Am. J. Respir. Crit. Care Med., Volume 165, Number 7, April 2002, 983-991

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

G. Umberto Meduri, Elizabeth A. Tolley, George P. Chrousos, and Frankie Stentz

Memphis Lung Research Program, Divisions of Pulmonary and Critical Care Medicine, Department of Medicine, and Department of Preventive Medicine, University of Tennessee, Memphis, Tennessee; and Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

Nuclear factor-B (NF-B) and glucocorticoid receptor- (GR-) 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- (TNF-), interleukins (IL) IL-1 and IL-6, adrenocorticotropic hormone (ACTH), and cortisol. The ability of patient plasma to influence the NF-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-, 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 NF-B DNA-binding and transcription of TNF- and 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.

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