The experimental model we used to base our conclusion on is a transgenic model. The disadvantage of transgenic models is that the life-long exposure to in this case hypoargininemia may have additional features that could affect the response to allergic asthma. The physiologically most attractive option to assess such a potential confounder would be to supplement
F/A2
tg/tg
mice with arginine. When we carried out this experiment by treating mice twice daily for 5 days with 5 mmol/kg arginine and measuring plasma arginine concentration 6 h after the last injection [
26], circulating arginine concentration in wild-type mice increased > 2-fold, but the intervention was without any effect in
F/A2
tg/tg
mice. Since circulating arginine concentrations vary directly with transgenic arginase activity in the small intestine of
F/A2
tg/tg
mice [
19], the high turnover of plasma arginine in
F/A2
tg/tg
mice apparently neutralizes the supplemented arginine. An alternative option would be to infuse arginase intravenously into wild-type mice. This intervention is very effective in lowering circulating arginine concentrations, but also short-lived [
34], so that it could not be used in the present setting. A third approach could have been treatment of
F/A2
tg/tg
mice with a well-established arginase inhibitor such as nor-NOHA. However, nor-NOHA is an arginine analogue which requires ~ 10-fold higher concentration to inhibit intracellular than dissolved arginase [
35], suggesting it has to compete with arginine-like molecules for membrane transport. Probably more seriously, its K
i for mouse macrophage arginase is 50 μmol/L, that is, similar to circulating arginine concentrations in
F/A2
tg/tg
mice. These considerations show that the
F/A2
tg/tg
mouse model was instrumental in revealing a potential requirement for circulating arginine in severe allergic asthma, but that additional studies are necessary to reaffirm this function.