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Evidence of biological efficacy for prolonged glucocorticoid treatment in patients with unresolving ARDS

Memphis Lung Research Program, Dept of Medicine, Pulmonary and Critical Care Division, The University of Tennessee Health Science Center, Memphis, Tennessee, USA

CORRESPONDENCE: G.U. Meduri, University of Tennessee Health Science Center, Division of Pulmonary and Critical Care Medicine, 956 Court Avenue, Room H316, Memphis, TN 38163, USA. Fax: 901 4487726. E-mail: umeduri@utmem.edu

Keywords: acute respiratory distress syndrome, biology, glucocorticoid, glucocorticoid receptor, nuclear factor-B, outcome

This work was supported by the Baptist Memorial Health Care Foundation and the Assisi Foundation of Memphis.

Acute respiratory distress syndrome (ARDS) is a disease of multifactorial etiology characterised by rapid development of severe diffuse and nonhomogenous inflammation of the pulmonary lobules causing life-threatening hypoxaemic respiratory failure. The current authors tested a therapeutic intervention on a previously defined pathophysiological model of ARDS. The model was defined by investigating, during the natural history of ARDS, the relationship among the three fundamental elements of a disease process pathogenesis, structural alterations, and functional consequences. In these studies, the present authors provided biological and morphological evidence indicating that ARDS patients failing to improve after 1 week of mechanical ventilation (unresolving ARDS) have intense and protracted (dysregulated) pulmonary and systemic inflammatory and neo-fibrogenetic activity.

Nuclear factor-B and the glucocorticoid receptor have diametrically opposed functions in regulating inflammation. This chapter will review recent data indicating that poor outcome in acute respiratory distress syndrome might be related in part to failure of the activated glucocorticoid receptors to downregulate the transcription of inflammatory cytokines despite elevated levels of circulating cortisol. In a small randomised study of patients with unresolving acute respiratory distress syndrome, the current authors have shown that prolonged glucocorticoid supplementation improved all aspects of glucocorticoid receptors function and enhanced glucocorticoid-mediated anti-inflammatory action by interfering with nuclear factor-B activation.