A Novel Therapeutic Approach for Liver Injury

描述（由申请人提供）：肝脏缺血再灌注（I/R）所致的肝损伤是严重创伤、热损伤、出血性和败血性休克、肝切除或肝移植后肝衰竭的主要原因。肝I/R对多器官衰竭和死亡率有重要影响。虽然已经研究了各种方式和物质来降低I/ r引起的肝脏死亡率，但没有一种是完全成功的。因此，开发新的治疗方法来预防或至少减少肝I/R损伤对患者有巨大的好处。仅在美国，肝脏I/R治疗的市场潜力估计为每年100亿美元。我们最近证明，在肝I/R大鼠模型中，在再灌注开始时立即将人肾上腺髓素（AM，一种最近发现的强效血管活性肽）与人肾上腺髓素结合蛋白-1 （AMBP-1，一种新的AM特异性结合蛋白）联合使用，可下调促炎细胞因子，减少肝中性粒细胞浸润，抑制肝细胞凋亡和坏死，并减少肝损伤和死亡率。然而，延迟给药人类AM/AMBP-1（更具有临床相关性）是否在肝I/R损伤（伴或不伴既往肝脏疾病，如胆管结扎（BDL）引起的肝损伤）后同样具有保护作用尚不清楚。阻碍人类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类AMBP-1的极高成本。为了克服这一问题，我们成功地从正常人血清中分离和纯化了AMBP-1，成本低得多。因此，我们假设，延迟给药人类AM/AMBP-1可以减轻肝损伤和炎症，并降低肝I/ r诱导的死亡率，即使在已有肝脏疾病的情况下也是如此。该项目的主要目的是为了证明进一步开发和商业化人类AM/AMBP-1作为降低肝I/R后死亡率的新治疗方法的可行性。人AM/AMBP-1（延迟治疗）的最佳剂量将通过评估1)人AM/AMBP-1对肝脏I/R后组织损伤和炎症反应的量效效应来确定；2)人体AM/AMBP-1有益作用的时间过程；3) AM/AMBP-1对伴有或不伴有BDL的肝I/R致死亡的影响。我们的最终目标（SBIR II期及以后）是获得人类AM/AMBP-1的商业利用，作为一种安全有效的治疗与既往肝脏疾病相关的肝I/R损伤患者的药物。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、肝移植和休克的预后。然而，由于缺血再灌注（I/R）损伤引起的肝衰竭仍然是临床领域的主要并发症。伴有或不伴有既往肝病的肝I/R显著导致这类患者的多器官衰竭和死亡。很明显，迫切需要开发新的治疗方法来预防或至少减少肝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.