Goodwin Julie E, Feng Yan, Velazquez Heino, Zhou Han, Sessa William C
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Department of Internal Medicine, Veterans Affairs Hospital, West Haven, Connecticut, United States of America.
PLoS One. 2014 Oct 9;9(10):e108126. doi: 10.1371/journal.pone.0108126. eCollection 2014.
Glucocorticoids are normally regarded as anti-inflammatory therapy for a wide variety of conditions and have been used with some success in treating sepsis and sepsis-like syndromes. We previously demonstrated that mice lacking the glucocorticoid receptor in the endothelium (GR EC KO mice) are extremely sensitive to low-dose LPS and demonstrate prolonged activation and up regulation of NF-κB. In this study we pre-treated these GR EC KO mice with dexamethasone and assessed their response to an identical dose of LPS. Surprisingly, the GR EC KO mice fared even worse than when given LPS alone demonstrating increased mortality, increased levels of the inflammatory cytokines TNF-α and IL-6 and increased nitric oxide release after the dexamethasone pre-treatment. As expected, control animals pre-treated with dexamethasone showed improvement in all parameters assayed. Mechanistically we demonstrate that GR EC KO mice show increased iNOS production and NF-κB activation despite treatment with dexamethasone.
糖皮质激素通常被视为针对多种病症的抗炎疗法，并且在治疗败血症和败血症样综合征方面已取得一定成功。我们之前证明，在内皮细胞中缺乏糖皮质激素受体的小鼠（GR EC基因敲除小鼠）对低剂量脂多糖极其敏感，并表现出NF-κB的持续激活和上调。在本研究中，我们用地塞米松预处理这些GR EC基因敲除小鼠，并评估它们对相同剂量脂多糖的反应。令人惊讶的是，GR EC基因敲除小鼠的情况比单独给予脂多糖时更糟，表现出死亡率增加、炎性细胞因子TNF-α和IL-6水平升高以及地塞米松预处理后一氧化氮释放增加。正如预期的那样，用地塞米松预处理的对照动物在所有检测参数上均有改善。从机制上来说，我们证明，尽管使用了地塞米松治疗，GR EC基因敲除小鼠仍表现出诱导型一氧化氮合酶产生增加和NF-κB激活。
