Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands (T.P., A.B.Z., M.S., M.H.M., J.Z., H.Me., H.Ma.); and Brains On-Line BV, Groningen, The Netherlands (T.K., G.F.).
J Pharmacol Exp Ther. 2014 May;349(2):229-38. doi: 10.1124/jpet.113.210138. Epub 2014 Feb 21.
Airway inflammation and remodeling are major features of chronic obstructive pulmonary disease (COPD), whereas pulmonary hypertension is a common comorbidity associated with a poor disease prognosis. Recent studies in animal models have indicated that increased arginase activity contributes to features of asthma, including allergen-induced airway eosinophilia and mucus hypersecretion. Although cigarette smoke and lipopolysaccharide (LPS), major risk factors for COPD, may increase arginase expression, the role of arginase in COPD is 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 LPS or saline twice weekly for 12 weeks and pretreated by inhalation of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) or vehicle. Repeated LPS exposure increased lung arginase activity, resulting in increased l-ornithine/l-arginine and l-ornithine/l-citrulline ratios. Both ratios were reversed by ABH. ABH inhibited the LPS-induced increases in pulmonary IL-8, neutrophils, and goblet cells as well as airway fibrosis. Remarkably, LPS-induced right ventricular hypertrophy, indicative of pulmonary hypertension, was prevented by ABH. Strong correlations were found between arginase activity and inflammation, airway remodeling, and right ventricular hypertrophy. Increased arginase activity contributes to pulmonary inflammation, airway remodeling, and right ventricular hypertrophy in a guinea pig model of COPD, indicating therapeutic potential for arginase inhibitors in this disease.
气道炎症和重塑是慢性阻塞性肺疾病（COPD）的主要特征，而肺动脉高压是与疾病预后不良相关的常见合并症。最近的动物模型研究表明，精氨酸酶活性的增加与哮喘的特征有关，包括过敏原诱导的气道嗜酸性粒细胞增多和粘液分泌过度。虽然香烟烟雾和脂多糖（LPS）是 COPD 的主要危险因素，可能会增加精氨酸酶的表达，但精氨酸酶在 COPD 中的作用尚不清楚。本研究旨在通过 COPD 动物模型来研究精氨酸酶在肺炎症和重塑中的作用。豚鼠每周两次通过鼻腔内滴注 LPS 或生理盐水 12 周，并通过吸入精氨酸酶抑制剂 2(S)-氨基-6-硼代己酸（ABH）或载体进行预处理。重复 LPS 暴露增加了肺精氨酸酶活性，导致 l-鸟氨酸/l-精氨酸和 l-鸟氨酸/l-瓜氨酸的比值增加。ABH 逆转了这两种比值的增加。ABH 抑制了 LPS 诱导的肺 IL-8、中性粒细胞和杯状细胞以及气道纤维化的增加。值得注意的是，ABH 预防了 LPS 诱导的右心室肥大，这是肺动脉高压的标志。精氨酸酶活性与炎症、气道重塑和右心室肥大之间存在强烈的相关性。豚鼠 COPD 模型中精氨酸酶活性的增加导致肺炎症、气道重塑和右心室肥大，表明精氨酸酶抑制剂在该疾病中的治疗潜力。
