Arginase Inhibition Prevents Inflammation and Remodeling in a Guinea Pig Model of Chronic Obstructive Pulmonary Disease

Abstract

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 allergeninduced 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.

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

“…ing, which is consistent with our current observations, but also prevented increased lung IL-8 and neutrophil influx (44). This is in contrast to our observation in the neonatal rat, since arginase inhibition did not affect the bleomycin-induced markers of inflammation.…”

“…Arginase has previously been shown to be involved in the development of PHT and lung fibrosis (9,25,29,32,44,63). Using repeated intraperitoneal administration of bleomycin in neonatal rats as a model of chronic neonatal lung injury and PHT, we report increased expression of arginase I, arginase II, and NOS2 in the bleomycin-exposed lung.…”

“…The finding that arginase inhibition in our model prevented the bleomycin-induced development of PHT and collagen deposition is therefore in keeping with previous observations. The importance of arginase in the development of PHT and the efficacy of arginase inhibition in prevention have also recently been shown in a guinea pig model of lipopolysaccharide-induced chronic obstructive pulmonary disease (COPD) (44). Evidence supporting a role for arginase II in the development of PAH comes from a transgenic mouse model in which IL-13 was specifically overexpressed in the lung (5).…”

Functions of Galectin-3 and Its Role in Fibrotic Diseases

“…Acute inflammation is the normal response of vascularized tissues to injury, irritation, and infection, while chronic inflammation is a harmful process that occurs through failure to resolve acute inflammation or persistence of an inflammatory stimulus (Nathan and Ding, 2010;Pera et al, 2014). Gal-3 is a novel and potent inflammatory protein, largely owing to macrophage activation and migration (Liu and Hsu, 2007;MacKinnon et al, 2008;Hsu et al, 2009).…”

Is arginase a potential drug target in tobacco-induced pulmonary endothelial dysfunction?

“…Over the last few years, it has become increasingly clear that arginases have a harmful role in systemic vascular conditions in animal models and in humans (including atherosclerosis, coronary artery disease, myocardial ischemia-reperfusion, diabetes mellitus, heart failure, hypertension and ageing) [11][12][13][14][15][16][17][18]. Cigarette smoke can increase arginase activity and protein expression in systemic vessels or in the lung [19][20][21]. Although arginases are also expressed in the pulmonary vasculature, [22,23] there are no literature data on the latter's role in tobacco-induced pulmonary endothelial dysfunction in humans.…”