Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea pig lungs using methylprednisolone
Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea pig lungs using methylprednisolone
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DOI：
10.1152/ajplung.00459.2007
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发表时间：
2008-12-01
影响因子：
4.9
通讯作者：
Hattori, Yuichi
中科院分区：
文献类型：
--
作者：
Kamiyama, Koki;Matsuda, Naoyuki;Hattori, Yuichi
在过去的几十年中，糖皮质激素治疗脓毒症的使用有起有落，最近的随机对照试验引起了对这种疗法的重新评估。大多数糖皮质激素的作用是由其特异性细胞内受体（GR）介导的。因此，我们最初评估了脓毒症和高剂量皮质类固醇治疗是否可以调节豚鼠肺GR的表达：活性受体GR α和显性负性受体GR β。LPS注射（300 μ g/kg ip）诱导脓毒症，降低肺GR α的mRNA和蛋白水平，增加GR β的蛋白表达。高剂量甲基强的松龙（40 mg/kg ip），同时给予LPS，显着加强GR α表达的减少，但轻微影响GR β表达的增加。因此，这导致GR α核转位显著减少。然而，甲基强的松龙治疗强烈消除了LPS诱导的NF-κ B活性，如通过NF-κ B核转位和凝胶迁移率变化测定。此外，LPS诱导的支气管肺泡灌洗液中炎性细胞的增加被皮质类固醇的给药所减弱。另一方面，裂解的caspase-3的免疫荧光染色显示，在肺切片中，这一促凋亡标记物显着增加，末端脱氧核苷酸转移酶dUTP介导的缺口末端标记（TUNEL）表示增强的外观时，甲基强的松龙与LPS一起给予肺和脾细胞凋亡。细胞凋亡被认为在脓毒症的发病机制中发挥作用。因此，我们认为高剂量糖皮质激素加速脓毒症诱导的细胞凋亡的作用可能会压倒其在脓毒症休克中的治疗优势。
The use of glucocorticoids for treatment of sepsis has waxed and waned during the past several decades, and recent randomized controlled trials have evoked a reassessment of this therapy. Most glucocorticoid actions are mediated by its specific intracellular receptors (GRs). Thus we initially evaluated whether sepsis and high-dose corticosteroid therapy can regulate guinea pig pulmonary expression of GRs: active receptor, GR alpha, and dominant negative receptor, GR beta. Sepsis induction by LPS injection (300 mu g/kg ip) decreased mRNA and protein levels of GR alpha and increased protein expression of GR beta in lungs. High-dose methylprednisolone ( 40 mg/kg ip), administered simultaneously with LPS, markedly potentiated the decrease in GR alpha expression but slightly affected the increase in GR beta expression. Consequently, this led to a significant reduction in GR alpha nuclear translocation. Nevertheless, methylprednisolone treatment strongly eliminated LPS induction of NF-kappa B activity, as determined by NF-kappa B nuclear translocation and by gel mobility shift assays. Furthermore, the LPS-induced increase in inflammatory cells in bronchoalveolar lavage fluid was blunted by administration of the corticosteroid. On the other hand, immunofluorescent staining for cleaved caspase-3 showed a marked increase in this proapoptotic marker in lung sections, and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling ( TUNEL) represented an enhanced appearance of cell apoptosis in lungs and spleen when methylprednisolone was given together with LPS. Cell apoptosis is now considered to play a role in the pathogenesis of septic syndrome. We thus suggest that the action of glucocorticoids at high doses to accelerate sepsis-induced cell apoptosis may overwhelm their therapeutic advantages in septic shock.