title: Inhibition of arginase activity enhances inflammation in mice with allergic airway disease, in association with increases in protein S-nitrosylation and tyrosine nitration.
abstract: Pulmonary inflammation in asthma is orchestrated by the activity of NF-kappaB. NO and NO synthase (NOS) activity are important modulators of inflammation. The availability of the NOS substrate, l-arginine, is one of the mechanisms that controls the activity of NOS. Arginase also uses l-arginine as its substrate, and arginase-1 expression is highly induced in a murine model of asthma. Because we have previously described that arginase affects NOx content and interferes with the activation of NF-kappaB in lung epithelial cells, the goal of this study was to investigate the impact of arginase inhibition on the bioavailability of NO and the implications for NF-kappaB activation and inflammation in a mouse model of allergic airway disease. Administration of the arginase inhibitor BEC (S-(2-boronoethyl)-l-cysteine) decreased arginase activity and caused alterations in NO homeostasis, which were reflected by increases in S-nitrosylated and nitrated proteins in the lungs from inflamed mice. In contrast to our expectations, BEC enhanced perivascular and peribronchiolar lung inflammation, mucus metaplasia, NF-kappaB DNA binding, and mRNA expression of the NF-kappaB-driven chemokine genes CCL20 and KC, and lead to further increases in airways hyperresponsiveness. These results suggest that inhibition of arginase activity enhanced a variety of parameters relevant to allergic airways disease, possibly by altering NO homeostasis.
authors.affiliation: Department of Pathology, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Ckless
authors.forename: Anniek
authors.initials: A
authors.lastname: Lampert
authors.forename: Jessica
authors.initials: J
authors.lastname: Reiss
authors.forename: David
authors.initials: D
authors.lastname: Kasahara
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
authors.forename: Lennart K A
authors.initials: LK
authors.lastname: Lundblad
authors.forename: Ryan
authors.initials: R
authors.lastname: Norton
authors.forename: Albert
authors.initials: A
authors.lastname: van der Vliet
authors.forename: Yvonne M W
authors.initials: YM
authors.lastname: Janssen-Heininger