Necroptosis is a recently described Caspase 8-independent method of cell death that denotes organized cellular necrosis. The roles of RIP1 and RIP3 in mediating hepatocyte death from acute liver injury are incompletely defined. Effects of necroptosis blockade were studied by separately targeting RIP1 and RIP3 in diverse murine models of acute liver injury. Blockade of necroptosis had disparate effects on disease outcome depending on the precise etiology of liver injury and component of the necrosome targeted. In ConA-induced autoimmune hepatitis, RIP3 deletion was protective, whereas RIP1 inhibition exacerbated disease, accelerated animal death, and was associated with increased hepatocyte apoptosis. Conversely, in acetaminophen-mediated liver injury, blockade of either RIP1 or RIP3 was protective and was associated with lower NLRP3 inflammasome activation. Our work highlights the fact that diverse modes of acute liver injury have differing requirements for RIP1 and RIP3; moreover, within a single injury model, RIP1 and RIP3 blockade can have diametrically opposite effects on tissue damage, suggesting that interference with distinct components of the necrosome must be considered separately.

Background & Aims Subsets of leukocytes synergize with regenerative growth factors to promote hepatic regeneration. γδT cells are early responders to inflammation-induced injury in a number of contexts. We investigated the role of γδT cells in hepatic regeneration using mice with disruptions in Tcrd (encodes the T cell receptor δ chain) and Clec7a (encodes C-type lectin domain family 7 member a, also known as DECTIN1). Methods We performed partial hepatectomies on wild-type C57BL/6, CD45.1, Tcrd−/−, or Clec7a−/− mice. Cells were isolated from livers of patients and mice via mechanical and enzymatic digestion. γδT cells were purified by fluorescence-activated cell sorting. Results In mice, partial hepatectomy upregulated expression of CCL20 and ligands of Dectin-1, associated with recruitment and activation of γδT cells and their increased production of interleukin (IL)17 family cytokines. Recruited γδT cells induced production of IL6 by antigen-presenting cells and suppressed expression of interferon γ by natural killer T cells, promoting hepatocyte proliferation. Absence of IL17-producing γδT cells or deletion of Dectin-1 prevented development of regenerative phenotypes in subsets of innate immune cells. This slowed liver regeneration and was associated with reduced expression of regenerative growth factors and cell cycle regulators. Conversely, exogenous administration of IL17 family cytokines or Dectin-1 ligands promoted regeneration. More broadly, we found that γδT cells are required for inflammatory responses mediated by IL17 and Dectin-1. Conclusions γδT cells regulate hepatic regeneration by producing IL22 and IL17, which have direct mitogenic effects on hepatocytes and promote a regenerative phenotype in hepatic leukocytes, respectively. Dectin-1 ligation is required for γδT cells to promote hepatic regeneration.

Background & Aims: Per-oral cholangioscopy with intraductal lithotripsy facilitates optically-guided stone fragmentation of difficult biliary stones refractory to conventional endoscopic therapy. The aim of this study was to evaluate the efficacy and safety of per-oral cholangioscopy with intraductal lithotripsy for difficult biliary stones. Methods: Searches of PubMed, EMBASE, Web of Science, and Cochrane databases were performed in accordance with PRISMA and MOOSE guidelines. Measured outcomes included overall fragmentation success, single-session fragmentation and duct clearance, and rate of adverse events. Sensitivity and subgroup analyses were performed based upon cholangioscopy technique and type of lithotripsy (laser versus electrohydraulic). Heterogeneity was assessed with I2 statistics. Publication bias was ascertained by funnel plot and Egger regression testing. Results: Thirty-five studies (n=1762; 43.36% male) were included. Mean age was 61.46±10.98 years. Thirty-seven percent of patients had prior cholecystectomy with a mean number of 1.56±0.49 ERCPs performed prior to lithotripsy. Mean stone size was 1.80±0.32 cm. Per-oral cholangioscopy with intraductal lithotripsy achieved an overall stone fragmentation success of 91.22% (95% CI 88.14-93.56;I2=63.16%) with an average of 1.32±0.62 lithotripsy sessions performed. Complete single-session fragmentation success was 76.86% (95% CI 71.55-81.44;I2=74.33%). Rate of adverse events was 8.94% (95% CI 6.50-12.17;I2=60.66%). Mean procedure time for per-oral cholangioscopy was 68.32±20.99 minutes. There was no difference in overall fragmentation rate or adverse events; however, laser lithotripsy was associated with a higher single-session fragmentation rate and shorter procedure time compared to electrohydraulic lithotripsy. Conclusions: Per-oral cholangioscopy with intraductal lithotripsy appears to be a relatively safe and effective modality for difficult biliary stones.

Patient reading materials reviewed in this study were written well above the recommended reading grade level. These findings suggest review of patient education materials in an effort to close the gap between the average reading level and the reading materials.

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/11-2-reading-gulati.html a video presentation of this article