Pathophysiological relevance of neutrophils in acetaminophen hepatotoxicity
Bibliographic record
Abstract
We read with interest the recent article by Marques et al.1 on the release of damage-associated molecular patterns during acetaminophen (APAP) hepatotoxicity in mice and humans. We were pleased to learn that the authors were able to confirm certain previously published data, especially the release of mitochondrial products in human pathophysiology, which we recently reported.2 However, we have concerns regarding the conclusion that neutrophils are aggravating APAP-induced hepatotoxicity based on the data presented.1 Pretreatment with the neutropenia-inducing antibody Gr-1 induces a preconditioning effect with up-regulation of numerous genes, many of which are highly protective against APAP hepatotoxicity.3 Thus, no reliable conclusions regarding the involvement of neutrophils can be obtained from these experiments. These data have been presented in the past and the problems have been extensively discussed.3-5 It is puzzling that the authors simply repeated the same mistakes that were previously pointed out. In contrast, treatment with Gr-1 after APAP did not affect liver injury6 and there is no evidence that neutrophils are even activated or primed during the major injury phase.5 The report that coincubation of isolated neutrophils with hepatoma cells leads to cell killing in vitro has no relevance for an alleged neutrophil-induced liver injury during APAP hepatotoxicity in vivo. These experimental conditions have nothing in common with the mechanism of APAP hepatotoxicity or neutrophil-induced killing of hepatocytes in vivo. The beneficial effect of drugs that are receptor antagonists for CXC chemokine receptor 2 and formyl-peptide receptor 1 is interesting. However, the authors have not tested if any of the drugs or the solvents affected the metabolic activation of APAP, which is critical for sound mechanistic interpretation of the data, or if they had off-target effects that could lead to protection independent of the receptor antagonism. In addition, evaluating only a single late timepoint with reduced injury and fewer neutrophils is insufficient, as the decrease in neutrophil infiltration could simply be a consequence of less liver injury. Taken together, the present study, which in part repeats previous experiments and mistakes, does not support the hypothesis that neutrophils are critical for APAP hepatotoxicity. Hartmut Jaeschke Ph.D.*, Mitchell R. McGill B.Sc.*, C. David Williams B.Sc.*, * Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS.
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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 | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.002 | 0.003 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.008 | 0.006 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".