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Karimian, Negin

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Karimian

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Negin

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Karimian, Negin
Author's Publications: search.filters.isAuthorOfPublication.1d7f8a08-f724-4511-bd4c-798350aef46d

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    Endothelial Dysfunction in Steatotic Human Donor Livers: A Pilot Study of the Underlying Mechanism During Subnormothermic Machine Perfusion
    (Lippincott Williams & Wilkins, 2018) Beijert, Irene; Mert, Safak; Huang, Viola; Karimian, Negin; Geerts, Sharon; Hafiz, Ehab O.A.; Markmann, James; Yeh, Heidi; Porte, Robert J.; Uygun, Korkut
    Background: Steatosis is a major risk factor for primary nonfunction in liver transplantations. Steatotic livers recover poorly from ischemia reperfusion injury, in part due to alterations in the microcirculation, although the exact mechanism is unclear. In this study, we tested if there were any alterations in the shear stress sensing Kruppel-like factor 2 (KLF2) and its likely downstream consequences in the ex vivo perfused human liver endothelium, which would imply perturbations in microcirculatory flow in macrosteatotic livers disrupts laminar flow to evaluate if this is a potential therapeutic target for steatotic livers. Methods: Using a subnormothermic machine perfusion system, 5 macrosteatotic and 4 nonsteatotic human livers were perfused for 3 hours. Flow, resistance, and biochemical profile were monitored. Gene expression levels of nitric oxide synthase 3 (eNOS), KLF2, and thrombomodulin were determined. Nitric oxide (NO) was measured in the perfusion fluid and activation of eNOS was measured with Western blotting. Results: Flow dynamics, injury markers, and bile production were similar in both groups. Kruppel-like factor 2 expression was significantly higher in nonsteatotic livers. Western blotting analyses showed significantly higher levels of activated eNOS in nonsteatotic livers, consistent with an increase in NO production over time. Macrosteatotic livers showed decreased KLF2 upregulation, eNOS activity, and NO production during machine perfusion. Conclusions: These results indicate a perturbed KLF2 sensing in steatotic livers, which aligns with perturbed microcirculatory state. This may indicate endothelial dysfunction and contribute to poor posttransplantation outcomes in fatty livers, and further studies to confirm by evaluation of flow and testing treatments are warranted.
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    Functional Human Liver Preservation and Recovery by Means of Subnormothermic Machine Perfusion
    (MyJove Corporation, 2015) Bruinsma, Bote G.; Avruch, James H.; Weeder, Pepijn D.; Sridharan, Gautham V.; Uygun, Basak; Karimian, Negin; Porte, Robert J.; Markmann, James; Yeh, Heidi; Uygun, Korkut
    There is currently a severe shortage of liver grafts available for transplantation. Novel organ preservation techniques are needed to expand the pool of donor livers. Machine perfusion of donor liver grafts is an alternative to traditional cold storage of livers and holds much promise as a modality to expand the donor organ pool. We have recently described the potential benefit of subnormothermic machine perfusion of human livers. Machine perfused livers showed improving function and restoration of tissue ATP levels. Additionally, machine perfusion of liver grafts at subnormothermic temperatures allows for objective assessment of the functionality and suitability of a liver for transplantation. In these ways a great many livers that were previously discarded due to their suboptimal quality can be rescued via the restorative effects of machine perfusion and utilized for transplantation. Here we describe this technique of subnormothermic machine perfusion in detail. Human liver grafts allocated for research are perfused via the hepatic artery and portal vein with an acellular oxygenated perfusate at 21 °C.