Address for correspondence: Dr. G. Umberto Meduri, University of Tennessee Health Science Center, College of Medicine, Pulmonary Division, Memphis, TN 38163. Voice: 901-448-5258; fax: 901-448-7726. umeduri{at}utmem.edu
Ann. N.Y. Acad. Sci. 1024: 24-53 (2004).
Dysregulated systemic inflammation with excess activation of
pro-inflammatory transcription factor nuclear factor-
B (NF-
B)—activated
by inflammatory signals—compared to the anti-inflammatory
transcription factor glucocorticoid receptor-
(GR
)—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-B and the inhibitory GR. 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.
