Nuclear factor-kappaB- and glucocorticoid receptor alpha- 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.

G. Umberto Meduri, Muthiah P. Muthiah, Pierluigi Carratu, Mahmoud Eltorky, George P. Chrousos

Research output: Contribution to journalArticle

Abstract

To test the hypothesis that the interaction between nuclear factor-kappaB (NF-kappaB) and glucocorticoid receptor alpha (GRalpha) 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. Naïve 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-kappaB and GRalpha nuclear staining in immunohistochemistry analysis of lung tissue obtained by open lung biopsy. We found that exposure of naïve cells to longitudinal plasma samples led to divergent directions in NF-kappaB and GRalpha 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 GRalpha-mediated activity (p = 0.0001) and a correspondent reduction in NF-kappaB nuclear binding (p = 0.0001) and transcription of TNF-alpha and IL-1beta (regulated, GRalpha-driven response). In contrast, plasma samples from nonimprovers with sustained elevation in cytokine levels over time elicited only a modest longitudinal increase in GC-GRalpha-mediated activity (p = 0.04) and a progressive increase in NF-kappaB nuclear binding over time (p = 0.0001) that was most striking in nonsurvivors (dysregulated, NF-kappaB-driven response). By days 3-5, no overlap was observed between groups for NF-kappaB and GC-GRalpha nuclear binding. In immunohistochemistry analyses, lung tissues of patients with severe versus mild ARDS had a higher intensity of NF-kappaB nuclear staining (13 +/- 1.3 vs. 7 +/- 2.9; p = 0.01) and a lower ratio of GRalpha:NF-kappaB in nuclear staining (0.5 +/- 0.2 vs. 1.5 +/- 0.2; p = 0.007). In conclusion, we demonstrated that the ability of GC-GRalpha to downregulate NF-kappaB 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.

Original languageEnglish (US)
Pages (from-to)321-338
Number of pages18
JournalNeuroImmunoModulation
Volume12
Issue number6
StatePublished - 2005
Externally publishedYes

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Adult Respiratory Distress Syndrome
Sepsis
Pneumonia
Inflammation
Glucocorticoids
Lung
Staining and Labeling
Survivors
Immunohistochemistry
Cytokines
glucocorticoid receptor alpha
Glucocorticoid Receptor Deficiency
Leukocytes
Down-Regulation
Tumor Necrosis Factor-alpha
Biopsy

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Immunology

Cite this

Nuclear factor-kappaB- and glucocorticoid receptor alpha- 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. / Meduri, G. Umberto; Muthiah, Muthiah P.; Carratu, Pierluigi; Eltorky, Mahmoud; Chrousos, George P.

In: NeuroImmunoModulation, Vol. 12, No. 6, 2005, p. 321-338.

Research output: Contribution to journalArticle

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abstract = "To test the hypothesis that the interaction between nuclear factor-kappaB (NF-kappaB) and glucocorticoid receptor alpha (GRalpha) 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. Na{\"i}ve 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-kappaB and GRalpha nuclear staining in immunohistochemistry analysis of lung tissue obtained by open lung biopsy. We found that exposure of na{\"i}ve cells to longitudinal plasma samples led to divergent directions in NF-kappaB and GRalpha 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 GRalpha-mediated activity (p = 0.0001) and a correspondent reduction in NF-kappaB nuclear binding (p = 0.0001) and transcription of TNF-alpha and IL-1beta (regulated, GRalpha-driven response). In contrast, plasma samples from nonimprovers with sustained elevation in cytokine levels over time elicited only a modest longitudinal increase in GC-GRalpha-mediated activity (p = 0.04) and a progressive increase in NF-kappaB nuclear binding over time (p = 0.0001) that was most striking in nonsurvivors (dysregulated, NF-kappaB-driven response). By days 3-5, no overlap was observed between groups for NF-kappaB and GC-GRalpha nuclear binding. In immunohistochemistry analyses, lung tissues of patients with severe versus mild ARDS had a higher intensity of NF-kappaB nuclear staining (13 +/- 1.3 vs. 7 +/- 2.9; p = 0.01) and a lower ratio of GRalpha:NF-kappaB in nuclear staining (0.5 +/- 0.2 vs. 1.5 +/- 0.2; p = 0.007). In conclusion, we demonstrated that the ability of GC-GRalpha to downregulate NF-kappaB 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.",
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AU - Chrousos, George P.

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