Biological differences between the sexes greatly impact the development and severity of pulmonary disorders such as emphysema. Recent studies have demonstrated crucial roles for osteopontin (OPN, also known as SPP1) in lung inflammation and alveolar destruction in human and experimental emphysema, but the impact of gender on OPN action remains unknown. Here, we report ovary-dependent induction of Opn mRNA with augmentation of experimental emphysema in adult female mice. Both male and female mice developed emphysematous lungs following intra-tracheal administration of porcine pancreatic elastase; however, compared with male mice, female mice developed more severe injury-related inflammation and pathologic alterations of the lungs. Notably, we observed female-specific induction of the Opn gene upon lung injury. Ovariectomy blocked this induction, with attenuation of lung inflammation and alveolar destruction, demonstrating the essential role of ovaries in injury-related Opn induction and augmentation of emphysema in adult female mice. Lastly, pre-treatment of adult female mice with pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, which blocks ATP-mediated wound response, suppressed Opn mRNA induction upon lung injury, resulting in attenuation of enhanced lung inflammation. Together, our findings define a novel, ovary-dependent mechanism underlying gender-specific augmentation of emphysema through transcriptional control of the Opn gene. (C) 2015 Elsevier Inc. All rights reserved.