Rationale. Hyperoxia exposure to developing lungs—critical in the pathogenesis of bronchopulmonary dysplasia—may augment lung inflammation by inhibiting anti-inflammatory mediators in alveolar macrophages. Objective. We sought to determine the O2-induced effects on the polarization of macrophages and the role of anti-inflammatory BRP-39 in macrophage phenotype and neonatal lung injury. Methods. We used RAW264.7, peritoneal, and bone marrow derived macrophages for polarization (M1/M2) studies. For in vivo studies, wild-type (WT) and BRP-39？/？ mice received continuous exposure to 21% O2 (control mice) or 100% O2 from postnatal (PN) 1 to PN7 days, along with intranasal lipopolysaccharide (LPS) administered on alternate days (PN2, -4, and -6). Lung histology, bronchoalveolar lavage (BAL) cell counts, BAL protein, and cytokines measurements were performed. Measurements and Main Results. Hyperoxia differentially contributed to macrophage polarization by enhancing LPS induced M1 and inhibiting interleukin-4 induced M2 phenotype. BRP-39 absence led to further enhancement of the hyperoxia and LPS induced M1 phenotype. In addition, BRP-39？/？ mice were significantly more sensitive to LPS plus hyperoxia induced lung injury and mortality compared to WT mice. Conclusions. These findings collectively indicate that BRP-39 is involved in repressing the M1 proinflammatory phenotype in hyperoxia, thereby deactivating inflammatory responses in macrophages and preventing neonatal lung injury. 1. Introduction Development of respiratory distress syndrome (RDS) adversely affects patient populations in neonatal intensive care units, which increases the risk of developing the chronic lung disease, bronchopulmonary dysplasia (BPD) [1]. This occurs primarily in preterm infants as a consequence of severe lung injury resulting from mechanical ventilation and oxygen exposure and is characterized by inflammation and epithelial cell death. Premature infants are also more likely to be exposed to infection; prenatal or postnatal inflammation accelerates the development of BPD by itself or combined with a variety of postnatal injuries, resulting in disruption of lung alveolar and vascular development [2–6]. Mouse breast regression protein-39 (BRP-39; Chi3l1) and its human homologue YKL-40 are chitinase-like proteins present in a variety of cells, including monocytes and macrophages, and have been shown to play a role in various macrophage mediated inflammatory diseases [7]. In our previous work, we demonstrated that the levels of tracheal YKL-40 are lower in premature babies that develop
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