title: Systemic inflammation-associated glucocorticoid resistance and outcome of ARDS.
abstract: Dysregulated systemic inflammation with excess activation of pro-inflammatory transcription factor nuclear factor-kappaB (NF-kappaB)-activated by inflammatory signals-compared to the anti-inflammatory transcription factor glucocorticoid receptor-alpha (GRalpha)-activated by endogenous or exogenous glucocorticoids (GCs)-is an important pathogenetic mechanism for pulmonary and extrapulmonary organ dysfunction in patients with acute respiratory distress syndrome (ARDS). Activation of one transcription factor in excess of the binding (inhibitory) capacity of the other shifts cellular responses toward increased (dysregulated) or decreased (regulated) transcription of inflammatory mediators over time. Recent data indicate that failure to improve in ARDS (unresolving ARDS) is frequently associated with failure of the activated GRs to downregulate the transcription of inflammatory cytokines despite elevated levels of circulating cortisol, a condition defined as systemic inflammation-associated acquired GC resistance; it is potentially reversible with prolonged GC supplementation. In the first part of this paper, after a brief description of inflammation in ARDS and our model of translational research, we review the two cellular signaling pathways that are central to the regulation of inflammation-the stimulatory NF-alphaB and the inhibitory GRalpha. In the second part, we review findings of recent studies indicating that excessive inflammatory activity in patients with unresolving ARDS may induce noncompensated GC resistance in target organs. In the third part, we review factors affecting cellular response to GC and potential mechanisms involved in inflammation-associated GC resistance.
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA. umeduri@utmem.edu
authors.forename: G Umberto
authors.initials: GU
authors.lastname: Meduri
authors.forename: Charles R
authors.initials: CR
authors.lastname: Yates
mesh_terms: D015415:Biomarkers / Q000032:analysis; D004351:Drug Resistance; D005938:Glucocorticoids / Q000502:physiology / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008137:Longitudinal Studies; D016328:NF-kappa B / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology*; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D005938:Glucocorticoids; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha