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.
Nuclear factor-kappaB (NF-kappaB) and glucocorticoid receptor-alpha (GR-alpha) 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-alpha (TNF-alpha), interleukins (IL) IL-1beta and IL-6, adrenocorticotropic hormone (ACTH), and cortisol. The ability of patient plasma to influence the NF-kappaB and GR-signal transduction systems of normal peripheral blood leukocytes (PBL) was examined. Patients treated with methylprednisolone had progressive and sustained reductions of TNF-alpha, IL-1beta, 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-kappaB DNA-binding and transcription of TNF-alpha and IL-1beta. 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.
Meduri
G Umberto
GU
Memphis Lung Research Program, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Tennessee, Memphis, Tennessee, USA. umeduri@utmem.edu
Tolley
Elizabeth A
EA
Chrousos
George P
GP
Stentz
Frankie
F
D000324:Adrenocorticotropic Hormone / Q000097:blood; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000150:complications* / Q000503:physiopathology; D015398:Signal Transduction; D018746:Systemic Inflammatory Response Syndrome / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D015533:Transcriptional Activation
D016207:Cytokines; D005938:Glucocorticoids; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone; D008775:Methylprednisolone