Jacob Asha, Wang Zhimin, Yen Hao Ting, Wang Ping
Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA.
Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA.
Heliyon. 2021 Aug 20;7(8):e07845. doi: 10.1016/j.heliyon.2021.e07845. eCollection 2021 Aug.
Liver injury caused by ischemia reperfusion (I/R) during surgical procedures, such as liver resection or liver transplantation, is a major cause of liver damage and graft failure. The current method of treatment is mostly preventative (i.e., ischemic preconditioning). While a number of pharmacological modalities have been studied to reduce hepatic I/R injury, none have been entirely successful. It has been demonstrated that the administration of adrenomedullin (AM) in combination with AM-binding protein (AM/AMBP-1) exerts significant protective effects in various pathological conditions. In an effort to develop AM/AMBP-1 as a novel therapeutic for hepatic I/R injury, the present study examined the effect of a low dose of human AM, which does not induce hypotension, in combination with human AMBP-1 in a rabbit model of hepatic I/R (i.e., non-rodent species).
Ischemia of 70% of the liver was induced by placing a microvascular clip across the hilum of the left and median lobes for 60 min. The clip was then removed to commence reperfusion. At 15 min following clip removal (i.e., reperfusion), human AM/AMBP-1 was administered intravenously via the ear marginal vein continuously for 30 min. At 20 h, blood and tissue samples were collected for various measurements.
The serum levels of liver enzymes (alanine aminotransferase and aspartate aminotransferase) and lactate dehydrogenase, were elevated following hepatic I/R. The administration of AM/AMBP-1 significantly decreased these levels by 58, 44, 41%, respectively. Hepatic I/R increased the direct and total bilirubin levels, whereas treatment with human AM/AMBP-1 decreased these levels by 60% and 69%, respectively. Treatment with AM/AMBP-1 also inhibited interleukin-6 gene expression by 95%. There were no changes in tumor necrosis factor-α (TNF-α) gene expression and myeloperoxidase activity (MPO), lactate and Suzuki scores after treatment. The treatment, however, reduced apoptosis post-hepatic I/R in the ischemic portion of the liver.
Additional experiments with AM and AMBP-1 alone are needed to completely interpret the experimental results in this non-rodent species of hepatic I/R injury. The present study suggests that human AM/AMBP-1 may be developed as a novel therapeutic to attenuate hepatic I/R associated inflammation and liver injury.
在诸如肝切除术或肝移植等外科手术过程中，缺血再灌注（I/R）所导致的肝损伤是肝损伤和移植物功能衰竭的主要原因。目前的治疗方法大多是预防性的（即缺血预处理）。虽然已经研究了多种药理学方法来减轻肝脏I/R损伤，但均未完全成功。已经证明，给予肾上腺髓质素（AM）与AM结合蛋白（AM/AMBP-1）在各种病理状况下发挥显著的保护作用。为了开发AM/AMBP-1作为治疗肝脏I/R损伤的新型疗法，本研究在肝脏I/R兔模型（即非啮齿类动物）中研究了低剂量、不引起低血压的人AM与人AMBP-1联合使用的效果。
通过在左叶和中叶肝门处放置微血管夹60分钟，诱导70%的肝脏缺血。然后移除夹子开始再灌注。在移除夹子后15分钟（即再灌注时），通过耳缘静脉静脉内连续给予人AM/AMBP-1 30分钟。在20小时时，采集血液和组织样本进行各种测量。
肝脏I/R后，肝酶（丙氨酸转氨酶和天冬氨酸转氨酶）和乳酸脱氢酶的血清水平升高。给予AM/AMBP-1分别使这些水平显著降低了58%、44%、41%。肝脏I/R增加了直接胆红素和总胆红素水平，而用人AM/AMBP-1治疗分别使这些水平降低了60%和69%。用AM/AMBP-1治疗还使白细胞介素-6基因表达抑制了95%。治疗后肿瘤坏死因子-α（TNF-α）基因表达、髓过氧化物酶活性（MPO）、乳酸和铃木评分没有变化。然而，该治疗减少了肝脏缺血部分肝脏I/R后的细胞凋亡。
需要单独用AM和AMBP-1进行更多实验，以完全解释该非啮齿类动物肝脏I/R损伤实验结果。本研究表明，人AM/AMBP-1可开发为一种新型疗法，以减轻肝脏I/R相关炎症和肝损伤。
