Arginases I and II in lungs of ovalbumin-sensitized mice exposed to ovalbumin: Sources and consequences

Abstract

Arginase gene expression in the lung has been linked to asthma both in clinical studies of human patients and in the well-studied mouse model of ovalbumin-induced airway inflammation. Arginase is thought to regulate NO levels in the lung by its ability to divert arginine, the substrate for nitric oxide synthases that produce citrulline and NO, into an alternative metabolic pathway producing ornithine and urea. In the present study arginase I and arginase II concentrations were measured in isolated microdissected airway preparations from sensitized Balb/c mice exposed to ovalbumin aerosol. We found that arginase II was constitutively expressed in the airways of normal mice, whereas arginase I was undetectable in normal airways, while its expression was increased in airways of mice exposed to ovalbumin. The expression of arginase I strongly correlated with the presence of lung inflammation, as quantified by differential cell counts in lung lavage, suggesting that most, or all, of the arginase I in lungs of mice exposed to ovalbumin is present in the inflammatory cells rather than in the airway epithelium. There was also a significant correlation between increased expression of arginase I in the isolated airways and decreased lung compliance. On the other hand, while we found arginase II expression to also be significantly increased in airways from mice exposed to ovalbumin as compared with normal airways, the relative increase was much less than that observed for arginase I, suggesting that there was a smaller contribution of inflammatory cells to the arginase II content of the airways in mice exposed to ovalbumin. There was no apparent correlation between the content of arginase in isolated airways and exhaled NO concentration in the expired air from mice exposed to ovalbumin. However, there was a correlation between exhaled NO concentration from mice exposed to ovalbumin and the lymphocyte content of the lung lavage.The concentration of arginine found in isolated airways from Balb/c mice exposed for 2 weeks to ovalbumin was about half of the value found in isolated microdissected airways from normal mice. Treatment of mice systemically with an arginase inhibitor significantly increased the amount of NO produced, as measured as the amount of nitrite + nitrate (NOx) in lung lavage supernatant prepared from mice exposed to ovalbumin. Our results are consistent with the hypothesis that the response of the lung to ovalbumin challenge includes an adaptive response in the large airways regulating the concentration of arginine within cells of the airway epithelium and subepithelial layer, by shunting of arginine into the metabolic pathway for increased synthesis of NO.

Arginase I Attenuates Inflammatory Cytokine Secretion Induced by Lipopolysaccharide in Vascular Smooth Muscle Cells

“…Arg I generally expresses in the liver and also exists in extrahepatic tissues, whereas Arg II is found in several extrahepatic tissues. 11 Because extrahepatic cells do not possess a complete urea cycle, the function of Arg in extrahepatic tissues has attracted attention. 12 Arginase is associated with inflammatory diseases, such as asthma and bowel disease.…”

Arginase in Asthma – Recent Developments in Animal and Human Studies~!2009-11-12~!2010-03-23~!2010-05-04~!

“…The effects of nor-NOHA were quantitively similar to the effect of treatment with L-arginine [86,98]. The importance of increased arginase in limiting the L-arginine bioavailability and NO production is supported by the observation that levels of L-arginine and L-citrulline are reduced in the airways of allergen-challenged mice, whereas the arginase activity is increased [110]. In conclusion, increased arginase activity underlies the deficiency of neuronal and nonneuronal NO and subsequent AHR after the EAR by limiting the substrate availability to cNOS isoforms.…”

“…Inflammation and expression of arginase has also been demonstrated in all commonly-studied animal models of allergic inflammation, including rat, guinea pig, and mouse, as well as in human asthma [39,43,86,[97][98][99]101,110]. While arginase expression has been found to be upregulated in epithelia, smooth muscle and the peribronchiolar region [39,43,99,102], this section will focus on new developments in our understanding of arginase expression and function in immune cells.…”

Competition of NO synthases and arginase in the airways hyperreactivity

“…Interestingly, in the chronic model, which generates an airway remodeling, arginase inhibition attenuated methacholine responsiveness of the central and peripheral airways. Another possible clarification for different effect of lung tissue is possibility that lung can respond to ovalbumin challenge with an adaptive response of the large airways that includes regulation of the concentration of arginine within cells of the airway epithelium and subepithelial layer (Kenyon et al 2008).…”