Christopher Monti, Seung-Keun Hong, Alice Lee, Johnny C Hong, Calvin M Eriksen, Amit Joshi, Ranjan K Dash, Said H Audi, Whayoung Lee, Suresh N Kumar, Joohyun Kim
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Under ischemic stress, multidrug resistance-associated protein 2 (MRP2) translocates from the hepatocyte membrane to the cytoplasm, resulting in loss of function.</p><p><strong>Methods: </strong>We measured the cytoplasmic proportion of MRP2 (MRP2 internalization index, MII) by immunofluorescence colocalization analysis using CD13 as a canalicular membrane marker.</p><p><strong>Results: </strong>The data showed that MII significantly correlated with ischemia time in both in situ ischemia-reperfusion injury and NMP rat models (R 2 = 0.331, P < 0.0001; R 2 = 0.632, P < 0.0001, respectively). Perfusate levels of liver injury markers at the end of NMP showed a significant positive correlation with MII for aspartate aminotransferase (R² = 0.444, P = 0.0013) and arginase 1 (R² = 0.637, P < 0.0001). Conversely, bile production exhibited a significant inverse correlation with MII (R² = 0.618, P < 0.0001). The maximum transport rate of MRP2 ( Vmax,MRP2 ), derived from kinetic modeling of sodium fluorescein biliary excretion, showed a significant inverse correlation with ischemia time (R 2 = 0.326, P = 0.0086) and MII (R 2 = 0.554, P = 0.0002). In human LT, MII values from donor liver biopsies preLT correlated significantly with peak postLT serum aminotransferase levels (R 2 = 0.398, P = 0.0007).</p><p><strong>Conclusions: </strong>MRP2 is a putative biomarker for the assessment of hepatic ischemia-reperfusion injury. The biliary excretion kinetics of sodium fluorescein reflects MRP2-mediated transport activity, providing a novel diagnostic method for predicting liver graft viability after LT.</p>","PeriodicalId":23316,"journal":{"name":"Transplantation","volume":" ","pages":"1495-1505"},"PeriodicalIF":5.0000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Acute Response of Hepatocyte MRP2 Internalization as an Indicator of Ischemia-reperfusion Injury in Liver Transplantation.\",\"authors\":\"Christopher Monti, Seung-Keun Hong, Alice Lee, Johnny C Hong, Calvin M Eriksen, Amit Joshi, Ranjan K Dash, Said H Audi, Whayoung Lee, Suresh N Kumar, Joohyun Kim\",\"doi\":\"10.1097/TP.0000000000005418\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The introduction of normothermic machine perfusion (NMP) offers new opportunities to evaluate liver graft viability before liver transplantation (LT). Under ischemic stress, multidrug resistance-associated protein 2 (MRP2) translocates from the hepatocyte membrane to the cytoplasm, resulting in loss of function.</p><p><strong>Methods: </strong>We measured the cytoplasmic proportion of MRP2 (MRP2 internalization index, MII) by immunofluorescence colocalization analysis using CD13 as a canalicular membrane marker.</p><p><strong>Results: </strong>The data showed that MII significantly correlated with ischemia time in both in situ ischemia-reperfusion injury and NMP rat models (R 2 = 0.331, P < 0.0001; R 2 = 0.632, P < 0.0001, respectively). Perfusate levels of liver injury markers at the end of NMP showed a significant positive correlation with MII for aspartate aminotransferase (R² = 0.444, P = 0.0013) and arginase 1 (R² = 0.637, P < 0.0001). Conversely, bile production exhibited a significant inverse correlation with MII (R² = 0.618, P < 0.0001). The maximum transport rate of MRP2 ( Vmax,MRP2 ), derived from kinetic modeling of sodium fluorescein biliary excretion, showed a significant inverse correlation with ischemia time (R 2 = 0.326, P = 0.0086) and MII (R 2 = 0.554, P = 0.0002). In human LT, MII values from donor liver biopsies preLT correlated significantly with peak postLT serum aminotransferase levels (R 2 = 0.398, P = 0.0007).</p><p><strong>Conclusions: </strong>MRP2 is a putative biomarker for the assessment of hepatic ischemia-reperfusion injury. 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引用次数: 0
