Heme oxygenase-1 deficiency promotes severity of sepsis in a non-surgical preterm mouse model
Heme oxygenase-1 deficiency promotes severity of sepsis in a non-surgical preterm mouse model
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DOI：
10.1038/s41390-018-0028-6
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发表时间：
2018-07-01
影响因子：
3.6
通讯作者：
Stevenson, David K.
中科院分区：
文献类型：
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作者：
Fujioka, Kazumichi;Kalish, Flora;Stevenson, David K.
背景：早产儿脓毒症与全身炎症反应有关。应激反应蛋白血红素加氧酶-1 （HO-1）具有保护性抗炎特性。最近，我们利用我们的非手术盲肠浆液（CS）模型报道了HO-1在野生型（WT）小鼠幼崽中的保护作用。在这里，我们将这些发现扩展到研究HO-1缺乏与脓毒症严重程度的关系。方法：采用Wynn模型，对4日龄HO-1缺陷（HO-1(+/-), Het）幼犬进行脓毒症诱导，以确定HO-1缺陷是否影响LD40 （2.0 mg/g）下WT幼犬的存活率。为了观察HO-1诱导是否影响脓毒症的严重程度，我们在脓毒症诱导前24小时给3日龄小鼠皮下注射30 μ mol血红素/kg。结果：脓毒症诱导后，Het幼鼠的死亡率为85.0% (n = 20)，肝脏中促炎基因表达增加，血液学特征受到影响。在脓毒症诱导前24小时使用血红素可显著增加肝脏HO活性，将死亡率降低至24.5% (n = 17)，减轻炎症反应，减少脾脏细菌计数，并显著增加外周中性粒细胞。结论：部分缺乏HO-1会增加败血症的进展和死亡率。此外，HO-1的诱导显著降低了Het幼鼠的死亡率。因此，我们得出结论，HO-1在预防早产败血症中起重要作用。
BACKGROUND: Sepsis in preterm infants is associated with systemic inflammatory responses. The stress-response protein heme oxygenase-1 (HO-1) has protective anti-inflammatory properties. Recently, we reported a protective role of HO-1 using our nonsurgical cecal slurry (CS) model in wild-type (WT) mouse pups. Here, we extend these findings to investigate the association of HO-1 deficiency with sepsis severity.METHODS: Adapting the Wynn model, we induced sepsis in 4-day-old HO-1-deficient (HO-1(+/-), Het) pups to determine if HO-1 deficiency affected survival rates at the LD40 (2.0 mg/g) of WT pups. To see if HO-1 induction affected sepsis severity, we gave 30 mu mol heme/kg subcutaneously to 3-day-old mice 24 h prior to sepsis induction.RESULTS: Post-sepsis induction, Het pups had a mortality of 85.0% (n = 20) and increased expression of the pro-inflammatory gene in the livers and affected hematologic profiles. Heme treatment 24 h prior to sepsis induction significantly increased liver HO activity, reduced mortality to 24.5% (n = 17), attenuated inflammatory responses, reduced spleen bacterial counts, and significantly increased peripheral neutrophils.CONCLUSIONS: A partial deficiency in HO-1 increased the progression and mortality in sepsis. Furthermore, induction of HO-1 significantly reduced the mortality even in Het pups. Thus, we conclude that HO-1 plays an important role in the protection against preterm sepsis.