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%).