Περίληψη:
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.
Συγγραφείς:
Meduri, GU
Muthiah, MP
Carratu, P
Eltorky, M
Chrousos,
GP
