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.
