Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance.
Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance.
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DOI：
10.1038/cddis.2016.218
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发表时间：
2016-07-21
影响因子：
9
通讯作者：
Rubartelli A
中科院分区：
文献类型：
--
作者：
Balza E;Piccioli P;Carta S;Lavieri R;Gattorno M;Semino C;Castellani P;Rubartelli A
脓毒症的发病率正在增加，这对卫生保健系统构成了巨大的负担。急性脓毒症的死亡归因于高炎症反应，但其潜在机制尚不清楚。我们在此报告，质子泵抑制剂（PPI），阻断胃酸分泌，选择性抑制肿瘤坏死因子-α（TNF-α）和白细胞介素-1 β（IL-1β）分泌的Toll样受体（TLR）激活的人单核细胞在体外，在没有毒性作用。值得注意的是，代表受cryopyrin相关周期性综合征影响的患者单核细胞标志的IL-1β的过度分泌也被阻断。基于这些初步实验，我们在内毒素休克小鼠模型中检测了高剂量PPI的体内作用。我们的数据表明，PPI单次给药可保护小鼠免于死亡（60%的存活率，而未给药小鼠的存活率为5%），并降低TNF-α和IL-1β的全身产生。PPI即使在脂多糖（LPS）注射后给药也有效。PPI治疗的存活小鼠产生了长期的交叉耐受性，对LPS和酵母多糖诱导的脓毒症产生了抵抗力。在体外，它们的巨噬细胞对不同的TLR配体表现出受损的TNF-α和IL-1β。PPI还可以预防硫乙醇酸钠诱导的腹膜炎症，这表明它们在非感染性环境中的功效也与TLR刺激无关。缺乏毒性和治疗效果使PPI成为治疗败血症和其他严重炎症疾病的有前途的新药。
Incidence of sepsis is increasing, representing a tremendous burden for health-care systems. Death in acute sepsis is attributed to hyperinflammatory responses, but the underlying mechanisms are still unclear. We report here that proton pump inhibitors (PPIs), which block gastric acid secretion, selectively inhibited tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) secretion by Toll-like receptor (TLR)-activated human monocytes in vitro, in the absence of toxic effects. Remarkably, the oversecretion of IL-1β that represents a hallmark of monocytes from patients affected by cryopyrin-associated periodic syndrome is also blocked. Based on these propaedeutic experiments, we tested the effects of high doses of PPIs in vivo in the mouse model of endotoxic shock. Our data show that a single administration of PPI protected mice from death (60% survival versus 5% of untreated mice) and decreased TNF-α and IL-1β systemic production. PPIs were efficacious even when administered after lipopolysaccharide (LPS) injection. PPI-treated mice that survived developed a long-term cross-tolerance, becoming resistant to LPS- and zymosan-induced sepsis. In vitro, their macrophages displayed impaired TNF-α and IL-1β to different TLR ligands. PPIs also prevented sodium thioglycollate-induced peritoneal inflammation, indicating their efficacy also in a non-infectious setting independent of TLR stimulation. Lack of toxicity and therapeutic effectiveness make PPIs promising new drugs against sepsis and other severe inflammatory conditions.