Inter-alpha Inhibitors in Neonatal Sepsis

新生儿败血症中的 Inter-α 抑制剂

• 批准号: 6814783
• 负责人: YOW-PIN LIM
• 金额: $ 21.32万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-05 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6814783
• 关键词: biotherapeutic agent; chromatography; disease /disorder model; dosage; enzyme inhibitors; enzyme linked immunosorbent assay; histopathology; infant human (0-1 year); infant mortality; inflammation; laboratory mouse; laboratory rat; newborn animals; pharmacokinetics; plasma; protein purification; septicemia; serine proteinases

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.

描述（由申请人提供）： 这项研究的主要目标是证明 Inter-α 抑制剂蛋白 (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（范围在 0.6-1.2 mg/mL 之间）。 Ialp 在炎症、伤口愈合和癌症转移中发挥着重要作用。血浆中正常循环的 Ialp 水平较高，表明这些蛋白质对于生命至关重要，并且尚未检测到完全缺乏 Ialp 的人。患有严重败血症和败血性休克的成年患者血浆中血浆 Ialp 水平显着降低，并且这种降低与死亡率相关。我们的初步结果表明，临床证实的新生儿败血症中 Ialp 水平也有类似的下降，表明 Ialp 参与了新生儿败血症的发病机制。我们假设 Ialp 的给药可以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脓毒症的死亡率。我们使用盲肠结扎穿刺 (CLP) 的多微生物脓毒症大鼠模型进行的动物研究已经证明了 Ialp 在维持血流动力学稳定性、预防器官损伤和提高成年动物脓毒症进展过程中的存活率方面的有益作用。