The effect of roflumilast on lipopolysaccharide-induced acute lung injury during neutropenia recovery in mice

Abstract

<b>Introduction:</b> Patients with acute respiratory failure after prolonged neutropenia complicated by pneumonia are at increased risk for acute respiratory distress syndrome (ARDS). The key molecule of endothelial barrier breakdown in sepsis is lipopolysaccharide (LPS), which is a component of the outer membrane of gram-negative bacterial cell walls. To maintain increased cyclic adenosine monophosphate (cAMP) levels in endothelial cells is effective for preventing endothelial dysfunction and microvascular permeability. The aim of this study was to elucidate whether roflumilast, PDE-4 inhibitor, is effective in LPS-induced ALI during neutropenia recovery in a murine model. <b>Methods:</b> To induce neutropenia, all mice were given intraperitoneal cyclophosphamide. On 2 days after neutropenia, mice were administrated LPS by intra-tracheal instillation. In the prevention group, roflumilast was given orally on day 0, when neutropenia is induced. In the treatment group, roflumilast was given orally 1 hour after LPS administration. <b>Results:</b> Roflumilast attenuated histopathological changes associated with LPS induced lung injury. The accumulation of neutrophils and the concentrations of inflammatory cytokines such as IL-1β, TNF-α and IL-6 in bronchoalveolar lavage fluids were inhibited effectively by roflumilast. Also, expression of MMP-9 and TGF-β was attenuated in roflumilast group. <b>Conclusion:</b> The present study demonstrated that roflumilast significantly attenuated LPS induced ALI during neutropenia recovery.