Experimental approaches for understanding pathogenesis and development of novel therapeutic modalities for ARDS

Abstract

The acute respiratory distress syndrome (ARDS) is characterized by acute inflammation and subsequent permeability edema of the lung. We have been investigating the pathogenesis of ARDS and efficacy of various agents, including inhibitors of inflammatory mediators, to establish a therapeutic modality for ARDS. Since endotoxin (LPS) is a major substance that induces acute lung inflammation and ARDS, we evaluated the effect of blocking LPS-signaling pathway, using a monoclonal antibody against CD14, an LPS receptor on the cell surface. CD14 blockade significantly attenuated LPS-induced lung injury in mice. Attenuation of LPS-induced lung injury was also observed in a mutant mouse of Toll-like receptor 4, a key molecule of LPS-signaling pathway. We showed protective effects of an analog of lipid A, which is a key component of biological activities of LPS. It has been known that circulating neutrophils play important roles in the pathogenesis of ARDS, but we revealed that activated mononuclear phagocytes also contribute by releasing cytokines and other inflammatory mediators. The efficacy of inhibitors for TNF-α converting enzyme (TACE) and neutrophil elastase were revealed in experimental models of acute lung injury. After clinical trials, the neutrophil elastase inhibitor has been launched in Japan as a prescription drug. We think that experimental approaches like ours may contribute to understanding pathogenesis and development of novel therapeutic modalities for ARDS.