Department of Pathophysiology, Anhui Medical University, Hefei, China.
Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany.
J Immunol Res. 2018 Nov 7;2018:6085095. doi: 10.1155/2018/6085095. eCollection 2018.
Sepsis is the primary cause of death from infection. We wanted to improve the outcome of sepsis by stimulating innate immunity in combination with modulating the severity of inflammatory responses in rats.
Sepsis was induced by the injection of feces suspension (control). A 5-day course of G-CSF treatment was given before the septic insult (G-CSF). The inflammatory response was decreased using various doses of the LPS-blocking peptide LBPK95A (5 mg/kg = 100% Combi group, 0.5 mg/kg = 10% Combi group, and 0.05 mg/kg = 1% Combi group). Survival rates were observed. Bacterial clearance, neutrophil infiltration, tissue damage, and the induction of hepatic and systemic inflammatory responses were determined 2 h and 12 h after the septic insult.
High-dose LBPK95A (100% Combi) reduced the survival rate to 10%, whereas low-dose LBPK95A (10% and 1% Combi) increased the survival rates to 50% and 80%, respectively. The survival rates inversely correlated with multiorgan damage as indicated by the serum levels of ALT and urea. G-CSF treatment increased the white blood cell counts, hepatic neutrophil infiltration, and bacterial clearance in the liver, lung, and blood. The blockade of the LPS-LBP interaction decreased neutrophil infiltration, led to increased white blood cell count, and decreased hepatic neutrophil infiltration, irrespective of dose. However, bacterial clearance improved in the 1% and 10% Combi groups but worsened in the 100% Combi group. G-CSF increased TNF- and IL-6 levels. Irrespective of dose, the blockade of the LPS-LBP interaction was associated with low systemic cytokine levels and delayed increases in hepatic TNF- and IL-6 mRNA expression. The delayed increase in cytokines was associated with the phosphorylation of STAT3 and AKT.
Our results revealed that increasing innate immunity by G-CSF pretreatment and decreasing inflammatory responses using LBPK95A improved the survival rates in a rat sepsis model and could be a novel strategy to treat sepsis.
脓毒症是感染导致死亡的主要原因。我们希望通过刺激固有免疫并调节大鼠炎症反应的严重程度来改善脓毒症的预后。
通过注射粪便悬浮液（对照组）诱导脓毒症。在感染前给予 G-CSF 治疗 5 天（G-CSF）。使用各种剂量的 LPS 阻断肽 LBPK95A（5mg/kg=100%Combi 组、0.5mg/kg=10%Combi 组和 0.05mg/kg=1%Combi 组）降低炎症反应。观察存活率。在感染后 2 小时和 12 小时测定细菌清除率、中性粒细胞浸润、组织损伤以及肝和全身炎症反应的诱导。
高剂量 LBPK95A（100%Combi）降低存活率至 10%，而低剂量 LBPK95A（10%和 1%Combi）分别将存活率提高至 50%和 80%。存活率与血清 ALT 和尿素水平所示的多器官损伤呈反比。G-CSF 治疗增加了白细胞计数、肝脏中性粒细胞浸润和肝脏、肺和血液中的细菌清除率。阻断 LPS-LBP 相互作用可减少中性粒细胞浸润，增加白细胞计数，并减少肝脏中性粒细胞浸润，而与剂量无关。然而，1%和 10%Combi 组的细菌清除率提高，但 100%Combi 组的细菌清除率恶化。G-CSF 增加 TNF-α 和 IL-6 水平。与剂量无关，阻断 LPS-LBP 相互作用与低系统细胞因子水平和延迟增加肝 TNF-α和 IL-6mRNA 表达有关。细胞因子的延迟增加与 STAT3 和 AKT 的磷酸化有关。
我们的结果表明，通过 G-CSF 预处理增加固有免疫和使用 LBPK95A 降低炎症反应可提高大鼠脓毒症模型的存活率，可能是治疗脓毒症的一种新策略。
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