Arginase: Expression and consequences in allergic airway hyperresponsiveness and inflammation

Arginase (ARG) gene expression in the lung is linked to asthma both in clinical studies and in murine models of allergic airway inflammation. Arginase is thought to contribute to the regulation of nitric oxide (NO) levels in the lung by diverting L-arginine, the substrate for nitric oxide synthase (NOS), into an alternative metabolic pathway.;Two longitudinal studies examined ARG1 and ARG2 expression in a murine model of allergic airway inflammation using Balb/C and C57BL/6 strains. Total L-arginine content in isolated airway tissue was measured in filtered air and ovalbumin (OVA)-exposed mice to determine if airway inflammation decreased L-arginine content in this compartment. We also assessed ARG mRNA and protein expression and correlated this with changes in lung function, airway inflammation and exhaled NO.;ARG1 mRNA and protein content in the airways was significantly greater in OVA-exposed mice and inversely correlated with parameters of airway function. OVA exposure also reduced L-arginine content at the time point of maximal ARG1 expression.;We examined NOS isoform protein content in NOS1, NOS2 and NOS3 knockout mice exposed to filtered air or OVA to assess whether knockout mice displayed compensatory overexpression of remaining NOS isoforms. NOS1 and NOS3 knockout mice displayed increased NOS2 expression in the airway epithelium and smooth muscle of the airway and vasculature under non-inflammatory conditions. OVA exposure in NOS3 knockout mice reduced NOS2 expression in these tissues but expression was unaffected in NOS1 knockout mice. Expression of NOS1 and NOS3 was unaffected in the NOS2 knockout mice. As such, we utilized the NOS2 knockout mice in subsequent studies.;Systemic administration of ARG inhibitor, nor-NOHA, in OVA-exposed C57BL/6 mice significantly increased total L-arginine content in the airway compartment and mitigated the reductions in lung function and inflammation. Comparison to identically treated NOS2 knockout mice noted no change in the parameters of lung function or inflammation despite greater ARG1 content compared to the C57BL/6 mice. OVA-exposed C57BL/6 wt mice administered nor-NOHA also displayed a decrease in Arginase1 protein content which was not observed in the NOS2 knockout mice indicating a potential role of NOS2 in the regulation of arginase1 protein expression.