LIVER

Improving hepatic ischaemia–reperfusion injury outcomes

Two new studies have extended our understanding of hepatic ischaemia–reperfusion injury (IRI), demonstrating how antibiotic pretreatment can improve outcomes in liver transplant recipients and finding that the administration of small-molecule inhibitors of cyclophilin D (CypD) can protect against this injury in mice.

Hepatic IRI is a pro-inflammatory response initiated when blood circulation is restored to tissues after a period of ischaemia. Despite being a major cause of early allograft dysfunction (EAD) following liver transplantation, and contributing to the problem of donor organ shortage, the mechanisms of IRI are not well understood and new treatment and prevention strategies are needed.

In the first of the new studies, a team of researchers built on other experimental studies that showed an effect of the microbiota in the survival of skin and heart allografts. Here, they examined how modifications of the gut microbiota with antibiotic pretreatment might affect hepatic IRI and liver transplantation outcomes.

First, using a clinically relevant allogeneic mouse model of orthotopic liver transplantation, 10-day antibiotic pretreatment in recipients was found to increase gut-derived prostaglandin E2 (PGE2) serum levels and the subsequent hepatic expression of the PGE2 receptor, EP4. In an EP4-dependent manner, antibiotic pretreatment decreased and increased markers of endoplasmic reticulum (ER) stress and autophagy, respectively, which are thought to protect against hepatic IRI. Indeed, 10-day antibiotic pretreatment in recipients conferred IRI protection in this mouse model, whereas an EP4 antagonist restored ER stress, decreased autophagy and recreated hepatic IRI.

In humans, the investigators found that patients who received a prolonged antibiotic regimen (≥10 days) prior to liver transplantation recapitulated the findings related to ER stress and autophagy from the mouse model, which coincided with improved liver function and a decreased incidence of EAD. Concluding their work on IRI and liver transplantation, the researchers say, “by integrating mouse and human data, our study clearly underscores the benefits of extended recipient antibiotic pretreatment.”

One mechanism for IRI involves mitochondrial dysfunction, in which CypD-regulated mitochondrial permeability transition pore (mPTP) opening is increased. In the second new study, the effects of nine small-molecule inhibitors of CypD were examined in cell models and in livers of mice undergoing hepatic IRI.

The researchers first identified the most potent CypD inhibitor in mouse livers and primary human hepatocytes. Using an assay of CypD activity with isolated hepatic mitochondria, the effects of the inhibitors on mPTP opening were assessed by measuring mitochondrial swelling and calcium retention.

The investigators then induced IRI in the livers of mice and administered an inhibitor or vehicle before and during reperfusion, collecting samples of blood and liver for histological analyses. In mice with hepatic IRI, they found that administration of the potent CypD inhibitor restored hepatic calcium retention capacity and oxidative phosphorylation parameters, and reduced liver damage compared with vehicle. The authors suggest that these compounds could be developed to protect patients from IRI after liver surgery or for other disorders related to mPTP opening.

References

Original articles

  1. Nakamura, K. et al. Antibiotic pretreatment alleviates liver transplant damage in mice and humans. J. Clin. Invest. 129, 3420–3434 (2019)

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  2. Panel, M. et al. Small-molecule inhibitors of cyclophilins block opening of the mitochondrial permeability transition pore and protect mice from hepatic ischemia–reperfusion injury. Gastroenterology https://doi.org/10.1053/j.gastro.2019.07.026 (2019)

    Article  PubMed  Google Scholar 

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Correspondence to Iain Dickson.

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Dickson, I. Improving hepatic ischaemia–reperfusion injury outcomes. Nat Rev Gastroenterol Hepatol 16, 583 (2019). https://doi.org/10.1038/s41575-019-0194-y

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