Arginase inhibition in airways from normal and nitric oxide synthase 2-knockout mice exposed to ovalbumin

Journal Article · Fri Jan 01 00:00:00 EST 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.09.018· OSTI ID:21344820

Bratt, Jennifer M; Franzi, Lisa M; Linderholm, Angela L; O'Roark, Erin M; Kenyon, Nicholas J ^[1]

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1. Department of Pulmonary and Critical Care Medicine, CCRBM, School of Medicine, University of California, Davis, CA 95616 (United States)

Arginase1 and nitric oxide synthase2 (NOS2) utilize L-arginine as a substrate, with both enzymes expressed at high levels in the asthmatic lung. Inhibition of arginase in ovalbumin-exposed C57BL/6 mice with the transition state inhibitor N{sup o}mega-hydroxy-nor-L-arginine (nor-NOHA) significantly increased total L-arginine content in the airway compartment. We hypothesized that such an increase in L-arginine content would increase the amount of nitric oxide (NO) being produced in the airways and thereby decrease airway hyperreactivity and eosinophilic influx. We further hypothesized that despite arginase inhibition, NOS2 knockout (NOS2-/-) mice would be unable to up-regulate NO production in response to allergen exposure and would demonstrate higher amounts of airway hyperreactivity and eosinophilia under conditions of arginase inhibition than C57BL/6 animals. We found that administration of nor-NOHA significantly decreased airway hyperreactivity and eosinophilic airway inflammation in ovalbumin-exposed C57BL/6 mice, but these parameters were unchanged in ovalbumin-exposed NOS2-/- mice. Arginase1 protein content was increased in mice exposed to ovalbumin, an effect that was reversed upon nor-NOHA treatment in C57BL/6 mice. Arginase1 protein content in the airway compartment directly correlated with the degree of airway hyperreactivity in all treatment groups. NOS2-/- mice had significantly greater arginase1 and arginase2 concentrations compared to their respective C57BL/6 groups, indicating that inhibition of arginase may be dependent upon NOS2 expression. Arginase1 and 2 content were not affected by nor-NOHA administration in the NOS2-/- mice. We conclude that L-arginine metabolism plays an important role in the development of airway hyperreactivity and eosinophilic airway inflammation. Inhibition of arginase early in the allergic inflammatory response decreases the severity of the chronic inflammatory phenotype. These effects appear to be attributable to NOS2, which is a major source of NO production in the inflamed airway, although arginase inhibition may also be affecting the turnover of arginine by the other NOS isoforms, NOS1 and NOS3. The increased L-arginine content in the airway compartment of mice treated with nor-NOHA may directly or indirectly, through NOS2, control arginase expression both in response to OVA exposure and at a basal level.

• OSTI ID: 21344820
• Journal Information: Toxicology and Applied Pharmacology, Vol. 242, Issue 1; Other Information: DOI: 10.1016/j.taap.2009.09.018; PII: S0041-008X(09)00410-4; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ARGINASE
ARGININE
ASTHMA
ENZYME INHIBITORS
INFLAMMATION
KNOCK-OUT REACTIONS
LUNGS
METABOLISM
MICE
NITRIC OXIDE
OVALBUMIN
AMIDASES
AMINO ACIDS
ANIMALS
BODY
CARBOHYDRATES
CARBOXYLIC ACIDS
CHALCOGENIDES
DIRECT REACTIONS
DISEASES
ENZYMES
GLUCOPROTEINS
GLYCOPROTEINS
HYDROLASES
MAMMALS
NITROGEN COMPOUNDS
NITROGEN OXIDES
NON-PEPTIDE C-N HYDROLASES
NUCLEAR REACTIONS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
OXIDES
OXYGEN COMPOUNDS
PATHOLOGICAL CHANGES
PROTEINS
RESPIRATORY SYSTEM
RESPIRATORY SYSTEM DISEASES
RODENTS
SACCHARIDES
SYMPTOMS
VERTEBRATES