Reducing Leukocyte Trafficking Preserves Hepatic Function After Sepsis
Bibliographic record
Abstract
INTRODUCTION: Leukocyte trafficking may induce hepatic dysfunction in sepsis. Herein, we hypothesize that reduction in leukocyte adhesion and, hence, leukocyte-endothelial interaction by activated protein C (aPC) may preserve hepatic function after sepsis. METHODS: Rats underwent sham or cecal ligation and puncture, followed by saline or aPC (1 mg/kg intravenously) infusion, twice daily for 4 days. Cytokine levels were determined by enzyme-linked immunosorbent assay. Liver function and injury were assessed by bile production and plasma aspartate transaminase, respectively. In parallel experiments, neutrophils were labeled with Rhodamine 6G, and trafficking determined by cell motion tracking using intravital microscopy. Leukocyte trafficking and traveling velocity were computed at baseline and at 10 minutes and 40 minutes after endothelin-1 infusion. RESULTS: Sepsis induced 90% mortality and elevated levels of interleukin (IL)-2 (167 pg/mL +/- 39 pg/mL vs. 68 pg/mL +/- 2 pg/mL, p < 0.05), IL-6 (5,806 pg/mL +/- 3,389 pg/mL vs. 0 pg/mL +/- 0 pg/mL, p < 0.05), and IL-8 (492 pg/mL +/- 22 pg/mL vs. 21 pg/mL +/- 17 pg/mL, p < 0.05). Aspartate transaminase levels increased (227 IU/L +/- 14 IU/L vs. 51 IU/L +/- 7 IU/L, p < 0.05) in cecal ligation and puncture animals, whereas bile production decreased by fivefold compared with sham (436 microg/kg/h +/- 247 microg/kg/h vs. 2,357 microg/kg/h +/- 147 microg/kg/h, p < 0.05). Hepatic leukocyte adhesion increased threefold in septic animals (42.7 WBC per image +/- 7.3 WBC per image vs. 14.8 WBC per image +/- 3.8 WBC per image, p < 0.01), whereas leukocyte velocity decreased compared with sham (10.5 microm/s +/- 2.2 microm/s vs. 22.3 microm/s +/- 2.4 microm/s, p < 0.01). By contrast, aPC treatment reduced mortality to 60%, attenuated inflammatory cytokines, reduced leukocyte trafficking, and preserved hepatic function. CONCLUSIONS: Our data demonstrate that sepsis may, in part, induce hepatic dysfunction by augmenting leukocyte trafficking into hepatic sinusoids. Treatment with aPC attenuated leukocyte trafficking and, in doing so, preserved hepatic function and improved survival. Collectively, these data suggest an important role for protein C-dependent leukocyte-endothelial interaction in sepsis.
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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 | 0.000 |
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".