Role of nitric oxide synthase/arginase balance in bronchial reactivity in patients with chronic obstructive pulmonary disease

Abstract

Competition between nitric oxide synthases (NOSs) and arginases for their common substrate l-arginine could be involved in the regulation of cholinergic airway reactivity and subsequent airway remodeling. The aims of this study were to evaluate the relationships between the expression of this enzymatic balance and the effects of NOS and arginase inhibition on bronchoconstrictive response to acetylcholine of patients without and with early chronic obstructive pulmonary disease (COPD). Twenty-two human bronchi [15 COPD (9 GOLD-0, 6 GOLD-1, -2-A), 7 nonsmokers] were investigated for immunohistochemistry and modulation of acetylcholine-induced airway constriction. Significantly increased expression of NOS2 in immunoblots of bronchial tissue and staining in smooth muscle cells was evidenced in patients with COPD compared with control subjects, whereas no modification of arginase expression was evidenced. Forced expiratory volume in 1 s (FEV1) and NOS2 expression were negatively correlated (rho=-0.54, P=0.027). Pharmacological experiments demonstrated that resting tension was elevated in COPD compared with control subjects (2,243+/-154 vs. 1,574+/-218 mg, P=0.03) and was positively correlated with the expression of NOS2 (rho=0.61, P=0.044), whereas constrictor response to acetylcholine was similar [active tension, sensitivity (-logEC10), and reactivity (slope)]. The sole effect of the specific arginase inhibitor Nomega-hydroxy-nor-L-arginine (1 microM) was to decrease sensitivity in COPD patients, whereas 1 mM NG-nitro-L-arginine methyl ester unexpectedly decreased resting tension because of a non-cGMP-dependent effect. In conclusion, an upregulation of NOS2 expression in COPD patients is involved in airway tone regulation and functional airflow limitation, whereas increased arginase activity is involved in airway sensitivity.

Association of ex vivo vascular and bronchial dysfunctions in smokers

“…A recent pulmonary perspective supported by the National Heart, Lung, and Blood Institute stated that there is a need for methods linking in vitro observations to in vivo disease state with regard to airway smooth muscle function [12]. Along this line we show an inverse relationship between the level of resting tone and FEV 1 , which is consistent with the fact that increased smooth muscle tone may contribute to airflow limitation in COPD, as previously suggested [5,13,14]. In our limited series of patients, airflow limitation was similar whether or not endothelial dysfunction was present.…”

“…Arterial rings were evaluated immediately after dissection, whereas bronchial rings were placed in oxygenated Krebs's solution and stored overnight at 4°C, as previously described [5,7,8].…”

“…At the end of the experiment, after an equilibrium period to resting tension, maximal dilation (10 -3 M theophylline) was assessed, as previously described [9]. The absence of epithelial damage has also been checked in preliminary experiments [5]. Results were expressed as raw values (g) or percentage of theophylline-induced relaxation, as specified.…”

“…We therefore conducted this study to assess whether endothelial dysfunction of pulmonary arteries was associated with modifications of the level of resting tone of isolated airways and their cGMP-mediated dilation. Both parameters are NOdependent, and the former has previously been suggested to be associated with the level of airflow limitation [5].…”

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

“…To the best of our knowledge, our study is the first to have demonstrated the role of increased arginase activity in tobacco associatedpulmonary endothelial dysfunction. Increased arginase activity has also been associated with airway hyperresponsiveness [33,34]; we previously demonstrated that increased arginase activity is involved in airway sensitivity in smokers [35]. Overall, elevated arginase activity may be one of the mechanisms underlying both pulmonary arterial dysfunction and bronchial dysfunction [36].…”