Nuclear factor-κB- and glucocorticoid receptor α-mediated mechanisms in the regulation of systemic and pulmonary inflammation during sepsis and acute respiratory distress syndrome -: Evidence for inflammation-induced target tissue resistance to glucocorticoids

To test the hypothesis that the interaction between nuclear factor-kappa B (NF-kappa B) and glucocorticoid receptor alpha (GR alpha) is a key pathogenetic mechanism regulating the progression of systemic and pulmonary inflammation in sepsis and acute respiratory distress syndrome (ARDS), we used an ex vivo model of systemic inflammation. Naive peripheral blood leukocytes (PBL) were exposed to longitudinal (days 1-10) plasma samples from ARDS patients divided into three groups based on physiological improvement and clinical outcome by days 7-10: improvers, nonimprovers-survivors, and nonimprovers-nonsurvivors. In a separate group of nonimprovers-survivors, we correlated the severity of lung histopathology with the intensity of NF-kappa B and GR alpha nuclear staining in immunohistochemistry analysis of lung tissue obtained by open lung biopsy. We found that exposure of naive cells to longitudinal plasma samples led to divergent directions in NF-kappa B and GR alpha activation that reflected the severity of systemic inflammation. Plasma samples from improvers with declining cytokine levels over time elicited a progressive increase in all measured aspects of glucocorticoid (GC)-induced GR alpha-mediated activity (p = 0.0001) and a correspondent reduction in NF-kappa B nuclear binding (p = 0.0001) and transcription of TNF-alpha and IL-1 (regulated, GR alpha-driven response). In contrast, plasma samples from nonimprovers with sustained elevation in cytokine levels over time elicited only a modest longitudinal increase in GC-GR alpha-mediated activity (p = 0.04) and a progressive increase in NF-kappa B nuclear binding over time (p = 0.0001) that was most striking in nonsurvivors (dysregulated, NF-kappa B-driven response). By days 3-5, no overlap was observed between groups for NF-kappa B and GC-GR alpha nuclear binding. In immunohistochemistry analyses, lung tissues of patients with severe versus mild ARDS had a higher intensity of NF-kappa B nuclear staining (13 +/- 1.3 vs. 7 +/- 2.9; p = 0.01) and a lower ratio of GR alpha:NF-kappa B in nuclear staining (0.5 +/- 0.2 vs. 1.5 +/- 0.2; p = 0.007). In conclusion, we demonstrated that the ability of GC-GR alpha to downregulate NF-kappa B activation is critical for the resolution of systemic and pulmonary inflammation in ARDS. The findings provide a rationale for the use of prolonged GC treatment in early ARDS. Copyright (C) 2005 S. Karger AG, Basel.