Therapeutic Use of Inter-alpha Inhibitor in Sepsis

这项研究的主要目标是证明人类血浆衍生α间抑制剂蛋白（IaIp）的商业利用是一种有效的脓毒症治疗方法。IaIp是一种丝氨酸蛋白酶抑制剂，通常在人血浆中含量较高。从未发现过完全缺乏IaIp的人，这一事实表明这些蛋白质具有重要的生理作用。严重脓毒症患者血浆IaIp水平明显下降，且与死亡率相关。我们建议使用IaIp来恢复这些天然保护性抑制剂和破坏性蛋白酶之间的不平衡，从而防止器官损伤，并最终降低败血症相关的死亡率。我们在盲肠结扎和穿刺（CLP）脓毒症大鼠模型中进行的初步动物研究表明，IaIp在维持脓毒症期间的血流动力学稳定性、预防器官损伤和提高生存率方面具有有益作用。在本研究中，我们建议优化纯化人粗血浆IaIp的方案，并评估和确认纯化后的IaIp在CLP大鼠模型中的有益作用。这些研究的最终目标是开发一种安全有效的新型血浆源性治疗败血症。建议的商业应用：全球每年有超过150万人患有败血症，这是一个严重的未满足的医疗需求。由于目前没有对败血症有效的药物，治疗仅限于抗生素和支持治疗。对降低败血症死亡率和发病率的有效新型治疗剂的需求是巨大的，它创造了巨大的市场潜力，估计仅在美国每年就有100 - 250亿美元。α间抑制蛋白是一种有效的脓毒症治疗剂。该研究有望开发出安全有效的新型人血浆源性蛋白。

The primary goal of this proposed research is targeted towards demonstrating the commercial utilization of human plasma derived inter- alpha inhibitor proteins (IaIp) an effective therapy of sepsis. IaIp are serine protease inhibitors found normally at high levels in human plasma. The fact that no person with complete absence of IaIp has ever been detected suggests an essential physiological role for these proteins. In patients with severe sepsis, the plasma level of IaIp decrease significantly and the decrease correlates with mortality. We propose that administration of IaIp to restore the imbalance between these natural protective inhibitors and destructive proteases will prevent organ injuries and ultimately reduce sepsis related mortality. Our preliminary animal studies in a sepsis rat model of cecal ligation and puncture (CLP) have demonstrated the beneficial effects of IaIp in maintaining hemodynamic stability, preventing organ injury, and improving survival during sepsis. In this study, we propose to optimize a protocol for purification of IaIp from human crude plasma and to evaluate and confirm the beneficial effects of the purified IaIp in the CLP rat model. The ultimate goal of these studies is to develop a novel plasma derived therapeutic that is safe and effective for sepsis. PROPOSED COMMERCIAL APPLICATIONS: There is a serious unmet medical need for more than 1.5 million people worldwide annually who suffer from sepsis. Since there are currently no agents effective for sepsis, treatment is limited to antibiotic and supportive therapy. The magnitude of the need for an effective novel therapeutic agent in reducing sepsis mortality and morbidity is immense and it creates an enormous market potential estimated at $10-25 billion/year in the US alone. Inter-alpha inhibitor proteins appear to be an effective therapeutic agent of sepsis. The proposed study is expected to lead to the development of novel human plasma derived protein that is safe and effective for sepsis.