A Novel Therapeutic Approach for Liver Injury

描述(申请人提供)：肝脏缺血再灌注(I/R)引起的肝脏损伤是严重创伤、热损伤、失血性和感染性休克、肝切除或肝移植后肝功能衰竭的主要原因。肝脏I/R在多器官功能衰竭和死亡率中起重要作用。虽然已经研究了各种方法和物质来降低肝脏I/R诱导的死亡率，但没有一种方法和物质完全成功。因此，开发新的治疗方法来预防或至少减少肝脏I/R损伤对患者来说是巨大的好处。仅在美国，肝脏I/R治疗的市场潜力估计为每年100亿美元。我们最近证实，在大鼠肝脏I/R模型中，人肾上腺髓质素(AM，一种新近发现的有效血管活性多肽)与人AM结合蛋白-1(AMBP-1，一种新的AM特异性结合蛋白)在再灌流开始时立即联合应用，可下调促炎细胞因子，减少肝中性粒细胞的浸润，抑制肝细胞凋亡和坏死，并减少肝损伤和死亡率。目前尚不清楚延迟给予人AM/AMBP-1(临床意义更大)是否对肝脏I/R损伤后有或不存在预先存在的肝病(如胆管结扎(BDL)所致的肝损伤)具有同等的保护作用。阻碍人AM/AMBP-1作为肝脏I/R新型治疗剂发展的另一个障碍是商业化的人AMBP-1的极高成本。为了克服这一点，我们以低得多的成本成功地从正常人血清中分离和纯化了AMBP-1。因此，我们假设，延迟给药人AM/AMBP-1可以减轻肝脏损伤和炎症，并降低肝脏I/R诱导的死亡率，即使在先前存在肝脏疾病的情况下也是如此。本项目的主要目的是论证进一步开发人AM/AMBP-1作为降低肝I/R后死亡率的新治疗方法并将其商业化的可行性。延迟治疗的最佳剂量(S)将通过评估以下各项来确定：1)人AM/AMBP-1对肝I/R后组织损伤和炎症反应的剂量-反应效应；2)人AM/AMBP-1‘S有益作用的时程；以及3)人AM/AMBP-1对肝I/R所致死亡率的影响。我们的最终目标(SBIR第二阶段及以后)是将人AM/AMBP-1作为一种安全有效的治疗与既往肝脏疾病相关的肝I/R损伤患者的方法获得商业应用。公共卫生相关性：外科技术和药物干预的最新进展适度改善了创伤手术、肝切除、肝移植和休克的结果。然而，缺血再灌注(I/R)损伤所致的肝功能衰竭仍然是临床上的主要并发症。肝脏I/R合并或不合并既往肝病是此类患者多器官衰竭和死亡的重要原因。显然，医学上迫切需要开发新的治疗方法来预防或至少减少肝脏I/R损伤。

DESCRIPTION (provided by applicant): Liver injury induced by hepatic ischemia and reperfusion (I/R) is a major cause of liver failure after severe trauma, thermal injury, hemorrhagic and septic shock, liver resection, or liver transplantation. Hepatic I/R contributes significantly to multiple organ failure and mortality. Although various modalities and substances have been studied to reduce hepatic I/R-induced mortality, none have been entirely successful. Thus, the development of novel treatments to prevent or at least minimize hepatic I/R injury is of tremendous benefit to the patient. The market potential for hepatic I/R treatment is estimated at >$10 billion per year in the US alone. We have recently demonstrated that administration of human adrenomedullin (AM, a recently-discovered potent vasoactive peptide) in combination with human AM binding protein-1 (AMBP-1, a novel specific binding protein for AM) immediately at the onset of reperfusion, downregulated pro-inflammatory cytokines, decreased hepatic neutrophil infiltration, inhibited liver cell apoptosis and necrosis, and reduced liver injury and mortality in a rat model of hepatic I/R. However, it remains unknown whether delayed administration of human AM/AMBP-1 (which is more clinically relevant) is also equally protective after hepatic I/R injury with or without pre-existing liver diseases such as hepatic injury induced by bile duct ligation (BDL). Another obstacle hampering the development of human AM/AMBP-1 as a novel therapeutic agent for hepatic I/R is the extremely high cost of commercial human AMBP-1. To overcome this, we have successfully isolated and purified AMBP-1 from normal human serum at a much lower cost. We therefore hypothesize that delayed administration of human AM/AMBP-1 attenuates hepatic injury and inflammation, and reduces hepatic I/R-induced mortality even under pre- existing liver diseases. The primary aim of this project is targeted toward demonstrating the feasibility of further development and commercialization of human AM/AMBP-1 as a novel therapeutic approach to reduce mortality after hepatic I/R. The optimal dosage(s) of human AM/AMBP-1 (delayed treatment) will be determined by assessing 1) the dose-response effect of human AM/AMBP-1 on tissue injury and inflammatory responses after hepatic I/R; 2) the time-course of human AM/AMBP-1's beneficial effects; and 3) the effect of human AM/AMBP-1 on mortality induced by hepatic I/R with or without BDL. Our ultimate goal (SBIR Phase II and beyond) is to obtain commercial utilization of human AM/AMBP-1 as a safe and effective treatment for patients with hepatic I/R injury associated with pre-existing liver conditions. PUBLIC HEALTH RELEVANCE: Recent advances in surgical techniques and pharmacological interventions have moderately improved the outcome of trauma surgery, liver resection, liver transplantation, and shock. However, liver failure due to ischemia-reperfusion (I/R) injury continues to be a major complication in the clinical arena. Hepatic I/R with or without pre-existing liver diseases contributes significantly to multiple organ failure and death of such patients. It is obvious that there is an urgent medical need for the development of novel treatments to prevent or at least minimize hepatic I/R injury.