期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 295, 期 6, 页码 L998-L1006出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00459.2007
关键词
lung inflammation; nuclear factor-kappa B
资金
- Grant-in-Aid for Scientific Research [18590233, 19399405]
- Ministry of Education, Culture, Sports, Science and Technology of Japan. [16659417]
- Grants-in-Aid for Scientific Research [18590233, 16659417] Funding Source: KAKEN
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.
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