Hepatic ischemia/reperfusion (I/R) is a major adverse reaction to liver transplantation, hemorrhagic shock, or resection. Recently, the anti-inflammatory properties of the axonal guidance cue netrin-1 were reported. Here, we demonstrate that netrin-1 also impacts the resolution of inflammation and promotes hepatic repair and regeneration during liver I/R injury. In initial studies, we investigated the induction of netrin-1 and its receptors in murine liver tissues after I/R injury. Hepatic I/R injury was performed in mice with a partial genetic netrin-1 deficiency (Ntn1 1/2 ) or wild-type C57BL/6 treated with exogenous netrin-1 to examine the endogenous and therapeutically administered impact of netrin-1. These investigations were corroborated by studies determining the characteristics of intravascular leukocyte flow, clearance of apoptotic neutrophils (polymorphonuclear cells [PMNs]), production of specialized proresolving lipid mediators (SPMs), generation of specific growth factors contributing to the resolution of inflammation, and liver repair. Hepatic I/R was associated with a significant reduction of netrin-1 transcript and protein in murine liver tissue. Subsequent studies in netrin-1-deficient mice revealed lower efficacies in reducing PMN infiltration, proinflammatory cytokine levels, and hepatic-specific injury enzymes. Conversely, mice treated with exogenous netrin-1 exhibited increased liver protection and repair, reducing neutrophil influx into the injury site, decreasing proinflammatory mediators, increasing efferocytosis of apoptotic PMNs, and stimulating local endogenous biosynthesis of SPMs and the generation of specific growth factors. Finally, genetic studies implicated the A2B adenosine receptor in netrin-1-mediated protection during hepatic I/R injury. Conclusion: The present study indicates a previously unrecognized role for netrin-1 in liver protection and its contribution to tissue homeostasis and regeneration. (HEPATOLOGY 2016;63:1689-1705 SEE EDITORIAL ON PAGE 1427H epatic ischemia/reperfusion (I/R) injury, characterized by the restoration of blood flow and reoxygenation, is a major adverse consequence of liver transplantation, hemorrhagic shock, or major hepatic surgery.(1,2) This underlying interruption of blood flow leads to severe changes in hemodynamic mechanisms. As a result, mortality in patients affected from I/R injury is high, because this disorder may also induce hypoxic hepatitis. This form of hepatic injury is particularly characterized by centrilobular liver cells necrosis. The prognosis in critically ill patients is reported to be poor and is accompanied Abbreviations: 19,19,19,19,20-epoxydocosapentaenoic acid; Adora2b, A2B adenosine receptor; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DAB, 3,3 0 -diaminobenzidine; DAPI, 4 0 ,6-diamidino-2-phenylindole; DCC, DCC netrin-1 receptor; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HB-EGF, heparin-binding epidermal growth factor; HETE, hydroxyeicosatetraenoic acid; HGF, hepatocyte ...

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Key Points Question Does a multimodal nonpharmacological approach prevent delirium in older patients undergoing elective surgical procedures? Findings This stepped-wedge cluster trial recruited 1470 patients 70 years and older who were randomized in 5 clusters to patient-centered evidence-based intervention (ie, personalized stimulation, company, relaxation) vs routine care. The intervention reduced delirium incidence after various major procedures, most significantly in patients undergoing noncardiac surgery; the intervention did not change cardiac surgery postoperative delirium incidence. Meaning Results of this stepped-wedge cluster trial suggest the implementation of this multimodal nonpharmacological delirium prevention program may improve delivery of targeted care and patient outcomes in older patients undergoing elective noncardiac surgical procedures.

Previously unappreciated, the phosphorylation of VASP performs a key function for the formation of PNCs that is crucially important for the extent of myocardial IR injury.