24 Neutrophils are also likely to contribute to liver injury in ALF, resulting from their overwhelming capacity to produce large quantities of ROS and proteases following recruitment and activation within the hepatic sinusoids. For this reason, the relationship between circulating neutrophil function and the progression and outcomes of acute liver injury was therefore explored in this study. The observation of a reduction in

NPA in ALF/SALF cohorts akin to that frequently Decitabine solubility dmso observed in sepsis8 may explain why patients with ALF exhibit phenotypic features of septic shock with microvascular dysfunction, hemodynamic instability, coagulopathy, encephalopathy, MODS, and high levels of circulating proinflammatory cytokines. Why the severity of NPA is less so in those presenting with ALF compared AZD6244 in vivo to SALF is less clear but the development of impaired NPA may occur in a time-dependent manner, as evidenced by the most severe reduction in phagocytic ability seen in cases of SALF, where the liver injury takes on a more insidious course over several weeks. Indeed, many patients with established SALF may present with moderate portal hypertension with features of splenomegaly and ascites. Nevertheless, NPA on admission appears to be a predictor of spontaneous survival compared to conventional organ

failure scores such as SOFA and MELD, which did not predict poor outcome in this study. Trying to understand the relationship between neutrophil phagocytic dysfunction and poor prognosis therefore seems critical. LT resulted in rapid improvement of neutrophil phagocytic function within 72 hours but not complete reversal, which could be the result of ischemia-reperfusion phenomena, ongoing production of proinflammatory cytokines/SIRS, or sepsis. The incidence of “culture-positive” sepsis was low in this ALF/SALF cohort medchemexpress overall, and indeed the deaths could not be directly attributed to infection, suggesting phagocytic dysfunction is either a reflection of general immune

activation or a specific factor related to liver failure. Peak plasma ammonia levels demonstrated a robust correlation with poor phagocytic function in SALF and high circulating levels of IL-10 and IL-17. Ammonia was previously shown to impair NPA and induce spontaneous OB in healthy neutrophils exposed to supraphysiological concentrations of ammonia ex vivo and in rats fed an ammonia-rich diet.11 The peak arterial ammonia concentration did not, however, correlate with impaired NPA in the ALF cohort but might be attributed to the impact of rapid ammonia reduction by continuous veno-venous hemofiltration prior to neutrophil sampling. Pro- and antiinflammatory cytokine profiles might be expected to show a closer association with neutrophil OB than phagocytic activity, although this was not generally the case.