Editors' ChoiceLiver disease

PGE2—The Immune System Tamer

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Science Translational Medicine  30 Apr 2014:
Vol. 6, Issue 234, pp. 234ec75
DOI: 10.1126/scitranslmed.3009255

Although most of us do not realize it, the immune system is constantly fending off infections on our behalf. It is only when it starts misfiring, leading to more frequent and severe infections, that we truly grasp the critical role played by this inconspicuous infantry. Chronic liver disease (CLD) and cirrhosis cause ~35,000 deaths each year in the United States, and bacterial infections are an important source of morbidity and mortality for these patients. It has long been hypothesized that this susceptibility to infections is caused by immunosuppression, but the underlying pathophysiology remained elusive. Now, a study by O’Brien et al. provides convincing evidence that immune dysfunction associated with liver cirrhosis is at least partly caused by two surprising coconspirators: prostaglandin E2 (PGE2) and albumin.

The authors used liquid chromatography coupled to mass spectrometry to compare plasma analytes in samples from 14 patients with CLD admitted to hospital for acute cirrhotic decompensation (AD) and eight from healthy controls. They found that PGE2 levels were 7 times higher in plasma from AD patients, and that adding either PGE2 at physiologic concentrations, or plasma from these patients, was sufficient to reduce macrophage activation triggered by bacterial lipopolysaccharides (LPSs). Because albumin binds to PGE2, and patients with diseased livers invariably have inadequate albumin production, the authors reasoned that hypoalbuminemia severity could be a determinant of free, bioactive PGE2 levels. They tested whether—and confirmed that—adding albumin to AD plasma samples in the laboratory restored normal LPS-induced macrophage activation. In parallel experiments, the authors showed that plasma samples from two mouse models of liver cirrhosis had characteristics similar to those of AD patients. Because COX-2 is a key enzyme in PGE2 metabolism, they treated cirrhotic mice with a nonselective COX inhibitor (indomethacin); it improved both bacterial killing and survival after a bacteremic challenge.

These data show that the interplay between elevated PGE2 levels and hypoalbuminemia interferes with normal immune functions in AD patients. Unfortunately, neither COX-2 inhibitors nor albumin infusions are suitable for long-term prophylaxis against bacterial infections in these patients; the first one is contraindicated, and the second is impractical. New targets may be identified, however, once researchers discover why PGE2 levels are so high in patients with severe liver diseases.

A. J. O’Brien et al., Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nat. Med., published online 13 April 2014 (10.1038/nm.3516). [PubMed]

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