Chronic Obstructive Pulmonary Disease

Biography

Biography: Hirofumi Nohara

Abstract

Chronic obstructive pulmonary disease (COPD) is mainly characterized by airway mucus obstruction, chronic inflammation and emphysema. Identification of novel factors that control the COPD pulmonary phenotypes is an important issue for better treatment of COPD patients. Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone, and because of its pancreatic supporting function, GLP-1 receptor agonist is clinically used as a drug for the treatment of type 2 diabetes. Interestingly, GLP-1 receptor is highly expressed in lung tissue compared with other tissues. But little is known about the physiological and pathophysiological roles of GLP-1 in lung. Here, we showed that intratracheal treatment of airway specific βENaC (epithelial Na+ channel β subunit)-transgenic mice, a murine model of COPD that basically exhibits airway mucus obstruction, with GLP-1 receptor agonist Exendin-4 (10 pmol/day, 2 weeks) significantly up-regulates mucin gene expression in lung tissue. Moreover, Exendin-4 significantly increased the alveolar mean linear intercept (MLI), a measure of emphysema, in βENaC-Tg mice. Notably, GLP-1 receptor agonist (Exendin-4 and Liraglutide) treatment (0.1 nM, 6-12 hrs) also enhanced mucin expression in β/γENaC-overexpressing 16HBE14o-cells, and the effect was possibly induced by p38 MAP kinase pathway. Despite observations of Exendin-4-dependent mucin up-regulation in WT mice and parental 16HBE14o- cells, exacerbation of pulmonary phenotypes were not observed in these conditions. Together, our studies demonstrate that pulmonary GLP-1 signal exacerbates the phenotypes of βENaC-Tg mice at least partly via p38 MAPK-dependent mucin induction, and our data may caution against the clinical use of inhaled GLP-1 receptor agonist in COPD patients with type 2 diabetes.