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

Jennifer M. Bratt, Lisa M. Franzi, Angela L. Linderholm, Erin M. O'Roark, Nicholas Kenyon, Jerold A Last

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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 Nω-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.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalToxicology and Applied Pharmacology
Volume242
Issue number1
DOIs
StatePublished - Jan 1 2010

Fingerprint

Arginase
Ovalbumin
Knockout Mice
Nitric Oxide Synthase
Nitric Oxide
Arginine
Inbred C57BL Mouse
Inflammation
Eosinophilia
Allergens
Metabolism
Protein Isoforms
Proteins
Up-Regulation
Animals

Keywords

  • Airway hyperreactivity
  • Asthma
  • Eosinophil
  • Inflammation
  • l-arginine
  • Nitric oxide
  • Nor-NOHA

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Arginase inhibition in airways from normal and nitric oxide synthase 2-knockout mice exposed to ovalbumin. / Bratt, Jennifer M.; Franzi, Lisa M.; Linderholm, Angela L.; O'Roark, Erin M.; Kenyon, Nicholas; Last, Jerold A.

In: Toxicology and Applied Pharmacology, Vol. 242, No. 1, 01.01.2010, p. 1-8.

Research output: Contribution to journalArticle

Bratt, Jennifer M. ; Franzi, Lisa M. ; Linderholm, Angela L. ; O'Roark, Erin M. ; Kenyon, Nicholas ; Last, Jerold A. / Arginase inhibition in airways from normal and nitric oxide synthase 2-knockout mice exposed to ovalbumin. In: Toxicology and Applied Pharmacology. 2010 ; Vol. 242, No. 1. pp. 1-8.
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