPV1 and/or TRPV4 by capsaicin and/or GSK1016790A, respectively. Results TRPV1 or TRPV4 deficiency or inhibition by either SB366791 or HC‐067047, respectively, attenuated VILI, and reduced the endothelial [Ca 2+ ] i response to high pressure inflation ex vivo , with exception of SB366791 treatment, which only diminished the sustained [Ca 2+ ]i response, but not the initial Ca 2+ influx. In vitro Ca 2+ measurements from HPMVECs showed a characteristic increase in endothelial [Ca 2+ ] i that in response to selective TRPV4, yet activation of TRPV1 alone had no effect. Dual activation of both TRPV channels, however, amplified and prolong the TRPV4‐mediated Ca 2+ influx into HPMVECs. Conclusions Here, we demonstrate a critical role of TRPV1 as amplifier of TRPV4‐mediated [Ca 2+ ] i response and barrier failure for VILI in vivo , ex vivo and in vitro , and identify a novel signalling axis that may present putative pharmacological targets for the prevention or treatment of ventilator‐associated lung disease.
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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 | 0.000 |
| 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 | 0.001 | 0.001 |
| 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".