Deficiency of arginase2 attenuates hyperoxia-induced inflammation and airway hyperreactivity in neonatal mice

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in pediatrics. Neonatal mice placed in hyperoxia (85% oxygen, HYP) develop lung injury reminiscent of BPD. We tested the hypothesis that mice deficient in arginase-2 (Arg2KO) exposed to HYP would have attenuated lung inflammation and injury compared with similarly exposed wild-type mice. Arg2KO and C57BL/6 (WT) mice were placed in either room air (NORM) or HYP on <i>postnatal day 0</i> (P0) and exposed for up to 14 days. RNAseq data on P1 and P14 showed that HYP differentially upregulated genes, particularly those related to development and inflammation, between the two genotypes. Neonatal mice exposed to HYP had evidence of alveolar simplification at P7 and P14, which was slightly attenuated in Arg2KO mice. After 14 days in HYP, mice were moved to NORM, and methacholine challenge testing was performed at 6, 8, or 12 wk of age. WT mice exposed to neonatal hyperoxia showed greater methacholine-induced respiratory system resistance (R_RS) at 6 and 8 wk of age compared with WT mice exposed to NORM. The methacholine-induced increase in R_RS in Arg2KO mice exposed to neonatal hyperoxia was not different from normoxia-exposed mice of either genotype. At 6, 8, and 12 wk, alveolar simplification was evident in both WT and Arg2KO mice exposed to neonatal hyperoxia with no differences between genotypes. These data demonstrate that Arg2KO attenuated both the hyperoxia-induced lung inflammation at P1 and P14 and the airway hyperreactivity at 6 and 8 wk of age.<b>NEW & NOTEWORTHY</b> Our findings suggest that inhibiting arginase 2 may be a potential therapeutic target for mitigating short-term and long-term adverse outcomes related to airway reactivity in bronchopulmonary dysplasia (BPD) that deserves further study. Furthermore, our results suggest that airway reactivity and lung architecture may be differentially regulated in neonates and may require specific and different targeting to prevent the specific outcome in neonates at risk for developing BPD.