Activation and regulation of systemic inflammation in ARDS: rationale for prolonged glucocorticoid therapy.
Experimental and clinical evidence has demonstrated a strong cause-and-effect relationship between persistence vs reduction in systemic inflammation and progression (unresolving) vs resolution (resolving) of ARDS. In this review, the cellular mechanisms involved in activating and regulating inflammation are contrasted between patients with resolving and unresolving ARDS. At the cellular level, patients with unresolving ARDS have deficient glucocorticoid (GC)-mediated down-regulation of inflammatory cytokine and chemokine transcription despite elevated levels of circulating cortisol, a condition defined as systemic inflammation-associated acquired GC resistance. These patients, contrary to those with resolving ARDS, have persistent elevation in levels of both systemic and BAL fluid inflammatory cytokines and chemokines, markers of alveolar-capillary membrane permeability and fibrogenesis. At the tissue level, the continued production of inflammatory mediators leads to tissue injury, intravascular and extravascular coagulation, and the proliferation of mesenchymal cells, all resulting in maladaptive lung repair and progression of extrapulmonary organ dysfunction. In ARDS, down-regulation of systemic inflammation is essential to restoring homeostasis, decreasing morbidity, and improving survival. Prolonged low-to-moderate dose GC therapy promotes the down-regulation of inflammatory cytokine transcription at the cellular level. Eight controlled studies have consistently reported a significant reduction in markers of systemic inflammation, pulmonary and extrapulmonary organ dysfunction scores, duration of mechanical ventilation, and ICU length of stay. In the aggregate (n = 628), reduction in mortality was substantial for all patients (relative risk [RR], 0.75; 95% CI, 0.63 to 0.89; p < 0.001; I(2), 43%) and for those treated before day 14 (RR, 0.71; 95% CI, 0.59 to 0.85; p < 0.001; I(2), 40%).
Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Tennessee Health Science Center, Memphis, TN; Memphis VA Medical Center, Memphis, TN. Electronic address: umeduri@utmem.edu.
G Umberto
GU
Meduri
Université de Versailles SQY (UniverSud Paris), Garches, France.
Djillali
D
Annane
Athens University Medical School, Athens, Greece.
George P
GP
Chrousos
East Virginia Medical School, Norfolk, VA.
Paul E
PE
Marik
Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Tennessee Health Science Center, Memphis, TN; Memphis VA Medical Center, Memphis, TN.
Scott E
SE
Sinclair
D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000378:metabolism
D016207:Cytokines; D005938:Glucocorticoids; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha