5-108]; P = 0.02), IL-10 (median, 2.0 pg/mL [1.1-2.6] versus median, 0.6 pg/mL [IQR, 0.4-1.8]; P = 0.03) and transforming growth factor-β1 (TGF-β1) (median, 3,364 pg/mL [IQR, 2,416-3,485] versus 681 pg/mL [IQR, 162-1,575]; P < 0.0001). Concentrations of CCL2 Selleckchem X-396 (median, 8,383 pg/mL [IQR, 5,747-45,647] versus median, 329 pg/mL [IQR, 132-3,678]; P = 0.001) and CCL3 (median, 755 pg/mL [IQR, 272-1,997] versus median, 77 pg/mL [IQR, 77-175]; P = 0.0009) followed the same pattern. No significant differences in proinflammatory cytokines (IL-1β, IL-4, IL-12p70, IL-17, IL-23, interferon-γ, and TNF-α)

were detected between AALF and pathological control liver tissue (Supporting Information, Results section; Supporting Table 2). The concentrations of TNF-α, IL-6, IL-10, CCL2, and CCL3 within necrotic areas in all AALF cases were

higher than in the nonnecrotic Nivolumab order areas (Fig. 6), whereas levels of TGF-β1 (median, 292 [IQR, 101-420] versus median, 211 [IQR, 63-514]; P = 1.0) and IL-18 (median, 111 [IQR, 65-229] versus median, 84 [IQR, 35-220]; P = 0.4) were similar. Levels of IL-12p70 (median, <0.2 pg/mL [IQR, 0-0]) and IL-1β (median, 0.25 pg/mL [IQR, 0-0.7]) were barely detectable/undetectable within necrotic areas and those of IL-8 were consistently lower (median, 43 [IQR, 38-74] versus median, 432 [IQR, 189-903]; P = 0.001) in necrotic than

nonnecrotic areas (Fig. 6D). We measured regional levels of TNF-α and IL-10 in five AALF patients at the time of OLT. In four out of five patients sampled, a transhepatic gradient was demonstrated where higher concentrations of IL-10 (715 versus 581 pg/mL; 903 versus 235 pg/mL; 600 versus 554 pg/mL; 349 versus 201 pg/mL; 1,054 versus 1,081 pg/mL) were detected in the hepatic vein than in the portal vein, whereas no discernible transhepatic Cediranib (AZD2171) TNF-α concentration gradient was observed in all five AALF patients sampled (93 versus 97 pg/mL; 25 versus 98 pg/mL; 20 versus 19 pg/mL; 27 versus 45 pg/mL; 24 versus 23 pg/mL). We demonstrate a marked expansion of the h-mϕ population in AALF. Our data suggest that this increased macrophage infiltrate is derived both from circulating monocytes and from the proliferation of the resident Kupffer cell (KC) population. In an APAP rodent model, Holt et al.14 identified a subpopulation of hepatic macrophages, distinct from resident KCs and derived from circulating monocytes, that infiltrated liver tissue within 12 hours and persisted until the resolution of hepatic injury up to 5 days later. Our data are suggestive of a similar process occurring in AALF.