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Abstract

Background: Acetaminophen-induced ALF (AALF) is characterised both by activation of innate immune responses and susceptibility to sepsis. Circulating monocytes and hepatic macrophages are central mediators of inflammatory responses and tissue repair processes during human AALF. Secretory leukocyte protease inhibitor (SLPI) modulates monocyte/macrophage function through inhibition of NF-κB signalling. The aims of this study were to establish the role of SLPI in AALF. Methods: Circulating levels of SLPI, monocyte CD163, HLA-DR and lipopolysaccharide-stimulated levels of NF-κBp65, TNF-α and IL-6 were determined in patients with AALF, chronic liver disease and healthy controls. Immunohistochemistry and multispectral imaging of AALF explant tissue determined the cellular sources of SLPI and hepatic macrophage phenotype. The phenotype and function of monocytes and macrophages was determined following culture with recombinant human (rh)-SLPI, liver homogenates and plasma derived from AALF patients in the presence and absence of anti-human (α)SLPI. Main results: Hepatic and circulatory concentrations of SLPI were elevated in AALF and immunohistochemistry revealed SLPI expression in biliary epithelial cells and within h-mϕ in areas of necrosis. Hepatic macrophages and circulating monocytes in AALF exhibited an anti-inflammatory phenotype and functional characteristics; typified by reductions in NF-κBp65, TNF-α and IL-6 and preserved IL-10 secretion following LPS challenge. Culture of healthy monocytes with AALF liver homogenates, plasma or rhSLPI induced monocytes with strikingly similar anti-inflammatory characteristics which were reversed by inhibiting the activity of SLPI. Conclusion: SLPI is a pivotal mediator of anti-inflammatory responses in AALF through modulation of monocyte/macrophage function which may account for the susceptibility to sepsis in AALF.