Sepsis‐Associated Proteinase 3 Induces Endothelial Permeability
Bibliographic record
Abstract
Sepsis is a systemic inflammatory response to known or suspected infection, and associated with microvascular dysfunction and capillary leak. The cause of capillary leak may be due to substances released by activated polymorphonuclear neutrophils (PMNs) that adhere to microvascular endothelial cells. Following binding, PMN often degranulate releasing azurophilic enzymes ( e.g. elastase and proteinase 3 (PR3)) at the endothelial surface and into plasma. We hypothesized that the actions of these enzymes, particularly PR3 contribute to the loss of endothelial integrity. Patients with severe sepsis (sepsis with evidence of at least one organ dysfunctioning), were recruited on admission to the intensive care unit. Patient samples were paired with age and sex‐matched controls. The mean age was 50 ± 14 years, 3/10 males for both sepsis and controls. Septic patient pathogens were determined to be 4 gram positive, 4 gram negative and 2 culture negative; survival outcomes were 9/10 patients surviving. We employed ELISAs to determine plasma PR3 concentrations and in vitro permeability assays using Texas Red‐Dextran flow to determine the effect of PR3 on human umbilical vein endothelial cell (HUVEC) monolayer integrity. The sepsis plasma PR3 concentration was significantly higher (p < 0.001) compared to controls (55.4 ±8.8 vs 7.7 ±2 ng/mL). For in vitro permeability assays, we employed concentrations of PR3 higher than the plasma measurements in order to more closely mimic conditions at the site of degranulation. 1 hour of PR3 treatment (5 μg/mL) significantly increased HUVEC permeability to Texas Red‐Dextran compared to controls. The loss of endothelial integrity secondary to PR3 release by adhered PMNs could result in microvascular dysfunction and capillary leak. Endothelial injury could also exacerbate further PMN recruitment. Since other enzymes are contained in the same granules as PR3, they may also have significant actions on endothelial cells, these will be studied in the future. We conclude that neutrophil degranulation, as evidenced by increased PR3 plasma concentrations, can lead to increased endothelial permeability through a mechanism which in part involves the actions of PR3. Support or Funding Information Funded by the Lawson Health Research Institute Internal Research Fund.
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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) | 0.002 | 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".