Inter-alpha Inhibitors in Neonatal Sepsis

描述（由申请人提供）： 本研究的主要目的是证明Inter-alpha抑制蛋白（Ialp）作为新生儿败血症潜在治疗药物的可行性。Ialp是天然丝氨酸蛋白酶抑制剂，在成人和新生儿血浆中浓度相对较高（范围为0.6-1.2 mg/mL）。Ialp在炎症、伤口愈合和肿瘤转移中发挥作用。在血浆中正常循环的高水平Ialp表明该蛋白质是生命所必需的，并且从未检测到完全缺乏Ialp的人。严重脓毒症和脓毒性休克成人患者血浆Ialp水平显著降低，且与死亡率相关。我们的初步研究结果表明，在临床证实的新生儿败血症中Ialp水平也有类似的降低，这表明Ialp参与了新生儿败血症的发病机制。我们假设，Ialp的管理恢复这些天然保护性抑制剂和破坏性蛋白酶之间的失衡，将防止器官损伤，并最终降低败血症的死亡率。我们使用盲肠结扎和穿孔（CLP）的多微生物脓毒症大鼠模型的动物研究已经证明了Ialp在维持血液动力学稳定性、预防器官损伤和改善成年动物脓毒症进展期间的存活率方面的有益作用。

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.