C107-19 Adoptive Transfer of Macrophages Attenuates Inflammation and Prevents Alveolar Simplification in Neonatal Hyperoxia-Induced Lung Injury

Abstract Rationale Alveolar macrophages (AMs) occupy the alveolar niche in mice during the first postnatal week and are critical for lung development and inflammatory resolution. Hyperoxia exposure leads to a decrease in the number of AMs, alters their phenotype and impairs alveolar growth. However, therapeutic strategies targeting AM function in neonatal lung injury remain limited. In this study, we investigated whether intranasal administration of mature bone marrow-derived macrophages (BMDMs) would successfully engraft into the available niche, attenuate hyperoxia-induced inflammatory responses, and promote alveolar structural development in a neonatal hyperoxia mouse model of bronchopulmonary dysplasia (BPD). Methods Neonatal FVB mice were exposed to hyperoxia (75% O2) from postnatal day 0 (PN0) to PN7, with intranasal administration of GFP-labeled BMDMs on PN2, followed by normoxic recovery until PN14. At PN7, lung homogenates were analyzed from a subgroup of mice via Luminex multiplex assay for cytokine profiling, and precision-cut lung slices made to confirm successful engraftment and AM differentiation (Siglec-F+) of delivered BMDMs. At PN14, alveolar structural development was quantitatively assessed by mean linear intercept (MLI) analysis of lung tissue sections. Results By PN7, intranasally delivered GFP+ BMDMs successfully engrafted and expressed Siglec-F, indicating acquisition of an AM phenotype. Luminex analysis of PN7 lung homogenates demonstrated that hyperoxia exposure significantly increased the level of pro-inflammatory cytokines (IL-1α and IL-6), which was markedly attenuated by BMDM treatment. Morphometric analysis at PN14 revealed that hyperoxia-induced alveolar simplification, as indicated by increased MLI, was significantly ameliorated by BMDM transfer, demonstrating improved alveolarization and partial reversal of hyperoxia-induced structural damage. Conclusions Intranasally administered BMDMs successfully engraft and differentiate into alveolar macrophage-like cells. BMDM administration effectively attenuates hyperoxia-induced injury through modulation of early inflammation, resulting in sustained alveolar structural improvement. These results demonstrate the potential of macrophage delivery to promote normal lung growth and support the development of translational strategies to target AM function as novel approaches for BPD. This abstract is funded by: None