Haruka Fujikawa
Reseracher and Master course student
Department of Molecular Medicine
Kumamoto University
Japan
Title: Plasma uric acid as a protective factor of respiratory dysfunction and emphysema in female mice and human with obstructive pulmonary diseases
Biography
researcher and Master course student, Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences,Kumamoto University
Abstract
One of the major pathophysiological hallmarks of COPD is oxidative stress. Our microarray analysis using the lung tissue of COPD-like murine models (ï¢ENaC-transgenic mice) suggested an imbalance between oxidants and antioxidants. Uric acid (UA), a product of purine metabolism, is one of the strongest endogenous anti-oxidants in the body. Interestingly, recent cohort studies showed that low levels of serum UA are associated with higher rates of COPD (Horsfall LJ, et al., Thorax 2014; Nicks ME, et al., COPD, 2011). However, the experimental evidence remains inconclusive. To clarify how serum UA levels affect pulmonary phenotypes of COPD, we treated βENaC-Tg mice with oxonate, a pharmacological inhibitor of uricase, which is an enzyme that oxidizes UA to allantoin, to increase blood concentration of UA in the mice. Notably, oxonate treatment (500 mg/kg/day, p.o., 4-5 weeks) in βENaC-Tg mice revealed that typical phenotypes of COPD, such as emphysema demonstrated by an alteration of the mean linear intercept (MLI), and pulmonary function (FEV0.1%) determined by the ventilator-based flexiVent system, tended to be improved in oxonate-treated βENaC-Tg female but not male mice. Moreover, a cross-sectional study and a retrospective longitudinal study with Japanese participants in a health screening program also demonstrated the association between plasma UA level and pulmonary function in a female-specific manner. Thus, ours studies demonstrate plasma UA as a protective factor of respiratory dysfunction and emphysema in female mice and human with obstructive pulmonary diseases.
Hirofumi Nohara
Researcher
Undergraduate student
Kumamoto University
Japan
Title: GLP-1 receptor agonist exacerbates mucus hypersecretory phenotype in βENaC-transgenic mouse with obstructive lung diseases
Biography
Researcher and Master course student, Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University 2016-present, Doctor course student, Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University
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.
