Carotid body‐specific shRNA knockdown of PKCɛ blunts TRPV1‐dependent asthmatic bronchoconstriction
Bibliographic record
Abstract
Rationale Aggravated airway bronchoconstriction and mucus production in response to allergen and/or bradykinin ( i.e. , airway hyperresponsiveness) is a primary defining symptom of asthma. Recently, we discovered a critical role for the carotid bodies: inhaled allergen causes an increase in arterial plasma concentrations of asthmakines which excite the carotid bodies via a transient receptor potential vanilloid 1 channel (TRPV1) dependent mechanism. Elevated carotid body excitation in turn increases efferent vagal activity, resulting in heightened bronchoconstriction. While our data demonstrate that the carotid bodies are strongly excited by multiple Th‐2 cytokines, in the ovalbumin primed and sensitized Brown Norway rat model of asthma, the primary asthmakine is likely lysophosphatidic acid (LPA). However, the cellular link between LPA receptors and TRPV1 has not been identified. Here we show that the effect of LPA on the carotid bodies is likely mediated by PKCɛ‐dependent phosphorylation of TRPV1. Methods Lentivirus vectors containing shRNA to knockdown PKCɛ or scrambled sequence were injected bilaterally into the carotid bodies of asthmatic rats (n=7, each). The responses of carotid bodies to LPA (5μM), and their subsequent responses to TRPV1 blockade (AMG9810, 10μM) were tested using the en bloc perfused carotid body preparation. The effects of carotid body‐specific PKCɛ knockdown on changes in lung mechanics in response to inhaled bradykinin were tested using the Flexivent system. Results Carotid bodies from asthmatic rats injected with PKCɛ knockdown sequence mounted smaller responses to LPA than those injected with scrambled sequence. No difference in LPA response was detected between groups following TRPV1 blockade, suggesting the primary target for PKCɛ is TRPV1. Asthmatic rats with carotid bodies injected with PKCɛ knockdown sequence had reduced lung resistance in response to bradykinin at 1, 10 and 20 minutes. Similar results were obtained using a PKCɛ inhibitory peptide. Conclusion We show for the first time that carotid body‐mediated bronchoconstriction in asthmatic rats occurs through LPA receptor activation of PKCɛ and subsequent TRPV1‐mediated carotid sinus nerve excitation. Targeting carotid body LPA receptors, PKCɛ and/or TRPV1 may provide a new therapeutic target to reduce asthmatic airway hyperresponsiveness. Support or Funding Information CIHR, Alberta Innovates, Alberta Lung Association and the Parker B. Francis Foundation.
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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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".