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Item Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance(Ingenta, 2017-07-07) Gao, Bin; Xu, Ming-Jiang; Bertola, Adeline; Wang, Hua; Zhou, Zhou; Liangpunsakul, Suthat; Medicine, School of MedicineAlcoholic liver disease (ALD), a leading cause of chronic liver injury worldwide, comprises a range of disorders including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Over the last five decades, many animal models for the study of ALD pathogenesis have been developed. Recently, a chronic-plus-binge ethanol feeding model was reported. This model induces significant steatosis, hepatic neutrophil infiltration, and liver injury. A clinically relevant model of high-fat diet feeding plus binge ethanol was also developed, which highlights the risk of excessive binge drinking in obese/overweight individuals. All of these models recapitulate some features of the different stages of ALD and have been widely used by many investigators to study the pathogenesis of ALD and to test for therapeutic drugs/components. However, these models are somewhat variable, depending on mouse genetic background, ethanol dose, and animal facility environment. This review focuses on these models and discusses these variations and some methods to improve the feeding protocol. The pathogenesis, clinical relevance, and translational studies of these models are also discussed.Item Blocking porcine sialoadhesin improves extracorporeal porcine liver xenoperfusion with human blood(Wiley, 2013-07) Waldman, Joshua P.; Vogel, Thomas; Burlak, Christopher; Coussios, Constantin; Dominguez, Javier; Friend, Peter; Rees, Michael A.; Surgery, School of MedicineBACKGROUND: Patients in fulminant hepatic failure currently do not have a temporary means of support while awaiting liver transplantation. A potential therapeutic approach for such patients is the use of extracorporeal perfusion with porcine livers as a form of "liver dialysis". During a 72-h extracorporeal perfusion of porcine livers with human blood, porcine Kupffer cells bind to and phagocytose human red blood cells (hRBC) causing the hematocrit to decrease to 2.5% of the original value. Our laboratory has identified porcine sialoadhesin expressed on Kupffer cells as the lectin responsible for binding N-acetylneuraminic acid on the surface of the hRBC. We evaluated whether blocking porcine sialoadhesin prevents the recognition and subsequent destruction of hRBCs seen during extracorporeal porcine liver xenoperfusion. METHODS: Ex vivo studies were performed using wild type pig livers perfused with isolated hRBCs for 72-h in the presence of an anti-porcine sialoadhesin antibody or isotype control. RESULTS: The addition of an anti-porcine sialoadhesin antibody to an extracorporeal porcine liver xenoperfusion model reduces the loss of hRBC over a 72-h period. Sustained liver function was demonstrated throughout the perfusion. CONCLUSIONS: This study illustrates the role of sialoadhesin in mediating the destruction of hRBCs in an extracorporeal porcine liver xenoperfusion model.Item Kupffer Cells: Inflammation Pathways and Cell-Cell Interactions in Alcohol-Associated Liver Disease(Elsevier, 2020) Slevin, Elise; Baiocchi, Leonardo; Wu, Nan; Ekser, Burcin; Sato, Keisaku; Lin, Emily; Ceci, Ludovica; Chen, Lixian; Lorenzo, Sugeily R.; Xu, Wenjuan; Kyritsi, Konstantina; Meadows, Victoria; Zhou, Tianhao; Kundu, Debiyoti; Han, Yuyan; Kennedy, Lindsey; Glaser, Shannon; Francis, Heather; Alpini, Gianfranco; Meng, Fanyin; Surgery, School of MedicineChronic alcohol consumption is linked to the development of alcohol-associated liver disease (ALD). This disease is characterized by a clinical spectrum ranging from steatosis to hepatocellular carcinoma. Several cell types are involved in ALD progression, including hepatic macrophages. Kupffer cells (KCs) are the resident macrophages of the liver involved in the progression of ALD by activating pathways that lead to the production of cytokines and chemokines. In addition, KCs are involved in the production of reactive oxygen species. Reactive oxygen species are linked to the induction of oxidative stress and inflammation in the liver. These events are activated by the bacterial endotoxin, lipopolysaccharide, that is released from the gastrointestinal tract through the portal vein to the liver. Lipopolysaccharide is recognized by receptors on KCs that are responsible for triggering several pathways that activate proinflammatory cytokines involved in alcohol-induced liver injury. In addition, KCs activate hepatic stellate cells that are involved in liver fibrosis. Novel strategies to treat ALD aim at targeting Kupffer cells. These interventions modulate Kupffer cell activation or macrophage polarization. Evidence from mouse models and early clinical studies in patients with ALD injury supports the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with this disease.Item Study of Physiologic and Immunologic Incompatibilities of Pig to Human Transplantation(2014) Chihara, Ray K.; Burlak, Christopher; Tector, A. Joseph; Basile, David P.; Tune, Johnathan D.Solid organ transplantation is limited by available donor allografts. Pig to human transplantation, xenotransplantation, could potentially solve this problem if physiologic and immunologic incompatibilities are overcome. Genetic modifications of pigs have proven valuable in the study of xenotransplantation by improving pig to human compatibility. More genetic targets must be identified for clinical success. First, this study examines platelet homeostasis incompatibilities leading to acute thrombocytopenia in liver xenotransplantation. Mechanisms for xenogeneic thrombocytopenia were evaluated using liver macrophages, Kupffer cells, leading to identification of CD18, beta-2 integrin, as a potential target for modification. When disruption of CD18 was accomplished, human platelet binding and clearance by pig Kupffer cells was inhibited. Further, human and pig platelet surface carbohydrates were examined demonstrating significant differences in carbohydrates known to be involved with platelet homeostasis. Carbohydrate recognition domains of receptors responsible for platelet clearance Macrophage antigen complex-1 (CD11b/CD18) and Asialoglycoprotein receptor 1 in pigs were found to be different from those in humans, further supporting the involvement of platelet surface carbohydrate differences in xenogeneic thrombocytopenia. Second, immunologic incompatibilities due to antibody recognition of antigens resulting in antibody-mediated rejection were studied. Identification of relevant targets was systematically approached through evaluation of a known xenoantigenic protein fibronectin from genetically modified pigs. N-Glycolylneuraminic acid, a sialic acid not found in humans, was expressed on pig fibronectin and was identified as an antigenic epitope recognized by human IgG. These studies have provided further insight into xenogeneic thrombocytopenia and antibody-mediated rejection, and have identified potential targets to improve pig to human transplant compatibility.