Evaluation of the Complement System and Human Complement 1 Inhibitor (C1-INH) in a Pig Lung Transplant Survival Model.
Bibliographic record
Abstract
Background: Primary graft dysfunction is the leading cause of early morbidity and mortality following lung transplantation. Inhibition of complement has been shown to be beneficial in human and animal studies related to lung transplantation. Our objective was to test the safety and efficacy of human complement 1 inhibitor (C1-INH) in a pre-clinical large animal lung transplant survival model. Methods: Yorkshire male pigs (25-35 kg) were used. Donor lungs were harvested and preserved for 24h at 4°C followed by left single lung transplantation. Animals in the control arm (n=5) received saline, and in the treatment arm (n=4) received 200 IU/kg of C1-INH one hour before reperfusion. Animals were kept alive for 3 days. Systemic blood samples were taken before thoracotomy and at 1, 6, 24, 48, and 72h after reperfusion. The complement system was evaluated with hemolytic assays and an ELISA-based functional assay. Results: All animals in the control arm survived to sacrifice on postoperative day 3. Two out of 4 animals in the treatment arm, however, developed graft failure and the experiments were terminated within the first postoperative day. Autopsy showed major right pulmonary artery thrombus in one and bronchial casts in the both failed animals. Human C1-INH dose-dependently blocked pig classical and lectin complement activation in vitro. However, the complement system, as determined by CH50 and C3H50 activity, was not significantly activated. Moreover, there was more complement activation in the sera of treated animals, especially for the lectin pathway. Pro-inflammatory cytokine IL-6 level was significantly higher in the treatment arm as well. Conclusions: In contrast to data from clinical and experimental lung transplantation, complement activation does not seem to be a major mechanism of ischemia-reperfusion related lung injury in this pig model. Administration of human C1-INH caused systemic and local side effects on pigs underwent lung transplantation after prolonged cold ischemia. For large animal pre-clinical trials, models with significant complement activation would be preferred for evaluation of the potential efficacy and safety oh human C1-INH in lung transplant setting. This project was partially supported by Canadian Institutes of Health Research and CSL Behring.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 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".