Mitochondrial Damage-Associated Molecular Patterns (MTDs) Released from Hepatic Ischemia Reperfusion Induce Inflammatory Response
Bibliographic record
Abstract
Background During liver transplantation ischemia and reperfusion injury (IRI), an immune driven inflammatory response provoked by cellular oxygen deprivation, is unavoidable. The inflammatory responses, resulting from acute oxidative stress and consequent hepatocellular death during the early reperfusion phase, cause the release of damage-associated molecular patterns. Recent studies show that the release of MTDs is directly linked with functionally important immune consequences and injury. We investigated the roles of MTDs in liver IRI. Methods Rat and human hepatocytes were used in the in vitro models, mice were used in an in vivo model of hepatic IR. Liver perfusate samples were obtained from porcine and human normothermic ex vivo liver perfusion (NMP) transplants from our collaborators and correlated to outcomes. MTDs were extracted and quantified by qPCR and PicoGreen assay. Liver biopsies were assayed by transmission electron microscopy (TEM) to assess for damaged mitochondria. MitoTracker was used to test the mitochondrial homeostasis by flow cytometry. The hepatocytes or macrophages were co-cultured with different concentrations of MTDs, and cell viability was demonstrated by apoptosis detection kit; the inflammatory cytokines (TNF-α, IL-6, and IL-1β) were tested by ELISA. Results The MTDs levels were significantly higher in IRI in vitro, and marked mitochondria damage was detected by TEM and flow cytometry. Co-culture of MTDs with hepatocytes significantly increased the cell death in a dose-dependent manner. Co-culture MTDs with macrophages significantly increased proinflammatory cytokine release via TLRs/MyD88 NF-κB pathway. The release of MTDs detected in vivo was associated with inflammatory cytokine secretion and more severe liver injury compared to the control. MTDs acted as an alarmin after hepatic IRI, which might contribute to the initiation of systemic inflammatory response. MTDs levels from pig DCD perfusate were higher than DBD perfusate samples in the pig NMP model, and higher level of MTDs were associated with worse clinical outcome in both the pig and human liver transplants following NMP. Conclusion Our results indicate that IRI can elicit a significant increase of MTDs both in vitro and in vivo, and that MTDs in ex vivo perfusates can be used as potential biomarkers of hepatic IRI and may predict outcomes after liver transplantation.
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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".