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Background & objectivesAlcoholic hepatitis (AH) is a common but life-threatening disease with limited treatment options. It is thought to result from hepatocellular damage, but the presence of cholestasis worsens prognosis, so we examined whether bile ducts participate in the pathogenesis of this disease.DesignCholangiocytes derived from human bile ducts were co-cultured with neutrophils from patients with AH or controls. Loss of type 3 inositol 1,4,5-trisphosphate receptor (ITPR3), an apical intracellular calcium channel necessary for cholangiocyte secretion, was used to reflect cholestatic changes. Neutrophils in contact with bile ducts were quantified in liver biopsies from patients with AH and controls and correlated with clinical and pathological findings.ResultsLiver biopsies from patients with AH revealed neutrophils in contact with bile ducts, which correlated with biochemical and histological parameters of cholestasis. Cholangiocytes co-cultured with neutrophils lost ITPR3, and neutrophils from patients with AH were more potent than control neutrophils. Biochemical and histological findings were recapitulated in an AH animal model. Loss of ITPR3 was attenuated by neutrophils in which surface membrane proteins were removed. RNA-seq analysis implicated integrin β1 (ITGB1) in neutrophil-cholangiocyte interactions and interference with ITGB1 on cholangiocytes blocked the ability of neutrophils to reduce cholangiocyte ITPR3 expression. Cell adhesion molecules on neutrophils interacted with ITGB1 to trigger RAC1-induced JNK activation, causing a c-Jun-mediated decrease in ITPR3 in cholangiocytes.ConclusionsNeutrophils bind to ITGB1 on cholangiocytes to contribute to cholestasis in AH. This previously unrecognised role for cholangiocytes in this disease alters our understanding of its pathogenesis and identifies new therapeutic targets.

Oxalis trilliifolia Hooker (1831:118; as “trilliifolium”) is distributed in western North America. The species was previously treated in a monotypic genus as Hesperoxalis triliifolia (Hook.) Small (1907: 27). However, it was recently included in Oxalis subsect. Oxalis by Lourteig (2000). It was the only species that could not be included in our previous phylogenetic analysis of O. subsect. Oxalis (Aoki et al. 2017). After the publication of our previous study, we obtained one DNA sample of O. trilliifolia from the DNA Bank of the Missouri Botanical Garden, i.e., MO-275113, which was collected from Oregon, USA. We confirmed a duplicate sheet of its voucher specimen that was deposited in herbarium P (Porter P. Lowry II 5059), even though we were unable to find the voucher specimen at MO. Therefore, its phylogenetic position was provided here, following the protocol from our previous study (Aoki et al. 2017).

Draf type II and III procedures with lacrimal sac exposure and a superior lateral anterior pedicle flap are convenient and seem to be effective. However, further studies with larger numbers of patients are needed to verify our technique.