Department of Pediatrics, Women & Infants' Hospital, Brown Medical School, Providence, RI 02905, USA.
Pediatr Res. 2010 Sep;68(3):242-7. doi: 10.1203/PDR.0b013e3181e9fdf0.
Inter-alpha inhibitor proteins (IaIp) are serine proteases inhibitors that modulate endogenous protease activity and have been shown to improve survival in adult models of sepsis. We evaluated the effect of IaIp on survival and systemic responses to sepsis in neonatal mice. Sepsis was induced in 2-d-old mice with lipopolysaccharide (LPS), Escherichia coli, and group B Streptococci. Sepsis was associated with 75% mortality. IaIp, given by i.p. administration at doses between 15 and 45 mg/kg from 1 to 6 h after the onset of sepsis, improved survival to approximately 90% (p = 0.0159) in both LPS-induced sepsis and with live bacterial infections. The greatest effect was on reversal of hemorrhagic pneumonitis. The effects were dose and time dependent. Systemic cytokine profile and tissue histology were examined. Survival was compared in IL-10 knock out animals. Systemic cytokine levels including TNF-[alpha] and IL-10 were increased after induction of sepsis and modulated significantly after IaIp administration. Because the effect of IaIp was still demonstrable in IL-10 deficient mice, we conclude the beneficial effects of IaIp is because of suppression of proinflammatory cytokines such as TNF-[alpha] rather than augmentation of IL-10. IaIp may offer significant benefits as a therapeutic
α 抑制素蛋白（IAIp）是一种丝氨酸蛋白酶抑制剂，可调节内源性蛋白酶活性，并已被证明可提高败血症成年模型的存活率。我们评估了 IaIp 对新生鼠败血症存活和全身反应的影响。使用脂多糖（LPS）、大肠杆菌和 B 组链球菌在 2 天大的小鼠中诱导败血症。败血症与 75%的死亡率相关。IAIp 在败血症发作后 1 至 6 小时内通过腹腔内给药，剂量在 15 至 45mg/kg 之间，可提高 LPS 诱导的败血症和活菌感染的存活率至约 90%（p=0.0159）。最大的作用是逆转出血性肺炎。作用具有剂量和时间依赖性。检查了系统细胞因子谱和组织病理学。在白细胞介素 10 敲除动物中比较了存活率。败血症诱导后，全身细胞因子水平（包括 TNF-α和白细胞介素 10）升高，IAIp 给药后显著调节。因为 IaIp 的作用在白细胞介素 10 缺乏的小鼠中仍然存在，我们得出结论，IAIp 的有益作用是因为抑制了促炎细胞因子如 TNF-α，而不是增强了白细胞介素 10。IAIp 作为一种治疗方法可能具有重要意义。
