Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury
Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury
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DOI：
10.1097/ccm.0b013e3182120cb8
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发表时间：
2011-06-01
影响因子：
8.8
通讯作者：
Natarajan, Ramesh
中科院分区：
文献类型：
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作者：
Fisher, Bernard J.;Seropian, Ignacio M.;Natarajan, Ramesh
目的：脓毒症所致肺损伤是一个长期存在的临床问题，目前尚无直接治疗方法。最近的研究表明，静脉注射抗坏血酸可以改善脓毒症的循环功能障碍。我们使用内毒素诱导的急性肺损伤模型，以确定肠外抗坏血酸是否调节了导致肺损伤的失调的促炎促凝状态。设计：C57BL/6小鼠暴露于致死性脂多糖剂量(10mUg/g体重)诱导急性肺损伤。地点：实验室研究。对象：野生型C57BL/6小鼠。干预：致死性脂多糖剂量后30分钟，以200 mg/kg的剂量给予抗坏血酸或其氧化形式(脱氢抗坏血酸)。测量和主要结果：我们量化了存活率、肺毛细血管渗漏、炎性趋化因子表达和肺微血管血栓形成。脂多糖在暴露后28小时内对小鼠造成100%的致死率，在肺内我们观察到中性粒细胞强烈的隔离，毛细血管屏障功能的丧失，旺盛的肺部炎症和广泛的微血栓形成。延时输注抗坏血酸和脱氢抗坏血酸均可显著延长存活期。抗坏血酸和脱氢抗坏血酸均保留了肺结构和屏障功能，同时减少了促炎性趋化因子的表达和微血管血栓形成。抗坏血酸和脱氢抗坏血酸可降低核因子-kappaB的激活和凝血参数的正常化。结论：在脓毒症动物模型中，介入性应用抗坏血酸可减轻导致肺血管损伤的促炎、促凝状态。(Crit Care Med 2011；39：1454-1460)
Objective: Sepsis-induced lung injury is a persisting clinical problem with no direct therapy. Recent work suggests that intravenously infused ascorbic acid improves the circulatory dysfunction of sepsis. We used a model of endotoxin-induced acute lung injury to determine whether parenteral ascorbic acid modulates the dysregulated proinflammatory, procoagulant state that leads to lung injury.Design: C57BL/6 mice were exposed to lethal lipopolysaccharide doses (10 mu g/g of body weight) to induce acute lung injury.Setting: Laboratory investigation.Subjects: Wild-type C57BL/6 mice.Interventions: Ascorbic acid or its oxidized form (dehydroascorbic acid) was administered intraperitoneally at 200 mg/kg 30 mins after the lethal lipopolysaccharide dose.Measurements and Main Results: We quantified survival, lung capillary leak, proinflammatory chemokine expression, and lung microvascular thrombosis. Lipopolysaccharide induced 100% lethality in mice within 28 hrs of exposure and in lung we observed intense neutrophil sequestration, loss of capillary barrier function, exuberant pulmonary inflammation, and extensive microthrombus formation. A time-delayed infusion protocol of both ascorbic acid and dehydroascorbic acid significantly prolonged survival. Both ascorbic acid and dehydroascorbic acid preserved lung architecture and barrier function while attenuating proinflammatory chemokine expression and microvascular thrombosis. Ascorbic acid and dehydroascorbic acid attenuated nuclear factor kappa B activation and normalized coagulation parameters.Conclusions: Ascorbic acid administered in an interventional manner following lipopolysaccharide infusion attenuates proinflammatory, procoagulant states that induce lung vascular injury in an animal model of sepsis. (Crit Care Med 2011; 39: 1454-1460)