摘要
背景：常温机器灌注（NMP）的引入为肝移植（LT）前评估肝移植活力提供了新的机会。缺血应激下，多药耐药相关蛋白2 （MRP2）从肝细胞膜转移到细胞质，导致功能丧失。方法：采用免疫荧光共定位分析法，以CD13作为小管膜标记物，测定MRP2的胞质比例（MRP2内化指数，MII）。结果：数据显示，原位缺血再灌注损伤模型和NMP模型大鼠的MII均与缺血时间显著相关(R2 = 0.331, P < 0.0001；R2 = 0.632, P < 0.0001)。NMP结束时肝损伤标志物灌注液水平与MII呈显著正相关：天冬氨酸转氨酶（R²= 0.444,P = 0.0013）、精氨酸酶1 （R²= 0.637,P < 0.0001）。相反，胆汁生成与MII呈显著负相关（R²= 0.618,P < 0.0001）。荧光素钠胆排泄动力学模型得出的MRP2最大转运率（Vmax,MRP2）与缺血时间（R2 = 0.326, P = 0.0086）和MII （R2 = 0.554, P = 0.0002）呈显著负相关。在人肝移植中，肝移植前供体肝活检的MII值与肝移植后血清转氨酶水平峰值显著相关（R2 = 0.398, P = 0.0007）。结论：MRP2可能是评估肝缺血再灌注损伤的生物标志物。荧光素钠的胆道排泄动力学反映了mrp2介导的转运活性，为预测肝移植后肝移植存活提供了一种新的诊断方法。
Acute Response of Hepatocyte MRP2 Internalization as an Indicator of Ischemia-reperfusion Injury in Liver Transplantation.
Background: The introduction of normothermic machine perfusion (NMP) offers new opportunities to evaluate liver graft viability before liver transplantation (LT). Under ischemic stress, multidrug resistance-associated protein 2 (MRP2) translocates from the hepatocyte membrane to the cytoplasm, resulting in loss of function.
Methods: We measured the cytoplasmic proportion of MRP2 (MRP2 internalization index, MII) by immunofluorescence colocalization analysis using CD13 as a canalicular membrane marker.
Results: The data showed that MII significantly correlated with ischemia time in both in situ ischemia-reperfusion injury and NMP rat models (R 2 = 0.331, P < 0.0001; R 2 = 0.632, P < 0.0001, respectively). Perfusate levels of liver injury markers at the end of NMP showed a significant positive correlation with MII for aspartate aminotransferase (R² = 0.444, P = 0.0013) and arginase 1 (R² = 0.637, P < 0.0001). Conversely, bile production exhibited a significant inverse correlation with MII (R² = 0.618, P < 0.0001). The maximum transport rate of MRP2 ( Vmax,MRP2 ), derived from kinetic modeling of sodium fluorescein biliary excretion, showed a significant inverse correlation with ischemia time (R 2 = 0.326, P = 0.0086) and MII (R 2 = 0.554, P = 0.0002). In human LT, MII values from donor liver biopsies preLT correlated significantly with peak postLT serum aminotransferase levels (R 2 = 0.398, P = 0.0007).
Conclusions: MRP2 is a putative biomarker for the assessment of hepatic ischemia-reperfusion injury. The biliary excretion kinetics of sodium fluorescein reflects MRP2-mediated transport activity, providing a novel diagnostic method for predicting liver graft viability after LT.
期刊介绍：
The official journal of The Transplantation Society, and the International Liver Transplantation Society, Transplantation is published monthly and is the most cited and influential journal in the field, with more than 25,000 citations per year.
Transplantation has been the trusted source for extensive and timely coverage of the most important advances in transplantation for over 50 years. The Editors and Editorial Board are an international group of research and clinical leaders that includes many pioneers of the field, representing a diverse range of areas of expertise. This capable editorial team provides thoughtful and thorough peer review, and delivers rapid, careful and insightful editorial evaluation of all manuscripts submitted to the journal.
Transplantation is committed to rapid review and publication. The journal remains competitive with a time to first decision of fewer than 21 days. Transplantation was the first in the field to offer CME credit to its peer reviewers for reviews completed.
The journal publishes original research articles in original clinical science and original basic science. Short reports bring attention to research at the forefront of the field. Other areas covered include cell therapy and islet transplantation, immunobiology and genomics, and xenotransplantation.
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