Perego Jessica, Bourbon Clarisse, Chasson Lionel, Laprie Caroline, Spinelli Lionel, Camosseto Voahirana, Gatti Evelina, Pierre Philippe
CIML, Aix-Marseille University, CNRS, INSERM, Marseille, France.
Aveiro Health Sciences Program, Institute for Research in Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal.
Front Immunol. 2017 Jun 13;8:679. doi: 10.3389/fimmu.2017.00679. eCollection 2017.
Multi-organ failure in response to uncontrolled microbial infection is characterized by low blood pressure accompanied by a systemic over-inflammation state, caused by massive pro-inflammatory cytokines release and liver damage. Recently, the integrated stress response (ISR), characterized by eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, was involved with controlling apoptosis in stressed hepatocytes and associated with poor survival to endotoxin challenge. Lipopolysaccharide (LPS) alone is able to induce the ISR in hepatocytes and can trigger massive liver damage along with tumor necrosis factor-alpha (TNF-α) expression. Consequently, drugs interfering with eIF2α phosphorylation may represent potential candidates for the treatment of such pathologies. We, therefore, used Guanabenz (GBZ), a small compound with enhancing eIF2α phosphorylation activity to evaluate its effect on bacterial LPS sensing and endotoxemia. GBZ is confirmed here to have an anti-inflammatory activity by increasing interleukin-10 (IL-10) production by LPS-stimulated dendritic cells. We further show that in the d-galactosamine (d-galN)/LPS-dependent lethality model, intraperitoneal injection of GBZ promoted mice survival, prevented liver damage, increased IL-10 levels, and inhibited TNF-α production. GBZ and its derivatives could therefore represent an interesting pharmacological solution to control systemic inflammation and associated acute liver failure.
因不受控制的微生物感染而引发的多器官功能衰竭，其特征为低血压并伴有全身过度炎症状态，这是由大量促炎细胞因子释放和肝损伤所致。最近，以真核翻译起始因子2α（eIF2α）磷酸化为特征的综合应激反应（ISR），参与调控应激肝细胞的凋亡，并与内毒素攻击后的低存活率相关。单独的脂多糖（LPS）能够在肝细胞中诱导ISR，并可引发严重肝损伤以及肿瘤坏死因子-α（TNF-α）的表达。因此，干扰eIF2α磷酸化的药物可能是治疗此类病症的潜在候选药物。所以，我们使用胍那苄（GBZ），一种具有增强eIF2α磷酸化活性的小分子化合物，来评估其对细菌LPS感知和内毒素血症的影响。在此证实GBZ通过增加LPS刺激的树突状细胞产生白细胞介素-10（IL-10）而具有抗炎活性。我们进一步表明，在d-半乳糖胺（d-galN）/LPS诱导的致死模型中，腹腔注射GBZ可提高小鼠存活率、预防肝损伤、增加IL-10水平并抑制TNF-α的产生。因此，GBZ及其衍生物可能是控制全身炎症和相关急性肝衰竭的一种有前景的药理学解决方案。
