Reduced plasma levels of Copine 5 correlate with sepsis-induced vascular leakage and mortality in human patients and a murine sepsis model
Bibliographic record
Abstract
BACKGROUND: Vascular leakage is a major cause of multiple organ failure and mortality in sepsis, and factors that regulate endothelial integrity could serve as promising biomarkers of septic shock development. Copine family members (CPNEs) are well-characterized as soluble membrane-binding proteins, whether CPNEs play a critical role in maintaining vascular integrity during sepsis, however, remains unclear. METHODS: Human aorta single-nucleus RNA-sequencing data were analyzed for the expression profile of all Copine family members (CPNE1-9). Plasma levels of CPNE5, Ang-II, sICAM-1, and SDC-1 were measured in human sepsis patients at admission and healthy donors as well as in septic mice induced by injection i.p. with cecal slurry. The correlation of CPNE5 levels to other three factors (Ang-II, sICAM-1, SDC-1) were analyzed. CPNE5-knockdown endothelial cells (ECs) and global CPNE5-knockout (KO) mice were utilized to determine the critical role of CPNE5 in sepsis-triggered vascular leakage, organ damage and mortality. RESULTS: Among nine CPNEs, only CPNE5 is predominantly expressed in human aorta endothelial cells. In sepsis patients (n = 77), plasma levels of CPNE5 were significantly reduced, whereas plasma levels of Ang-II, sICAM-1, and SDC-1 were markedly elevated, compared to healthy donors (n = 44; p < 0.01). Similar findings were also observed in a murine sepsis model induced by cecal slurry (CS)-injection intraperitoneally. Furthermore, in the supernatants of cultured ECs treated with LPS or pro-inflammatory cytokine mixture (Cytomix: TNFα/IL-1β/IFNγ, each 10 ng/mL), the concentrations of CPNE5 were significantly lower, which was negatively correlated with the higher EC permeability, compared to the control group. Accordingly, siRNA-mediated knockdown of CPNE5 in ECs caused hyperpermeability upon stimulation with LPS or Cytomix. In vivo, we observed that loss of CPNE5 increased vascular leakage, leading to severe organ injury and higher mortality, compared to WT mice upon septic conditions. The initial mechanistic analysis showed that the reduction of CPNE5 in cardiac and pulmonary ECs was linked to the increased cleavage of membrane tight junctions and adherens junctions. CONCLUSIONS: These observations from human sepsis patients and a murine sepsis model suggest that reduced plasma levels of CPNE5 may contribute to sepsis-induced vascular leakage and mortality.
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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 | 0.000 |
| 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".