Predictive value of inter-alpha inhibitors in sepsis

描述(由申请人提供)： 这项建议的主要目的是证明利用β-α抑制物作为成人和新生儿败血症的新的预测标记物的可行性。IaIp是一种天然的丝氨酸蛋白酶抑制剂，在成人和新生儿血浆中发现有较高的浓度(范围为600-1200 mg/L)。IaIp已被认为在炎症、伤口愈合和癌症转移中发挥作用。IaIp在血浆中正常循环的高水平表明，这些蛋白质是生命所必需的，还没有检测到完全缺乏IaIp的人。我们的初步结果显示，严重脓毒症和感染性休克的成人患者血浆IaIp水平显着下降，且这种下降与死亡率相关，提示IaIp作为脓毒症的预测标志物具有潜在的临床应用价值。在临床证实的新生儿败血症中也发现了类似的IaIp水平下降。此外，在我们使用盲肠结扎和穿孔(CLP)的多菌败血症大鼠模型的动物研究中，我们已经证明了IaIp在成年动物脓毒症进展过程中维持血流动力学稳定、防止器官损伤和提高存活率方面的有益效果。综上所述，这些数据强烈表明IaIp参与了脓毒症的发病机制。在这个第一阶段的应用中，我们将开发一种标准化和有效的免疫分析方法，该方法可靠，能够准确地测定生物液中的IaIp水平。这项经过验证的检测将用于证实我们的初步发现，即血浆IaIp水平是成人和新生儿败血症的一个有价值的诊断、预后和治疗标志物。

DESCRIPTION (provided by applicant): The primary goal of this proposal is to demonstrate the feasibility of utilizing Inter-alpha Inhibitor as a novel predictive marker for adult and newborn sepsis. IaIp are natural serine protease inhibitors found in relatively high concentration in human adult and newborn plasma (ranges between 600-1200 mg/L). IaIp have been implicated to play roles in inflammation, wound healing and cancer metastasis. The high level of IaIp circulating normally in plasma indicates that the proteins are essential for life and no person with complete absence of IaIp has ever been detected. Our preliminary results demonstrate a significant decrease of plasma IaIp levels in plasma of adult patients with severe sepsis and septic shock and the decrease correlates with the mortality suggesting the potential clinical utility of IaIp as a predictive marker in sepsis. A similar decrease of IaIp levels was found also in clinically proven neonatal sepsis. Furthermore, in our animal studies using a polymicrobial sepsis rat model of cecal ligation and puncture (CLP), we have demonstrated the beneficial effects of IaIp in maintaining hemodynamic stability, preventing organ injury, and improving survival during the progression of sepsis in adult animals. Taken together, the data strongly suggest the involvement of IaIp in the pathogenesis of sepsis. In this Phase I application, we will develop a standardized and validated immunoassay that is reliable and capable of accurately determining IaIp levels in biological fluids. This validated assay will be used to confirm our initial findings that IaIp levels in plasma constitute a valuable diagnostic, prognostic and theranostic marker for adult and neonatal sepsis.