Inter-alpha Inhibitors in Neonatal Sepsis

描述(由申请人提供)： 这项研究的主要目的是证明间α抑制蛋白(IALP)作为潜在的新生儿败血症治疗药物的可行性。IALP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的浓度相对较高(范围在0.6-1.2毫克/毫升之间)。IALP在炎症、伤口愈合和癌症转移中起重要作用。高水平的IALP在血浆中正常循环，表明这些蛋白是生命所必需的，还没有检测到完全缺乏IALP的人。成人重症脓毒症和感染性休克患者血浆IALP水平明显降低，且与病死率相关。我们的初步结果表明，在临床证实的新生儿败血症中，IALP水平也有类似的下降，提示IALP参与了新生儿败血症的发病机制。我们假设，应用IALP可以恢复这些天然保护性抑制物和破坏性蛋白水解酶之间的失衡，从而防止器官损伤，并最终降低脓毒症的死亡率。我们使用盲肠结扎穿孔(CLP)的多菌败血症大鼠模型进行的动物研究已经证明，在成年动物的脓毒症进展过程中，IALP在维持血流动力学稳定、防止器官损伤和提高存活率方面具有良好的效果。

DESCRIPTION (provided by applicant): The primary goal of this research is to demonstrate the feasibility of Inter-alpha inhibitor proteins (Ialp) as potential therapeutic agents in neonatal sepsis. Ialp are natural serine protease inhibitors found in relatively high concentration in human adult and newborn plasma (ranges between 0.6-1.2 mg/mL). Ialp have been implicated in play roles in inflammation, wound healing and cancer metastasis. The high level of Ialp circulating normally in plasma indicates that the proteins are essential for life and no person with complete absence of Ialp has ever been detected. A significant decrease of plasma Ialp levels occurs in plasma of adult patients with severe sepsis and septic shock and the decrease correlates with the mortality. Our preliminary results suggest a similar decrease of Ialp levels in clinically proven neonatal sepsis suggesting the involvement of Ialp in the pathogenesis of neonatal sepsis. We hypothesize that administration of Ialp restore the imbalance between these natural protective inhibitors and destructive proteases will prevent organ injury and ultimately reduce the mortality in sepsis. Our animal studies using a polymicrobial sepsis rat model of cecal ligation and puncture (CLP) have already demonstrated the beneficial effects of Ialp in maintaining hemodynamic stability, preventing organ injury, and improving survival during the progression of sepsis in adult animals.