Septic Murine Pulmonary Microvascular Endothelial Barrier Dysfunction <i>in vitro</i> is Regulated by TIMP3
Bibliographic record
Abstract
Sepsis often causes dysfunction of pulmonary microvascular endothelial cells (PMECs) leading to pulmonary edema. Metalloproteinases can regulate endothelial function through processing of cell surface proteins, including adherens junctions proteins, which has been associated with increased permeability. Tissue inhibitor of metalloproteinases 3 (TIMP3) regulates metalloproteinase function in the lung following injury. Thus, we hypothesize that TIMP3 promotes PMEC stability via inhibition of metalloproteinase activity. To test this hypothesis, we used PMECs isolated from WT and Timp3 ‐/‐ mice. We found that TIMP3 levels (mRNA and protein) were decreased in WT PMECs in a time‐dependent fashion under septic conditions (cytomix). Analysis of leak (transendothelial electrical resistance, dextran, and albumin flux) revealed that Timp3 ‐/‐ PMECs had significantly higher permeability under resting conditions (PBS) vs. WT PMECs. Although cytomix treatment significantly increased WT trans‐PMEC permeability, there was no effect on Timp3 ‐/‐ PMEC barrier function. Additionally, the increased basal Timp3 ‐/‐ PMEC permeability was associated with disrupted surface vascular endothelial‐cadherin localization, which was rescued by treatment with GM6001, a synthetic inhibitor of metalloproteinases. Together, our data suggest that TIMP3 supports normal PMEC barrier function and that septic downregulation of TIMP3 may be an important contributor to septic PMEC barrier dysfunction.
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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 | 0.000 |
| 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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".