Prolonged Methylprednisolone Treatment Suppresses Systemic Inflammation in Patients with Unresolving Acute Respiratory Distress Syndrome: Evidence for Inadequate Endogenous Glucocorticoid Secretion and Inflammation-induced Immune Cell Resistance to Glucocorticoids

Abstract Nuclear factor- κ B (NF- κ B) and glucocorticoid receptor- α (GR- α ) have diametrically opposed functions in regulating inflammation. We investigated whether unresolving acute respiratory distress syndrome (ARDS) is associated with systemic inflammation- induced 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- α (TNF- α ), interleukins (IL) IL-1 β and IL-6, adrenocorticotropic hormone (ACTH), and cortisol. The ability of patient plasma to influence the NF- κ B and GR-signal transduction systems of normal peripheral blood leukocytes (PBL) was examined. Patients treated with methylprednisolone had progressive and sustained reductions of TNF- α, IL-1 β, 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 NF- κ B DNA-binding and transcription of TNF- α and IL-1 β. 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.