The role of the host defence response in the progression and outcome of ARDS: Pathophysiological correlations and response to glucocorticoid treatment

Abstract

The host defence response (HDR) to insults is similar regardless of the tissue involved and consists of an interactive network of simultaneously activated pathways that act in synergy to increase the host's chance of survival. Among this cascade of integrated pathways, three aspects of the HDR, inflammation, coagulation and tissue repair, are analysed separately to explain the histological and physiological changes occurring at the tissue level in unresolving acute respiratory distress syndrome (ARDS). Cellular responses in HDR are regulated by a complex interaction among cytokines, and cytokines have concentration-dependent biological effects. The degree of initial RDR may determine the progression of ARDS. On Day 1 of mechanical ventilation and over time, nonsurvivors of ARDS have significantly higher plasma and bronchoalveolar lavage inflammatory cytokine levels than survivors. In the absence of inhibitory signals, the continued production of HDR mediators prevents effective restoration of lung anatomy and function by sustaining inflammation with tissue injury, intra- and extravascular coagulation and proliferation of mesenchymal cells (fibroproliferation) with deposition of extracellular matrix resulting in fibrosis. Glucocorticoids inhibit the HDR cascade at virtually all levels; their gradual and generalized suppressive influence protects the host from overshooting. In patients with exaggerated HDR, however, cytokine elevation may cause a concentration dependent resistance to glucocorticoids by reducing glucocorticoid receptor binding affinity. Recent clinical and experimental studies have shown that effective containment of the HDR in unresolving ARDS may be achieved only if glucocorticoid administration is prolonged. A double-blind randomized study is in progress to evaluate the role of prolonged glucocorticoid treatment in unresolving ARDS.