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To the Editor:

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.

References

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  • 1
    Marques PE, Amaral SS, Pires DA, Nogueira LL, Soriani FM, Lima BHF, et al. Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure. HEPATOLOGY 2012. DOI: 10.1002/hep.25801.
  • 2
    McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest 2012; 122: 1574-1583.
  • 3
    Jaeschke H, Liu J. Neutrophil depletion protects against murine acetaminophen hepatotoxicity: another perspective. HEPATOLOGY 2007; 45: 1588-9158.
  • 4
    Jaeschke H. Innate immunity and acetaminophen-induced liver injury: why so many controversies? HEPATOLOGY 2008; 48: 699-701.
  • 5
    Jaeschke H, Williams CD, Ramachandran A, Bajt ML. Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity. Liver Int 2012; 32: 8-20.
  • 6
    Cover C, Liu J, Farhood A, Malle E, Waalkes MP, Bajt ML, et al. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 2006; 216: 98-107.

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.