Ammonia impairs neutrophil phagocytic function in liver disease

✍ Scribed by Debbie L. Shawcross; Gavin A. K. Wright; Vanessa Stadlbauer; Stephen J. Hodges; Nathan A. Davies; Caroline Wheeler-Jones; Andrew A. Pitsillides; Rajiv Jalan

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 947 KB
• Volume: 48
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.22474

✦ Synopsis

Hyperammonemia is a feature of liver failure, which is associated with increased risk of infection. The aims of the present study were to determine in vitro, in rats fed an ammoniagenic diet and in patients with cirrhosis, whether induction of hyperammonemia results in neutrophil dysfunction. As hyperammonemia produces cell swelling, we explored the role of the osmoregulating, p38 mitogen-activated protein kinase (p38 MAPK ) pathway in mediating this neutrophil dysfunction. Neutrophils were isolated from blood of healthy volunteers and incubated with either 75 M ammonia or phosphate-buffered saline. Both groups were studied under hyponatremic conditions and/or with the addition of p38 MAPK modulators. Neutrophil phagocytosis was measured in naive rats and rats fed an ammoniagenic diet and in patients with stable cirrhosis given placebo (n ‫؍‬ 8) or an amino acid solution inducing hyperammonemia (n ‫؍‬ 8). Cell volume and phagocytosis was analyzed by fluorescentactivated cell sorting using fluorescein isothiocyanate-labeled E. coli. p38 MAPK phosphorylation was measured by western blotting. In healthy neutrophils incubated with ammonia and in rats fed an ammoniagenic diet, neutrophils showed evidence of swelling, impaired phagocytosis, and increased spontaneous oxidative burst compared to controls. Phagocytosis was significantly impaired in patients with induced hyperammonemia compared to placebo. The effects of hyperammonemia and hyponatremia were synergistic. The p38 MAPK intracellular signaling pathways were activated in healthy neutrophils exposed to ammonia in association with increased burst activity. Neutrophil phagocytic dysfunction was abrogated by the addition of a p38 MAPK agonist. Conclusion: Ammonia produces neutrophil swelling and impairs neutrophil phagocytosis. The p38 MAPK intracellular signaling pathway has been shown to be important in mediating the ammonia-induced neutrophil dysfunction.