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This Article Full Text Full Text (PDF) All Versions of this Article: 295/6/L998    most recent 00459.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kamiyama, K. Articles by Hattori, Y. PubMed PubMed Citation Articles by Kamiyama, K. Articles by Hattori, Y.

Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea pig lungs using methylprednisolone

¹Department of Molecular and Medical Pharmacology, ²Department of Surgery, ³Department of Diagnostic Pathology, and ⁴Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

Submitted 6 November 2007 ; accepted in final form 2 October 2008

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, and dominant negative receptor, GRβ. Sepsis induction by LPS injection (300 µg/kg ip) decreased mRNA and protein levels of GR and increased protein expression of GRβ in lungs. High-dose methylprednisolone (40 mg/kg ip), administered simultaneously with LPS, markedly potentiated the decrease in GR expression but slightly affected the increase in GRβ expression. Consequently, this led to a significant reduction in GR nuclear translocation. Nevertheless, methylprednisolone treatment strongly eliminated LPS induction of NF-B activity, as determined by NF-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.

lung inflammation; nuclear factor-B