To test the hypothesis that the interaction between nuclear factor-ĸB (NF-ĸB) and glucocorticoid receptor α (GRα) 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-ĸB and GRα 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-ĸB and GRα 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 GRα-mediated activity (p = 0.0001) and a correspondent reduction in NF-ĸB nuclear binding (p = 0.0001) and transcription of TNF-α and IL-1β (regulated, GRα-driven response). In contrast, plasma samples from nonimprovers with sustained elevation in cytokine levels over time elicited only a modest longitudinal increase in GC-GRα-mediated activity (p = 0.04) and a progressive increase in NF-ĸB nuclear binding over time (p = 0.0001) that was most striking in nonsurvivors (dysregulated, NF-ĸB-driven response). By days 3–5, no overlap was observed between groups for NF-ĸB and GC-GRα nuclear binding. In immunohistochemistry analyses, lung tissues of patients with severe versus mild ARDS had a higher intensity of NF-ĸB nuclear staining (13 ± 1.3 vs. 7 ± 2.9; p = 0.01) and a lower ratio of GRα:NF-ĸB in nuclear staining (0.5 ± 0.2 vs. 1.5 ± 0.2; p = 0.007). In conclusion, we demonstrated that the ability of GC-GRα to downregulate NF-ĸB 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.

BACKGROUND . In obese subjects with obstructive sleep apnea (OSA), chronic intermittent hypoxia (CIH) may be linked to systemic and adipose tissue inflammation. METHODS . We obtained abdominal subcutaneous adipose tissue biopsies from OSA and non-OSA obese (BMI > 35) subjects at baseline and after 24 weeks (T1) of weight-loss intervention plus continuous positive airway pressure (c-PAP) or weight-loss intervention alone, respectively. OSA subjects were grouped according to good (therapeutic) or poor (subtherapeutic) adherence to c-PAP. RESULTS . At baseline, anthropometric and metabolic parameters, serum cytokines, and adipose tissue mRNA levels of obesity-associated chemokines and inflammatory markers were not different in OSA and non-OSA subjects. At T1, body weight was significantly reduced in all groups. Serum concentrations of IL-2, IL-4, IL-6, MCP-1, PDGF β , and VEGF α were reduced by therapeutic c-PAP in OSA subjects and remained unaltered in non-OSA and subtherapeutic c-PAP groups. Similarly, adipose tissue mRNA levels of macrophage-specific (CD68, CD36) and ER stress (ATF4, CHOP, ERO-1) gene markers, as well as of IL-6, PDGF β , and VEGF α , were decreased only in the therapeutic c-PAP group. CONCLUSION . CIH does not represent an additional factor increasing systemic and adipose tissue inflammation in morbid obesity. However, in subjects with OSA, an effective c-PAP therapy improves systemic and obesity-associated inflammatory markers. FUNDING . Ministero dell’Università e della Ricerca and Progetti di Rilevante Interesse Nazionale.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which rapidly leads to chronic respiratory failure requiring mechanical ventilation. Currently, forced vital capacity (FVC) < 50% is considered as physiologic marker for admitting patients to Noninvasive Positive Pressure Ventilation (NPPV) intervention, although it has been recently shown the median survival of patients with baseline FVC < 75% much shorter than median survival of patients with baseline FVC > 75%, independently by any treatment.