Role of nitric oxide synthase/arginase balance in bronchial reactivity in patients with chronic obstructive pulmonary disease.
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.
Service de Réanimation Médicale, Hôpital Européen Georges Pompidou, 20-40, rue Leblanc, 75908 Paris cedex 15, and Unité Propre de Recherche de l'Enseignement Supérieur EA 4068, Saints-Pères-Université Paris, Paris, France.
Jean-Marc
JM
Tadié
Priscilla
P
Henno
Ingrid
I
Leroy
Claire
C
Danel
Emmanuel
E
Naline
Christophe
C
Faisy
Marc
M
Riquet
Marilyne
M
Levy
Dominique
D
Israël-Biet
Christophe
C
Delclaux
D000578:Amidines / Q000494:pharmacology; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000503:physiopathology*
C425062:(2-boronoethyl)-cysteine; D000578:Amidines; D001596:Benzylamines; D001897:Boronic Acids; D004791:Enzyme Inhibitors; C404735:N(omega)-hydroxynorarginine; C109599:N(omega)-propylarginine; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D001120:Arginine; D019001:Nitric Oxide Synthase; D001119:Arginase; D019331:NG-Nitroarginine Methyl Ester