The recombinant 23-kDa N-terminal fragment of bactericidal/permeability-increasing protein (rBPI23) decreases Escherichia coli-induced mortality and organ injury during immunosuppression-related neutropenia.
The recombinant 23-kDa N-terminal fragment of bactericidal/permeability-increasing protein (rBPI23) decreases Escherichia coli-induced mortality and organ injury during immunosuppression-related neutropenia.
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杀菌/通透性增加蛋白 (rBPI23) 的重组 23-kDa N 端片段可降低免疫抑制相关中性粒细胞减少症期间大肠杆菌诱导的死亡率和器官损伤。
DOI：
10.1097/00024382-199510000-00012
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
Matuschak,GM
中科院分区：
文献类型：
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作者：
Lechner,AJ;Lamprech,KE;Johanns,CA;Matuschak,GM
环磷酰胺诱导的中性粒细胞减少加剧了大肠杆菌（EC）菌血症期间有意识大鼠的脓毒性休克和多器官损伤，尽管有抗生素和液体管理。我们假设rBPI23的杀微生物活性和/或与EC内毒素的结合可以减轻这种休克和炎症性器官损伤。在100mg环磷酰胺/kg后第4天，< 300 PMNs/[mu] L的大鼠插管后5分钟用rBPI23或不相关的22 kDa蛋白thaumatin [3.3-6.6 mg/kg, iv in 0.9% NaCI (NS)]进行预处理，然后用EC血清型055:B5的5+/-109或1+/-1010 cfu进行分级iv感染，结束于t= 0。每种蛋白的后处理（3.3-6.6 mg/kg, 1 ml NS/h）持续8 h，并在t= 1.5和8 h时继续使用青霉素加硫酸阿米卡星。在预处理前和t= 1.5、4.5、8和24 h解剖动物时分别取动脉样本。8只thaumatin+ 5+/-109 EC大鼠中有1只存活了24小时，6只thaumatin+ 1010 EC大鼠中没有一只存活了24小时。相比之下，rBPI23显著降低了接种后的死亡率，改善了细菌清除，并导致早期EC诱导的低血压、低体温、呼吸急促、高氧血症和低碳血症的重新正常化。然而，与thaumatin相比，rBPI23没有降低循环内毒素或生物活性和抗原肿瘤坏死因子-[α]。所有EC大鼠在t= 1.5 h时出现的脓毒症诱导的严重中性粒细胞减少（< 50 PMNs/[mu] L）在t= 8 h时被rBPI23逆转，但在t= 4.5 h时各组明显的血小板减少（< 5+/-104血小板/[mu] L）没有改变。虽然rBPI23不能阻止ec诱导的微血管通透性增加，但它可以减少肺间质水肿、微血管充血和肝细胞脂肪变性。因此，rBPI23在中性粒细胞减少菌血症期间增强宿主防御，不依赖于循环内毒素水平或包括TNF在内的促炎细胞因子。
Cyclophosphamide-induced neutropenia exacerbates septic shock and multiple organ injury in conscious rats during Escherichia coli (EC) bacteremia despite antibiotics and fluid administration. We hypothesized that such shock and inflammatory organ injury would be mitigated by rBPI23's microbicidal activity and/or binding of EC endotoxins. Four days after 100 mg cyclophosphamide/kg, catheterized rats with< 300 PMNs/[mu] L were pretreated with rBPI23 or the irrelevant 22 kDa protein thaumatin [3.3-6.6 mg/kg, iv in 0.9% NaCI (NS)] 5 min before graded iv infection with 5+/-109 or 1+/-1010 cfu of EC serotype 055: B5 ending at t= 0. Posttreatment with each protein continued (3.3-6.6 mg/kg in 1 ml NS/h) through 8 h, in addition to penicillin plus amikacin sulfate at t= 1.5 and 8 h. Arterial samples were obtained before pretreatment and at t= 1.5, 4.5, 8, and 24 h when animals were necropsied. One of eight thaumatin+ 5+/-109 EC rats and none of six thaumatin+ 1010 EC rats survived 24 h. In contrast, rBPI23 significantly reduced mortality after either inoculum, improved bacterial clearance, and led to renormalization of early EC-induced hypotension, hypothermia, tachypnea, hyperoxemia, and hypocarbia. Compared with thaumatin, however, rBPI23 did not reduce circulating endotoxin or bioactive and antigenic tumor necrosis factor-[alpha]. Sepsis-induced severe neutropenia (< 50 PMNs/[mu] L) evident in all EC rats by t= 1.5 h was reversed with rBPI23 by t= 8 h, but thrombocytopenia (< 5+/-104 platelets/[mu] L) evident in all groups by t= 4.5 h was not altered. Although rBPI23 did not prevent EC-induced increases in microvascular permeability, it reduced pulmonary interstitial edema, microvascular congestion, and hepatocytic steatosis. Thus rBPI23 enhances host defense during neutropenic bacteremia, independent of circulating levels of endotoxin or of proinflammatory cytokines including TNF.