Prolonged Methylprednisolone Treatment Suppresses Systemic Inflammation in Patients with Unresolving Acute Respiratory Distress Syndrome

TLDR

NF‑κB and glucocorticoid receptor‑α have opposing roles in inflammation regulation. The study examined whether unresolving ARDS is linked to systemic inflammation‑induced glucocorticoid resistance and whether prolonged methylprednisolone can accelerate suppression of systemic inflammatory markers and restore immune sensitivity to glucocorticoids. In a randomized trial, patients with unresolving ARDS had serial plasma samples taken before and after methylprednisolone treatment, and concentrations of TNF‑α, IL‑1β, IL‑6, ACTH, and cortisol were measured, while the effect of plasma on NF‑κB and GR signaling in normal peripheral blood leukocytes was assessed. Methylprednisolone treatment led to progressive reductions in TNF‑α, IL‑1β, IL‑6, ACTH, and cortisol, increased GR‑mediated activity and decreased NF‑κB DNA‑binding in peripheral leukocytes, supporting endogenous glucocorticoid inadequacy and demonstrating that prolonged therapy accelerates resolution of systemic inflammation and glucocorticoid resistance in ARDS.

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.