Kadl Alexandra, Pontiller Jens, Exner Markus, Leitinger Norbert
Cardiovascular Research Center and Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.
Shock. 2007 Nov;28(5):582-8. doi: 10.1097/shk.0b013e31804d41dd.
Increasing serum levels of biliverdin and bilirubin was shown to be beneficial in settings of inflammation. Bilirubin was shown to be protective in LPS-induced lung injury in rats; however, the exact mechanism remains elusive. Here, we investigated whether a single bolus injection of bilirubin would exert anti-inflammatory effects in a mouse model of endotoxemia. Mice were challenged with sublethal doses (2 mg/kg body weight) of LPS, and the effects of intravenously administered bilirubin (40 mg/kg body weight) were assessed. In contrast to control animals, bilirubin-treated animals fully recovered from endotoxin shock within 24 h. Bilirubin treatment improved the clinical score significantly at all time points assessed, attenuated weight loss, and improved LPS-induced anorexia. Furthermore, bilirubin treatment inhibited LPS-induced leukocyte-endothelial interactions and leukocyte accumulation in various tissues. Expression of inflammatory genes, including endothelial adhesion molecules, but also IL-1beta and TNF-alpha, was significantly reduced in bilirubin-treated animals. Moreover, bilirubin inhibited LPS-induced expression of inflammatory genes in isolated cultured aortic endothelial cells and in bone marrow-derived macrophages. These data show that single-dose administration of bilirubin attenuates tissue injury induced by endotoxin, and that bilirubin, in addition to its antioxidant effects, also exerts potent anti-inflammatory activity.
血清中胆绿素和胆红素水平升高在炎症环境中显示出有益作用。胆红素在大鼠脂多糖诱导的肺损伤中具有保护作用；然而，确切机制仍不清楚。在此，我们研究了单次推注胆红素是否会在内毒素血症小鼠模型中发挥抗炎作用。用亚致死剂量（2毫克/千克体重）的脂多糖攻击小鼠，并评估静脉注射胆红素（40毫克/千克体重）的效果。与对照动物相比，胆红素处理的动物在24小时内从内毒素休克中完全恢复。胆红素处理在所有评估时间点均显著改善临床评分，减轻体重减轻，并改善脂多糖诱导的厌食症。此外，胆红素处理抑制脂多糖诱导的白细胞与内皮细胞相互作用以及白细胞在各种组织中的积聚。在胆红素处理的动物中，包括内皮粘附分子、白细胞介素-1β和肿瘤坏死因子-α在内的炎症基因表达显著降低。此外，胆红素抑制脂多糖诱导的分离培养的主动脉内皮细胞和骨髓来源巨噬细胞中炎症基因的表达。这些数据表明，单剂量胆红素可减轻内毒素诱导的组织损伤，并且胆红素除了具有抗氧化作用外，还具有强大的抗炎活性。
