Airway inflammation and remodeling are major features of COPD. In addition, pulmonary hypertension is a common comorbidity that is associated with a poor prognosis in COPD. Recent studies indicated that increased arginase activity contributes to allergen-induced airway inflammation, hyperresponsiveness and remodeling in a guinea pig model of allergic asthma. Although there is evidence that cigarette smoke and lipopolysaccharide (LPS), two risk factors of COPD, increase arginase expression, the role of arginase in the pathogenesis of COPD is currently unknown. This study aimed to investigate the role of arginase in pulmonary inflammation and remodeling using an animal model of COPD. Guinea pigs were instilled intranasally with either lipopolysaccharide (LPS) or saline twice weekly for 12 weeks and were pretreated by inhalation with the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) or phosphate-buffered saline. Repeated LPS exposure increased lung arginase activity, resulting in increased L-ornithine/L-arginine and L-ornithine/L-citrulline ratio's. Both amino acid ratio's were reversed by ABH treatment. Repeated LPS exposure also induced increased IL-8 levels, neutrophils, goblet cells and hydroxyproline in the lung, which were all attenuated by ABH. Remarkably, LPS-induced increase in right ventricular mass, indicative of pulmonary hypertension, was fully abrogated by the arginase inhibitor. In conclusion, increased arginase activity contributes to pulmonary inflammation, airway remodeling and right ventricular hypertrophy in a guinea pig model of COPD, indicating that arginase inhibitors may have therapeutic potential in the treatment of this disease.