Biliverdin administration protects against endotoxin-induced acute lung injury in rats
Biliverdin administration protects against endotoxin-induced acute lung injury in rats
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DOI：
10.1152/ajplung.00458.2004
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发表时间：
2005-12-01
影响因子：
4.9
通讯作者：
Otterbein, LE
中科院分区：
文献类型：
--
作者：
Sarady-Andrews, JK;Liu, F;Otterbein, LE
鉴于脓毒症肺部炎症的高发病率和死亡率，迫切需要新的治疗方法来预防急性呼吸窘迫。血红素加氧酶-1(HO-1)对肺损伤具有很强的细胞保护作用，但其作用机制尚不清楚。HO-1将血红素分解成胆绿素，胆绿素在胆绿素还原酶的作用下迅速转化为胆红素。我们测试了BV给药可以替代HO-1所观察到的效果的假设。利用众所周知的脂多糖诱导休克的大鼠模型，我们证明暴露于BV可以在系统和肺部提供对致死性内毒素血症的有效防御，并有效地消除炎症反应。在注射致死剂量的内毒素之前注射BV可显著提高长期存活率：假手术对照组为87%，假手术对照组为20%。BV治疗可抑制内毒素诱导的肺通透性增加和肺泡炎，并显著降低内毒素诱导的促炎细胞因子IL-6的水平。此外，在脂多糖后立即给予胆红素也可减轻肺部炎症。BV治疗还增强了抗炎细胞因子IL-10的表达。BV对体外培养的小鼠肺内皮细胞和脂多糖处理的RAW 264.7巨噬细胞产生的影响相似。综上所述，这些数据表明，BV可以调节炎症反应，抑制肺内的病理生理变化，因此可能在肺部炎症性疾病状态下具有治疗作用。
Given the high morbidity and mortality rates associated with pulmonary inflammation in sepsis, there is a pressing need for new therapeutic modalities to prevent acute respiratory distress. The enzyme heme oxygenase-1 (HO-1) provides potent cytoprotection against lung injury; however, the mechanism by which it does so is unclear. HO-1 catabolizes heme into biliverdin (BV), which is rapidly converted to bilirubin by BV reductase. We tested the hypothesis that BV administration could substitute for the effects observed with HO-1. Using the well-described rat model of LPS-induced shock, we demonstrate that exposure to BV imparts a potent defense against lethal endotoxemia systemically, as well as in the lungs, and effectively abrogates the inflammatory response. BV administration before a lethal dose of LPS leads to a significant improvement in long-term survival: 87% vs. 20% in sham-treated controls. BV treatment suppressed LPS-induced increases in lung permeability and lung alveolitis and significantly reduced serum levels of the LPS-induced proinflammatory cytokine IL-6. Moreover, bilirubin administered just after LPS also abrogated lung inflammation. BV treatment also augmented expression of the anti-inflammatory cytokine IL-10. Similar effects on production were observed with BV treatment in vitro in mouse lung endothelial cells and RAW 264.7 macrophages treated with LPS. In conclusion, these data demonstrate that BV can modulate the inflammatory response and suppress pathophysiological changes in the lung and may therefore have therapeutic application in inflammatory disease states of the lung.