Higher Blood Uric Acid in Female Humans and Mice as a Protective Factor against Pathophysiological Decline of Lung Function

The oxidant/antioxidant imbalance plays a pivotal role in the lung. Uric acid (UA), an endogenous antioxidant, is highly present in lung tissue, however, its impact on lung function under pathophysiological conditions remains unknown. In this work, pharmacological and genetic inhibition of UA metabolism in experimental mouse models of acute and chronic obstructive pulmonary disease (COPD) revealed that increased plasma UA levels improved emphysematous phenotype and lung dysfunction in accordance with reduced oxidative stress specifically in female but not in male mice, despite no impact of plasma UA induction on the pulmonary phenotypes in nondiseased mice. In vitro experiments determined that UA significantly suppressed hydrogen peroxide (H2O2)-induced oxidative stress in female donor-derived primary human bronchial epithelial (NHBE) cells in the absence of estrogen, implying that the benefit of UA is limited to the female airway in postmenopausal conditions. Consistently, our clinical observational analyses confirmed that higher blood UA levels, as well as the SLC2A9/GLUT9 rs11722228 T/T genotype, were associated with higher lung function in elderly human females. Together, our findings provide the first unique evidence that higher blood UA is a protective factor against the pathological decline of lung function in female mice, and possibly against aging-associated physiological decline in human females.