Macrophage activation by gastric fluid suggests MMP involvement in aspiration-induced lung disease

Abstract

Asthma occurs in more than 5% of the population in industrialized countries and is now characterized as a chronic inflammatory disease. The chronic aspiration of gastric fluid is considered by many investigators to be a primary inflammatory factor exacerbating or predisposing patients to asthma, with more than 50 medical papers per year linking asthma with gastroesophageal reflux disease (GERD), which can lead to aspiration events. However, the mechanisms involved in the inflammatory effects caused by gastric-fluid aspiration are not clear at the present time. The role of macrophages in the pathogenesis of disease seems likely given the involvement of those cells in a variety of chronic inflammatory diseases. To investigate the potential role of gastric fluid and the mechanisms potentially underlying chronic aspiration-associated pathogenesis, we examined the activation of murine macrophages (Raw 264.7 cell line) with gastric fluid. Inflammatory cytokine production and activation of the NF-kappaB signaling pathway were observed. Toll-like receptor (TLR)-4-dependent activation was observed under some conditions, indicating that bacterial components within the gastric fluid are involved in macrophage activation. Matrix metalloproteinase-9 (MMP-9) expression by macrophages was enhanced by gastric fluid, suggesting a potential mechanism by which remodeling of airways might be induced by gastric-fluid aspiration.