Excessive systemic inflammation is the pathophysiologic hall- mark of pulmonary and extrapulmonary organ dysfunction in patients with acute respiratory distress syndrome (ARDS)

DOI: 10.1164/rccm.2106014 Internet address: www.atsjournals.org Nuclear factorB (NFB) and glucocorticoid receptor(GR) have diametrically opposed functions in regulating inflammation. We investigated whether unresolving acute respiratory distress syndrome (ARDS) is associated with systemic inflammationinduced glucocorticoid resistance and whether prolonged methylprednisolone administration accelerates the suppression of systemic inflammatory indices and normalizes the sensitivity of the immune system to glucocorticoids. Patients enrolled into a randomized trial evaluating prolonged methylprednisolone administration in unresolving ARDS had serial plasma samples collected before and after randomization. In the plasma, we measured the concentrations of tumor necrosis factor(TNF), interleukins (IL) IL-1 and IL-6, adrenocorticotropic hormone (ACTH), and cortisol. The ability of patient plasma to influence the NFB and GR-signal transduction systems of normal peripheral blood leukocytes (PBL) was examined. Patients treated with methylprednisolone had progressive and sustained reductions of TNF, IL-1 , IL-6, ACTH, and cortisol concentrations over time. Normal PBL exposed to plasma samples collected during methylprednisolone exhibited significant progressive increases in all aspects of GR-mediated activity and significant reductions in NFB DNA-binding and transcription of TNFand IL-1 . These findings provide support for the presence of endogenous glucocorticoid inadequacy in the control of inflammation and systemic inflammation-induced peripheral glucocorticoid resistance in ARDS. Prolonged methylprednisolone administration accelerated the resolution of both systemic inflammation and peripheral acquired glucocorticoid resistance in ARDS.