Multiple-Site Activation of the Cysteinyl Leukotriene Receptor 2 Is Required for Exacerbation of Ischemia/Reperfusion Injury
Bibliographic record
Abstract
OBJECTIVE: Transgenic overexpression of the human cysteinyl leukotriene receptor 2 (CysLT2R) in murine endothelium exacerbates vascular permeability and ischemia/reperfusion injury. Here, we explore the underlying mechanisms of CysLT2R activation-mediated inflammation and delineate the relative contributions of endogenous murine CysLT2R and the transgene-derived receptor. APPROACH AND RESULTS: We created a novel mouse with only endothelial-expressed CysLT2R (endothelium-targeted overexpression mice [EC]/CysLT2R-knockout mice [KO]) by crossing EC with KO to dissect the role of endothelial CysLT2R in tissue injury. Surprisingly, we discovered that damage in EC/KO mice was not elevated (24% versus 47% EC) after ischemia/reperfusion. We examined vascular permeability and leukocyte recruitment/rolling responses in the cremaster vasculature after cysteinyl leukotriene (cysLT) stimulation. Mice possessing transgenic endothelial CysLT2R overexpression, whether EC or EC/KO, when stimulated with cysLTs, exhibited vascular hyperpermeability, declining leukocyte flux, and a transient increase in slow-rolling leukocyte fraction. Mice lacking endogenous CysLT2R (both KO [20 ± 3 cells/min] EC/KO [24 ± 3]) showed lower-rolling leukocyte flux versus wild-type (38 ± 6) and EC (35 ± 6) mice under unstimulated conditions. EC/KO mice differed from EC counterparts in that vascular hyperpermeability was not present in the absence of exogenous cysLTs. CONCLUSIONS: These results indicate that endothelial and nonendothelial CysLT2R niches have separate roles in mediating inflammatory responses. Endothelial receptor activation results in increased vascular permeability and leukocyte slow-rolling, facilitating leukocyte transmigration. Nonendothelial receptors, likely located on resident/circulating leukocytes, facilitate endothelial receptor activation and leukocyte transit. Activation of both receptor populations is required for injury exacerbation.
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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) | 0.001 | 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) | 0.002 | 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".