567 - Lack of surfactant protein A alters response to hyperoxia in a mouse model of BPD

Poster Number: 567
Publication Number: 567.1632

Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity. BPD is characterized by abnormal alveolarization and vascular growth secondary to persistent lung injury from a constellation of antenatal and postnatal factors, including infection, genetic variation, and oxidative stress. There is limited understanding of risk factors during pregnancy and after birth affecting lung development. Our published studies have implicated surfactant protein A (SP-A) genetic variants in the development of neonatal respiratory distress syndrome. Produced in late gestation by the fetal lung, SP-A serves in host defense against pathogens and in precise modulation of alveolar macrophage activation and the onset of parturition. The role of SP-A is not well understood in the development of BPD.

Objective: To determine whether disruption of SP-A promotes the development of BPD.

Design/Methods: Male and female wild-type (WT) and SP-A-deficient (KO) mice on a C57BL/6 background were used. Newborn pups were exposed either to 60% O2 or maintained in normoxia until postnatal days 5 to 7. Morphometric analysis of lung architecture measured by mean linear intercept (MLI) and radial alveolar count (RAC) were used to monitor the alveolar simplification that occurs in BPD. Statistical differences were assessed by ANOVA test and adjusted with a false discovery rate (GraphPad Prism). Spatial proteomic profiling (GeoMx® Nanostring) was used to assess the activation of CD11b+ macrophages.

Results: Oxygen exposure at 60% in SP-A KO mouse pups resulted in increased MLI in hyperoxic SP-A-deficient lungs compared to hyperoxic and normoxic WT lungs (47.4±12.4 (Mean±SD) vs 34.7±2.3,p=0.0005, and 34.5±4.1 adjusted p=0.0006, respectively (Fig 1A). Female SP-A KO lungs in hyperoxia had increased MLI compared to WT male or female counterparts (adj p< 0.05)( Fig 1B). SP-A KO pups had reduced RAC compared to the WT counterparts exposed to normoxia or hyperoxia ( adj p< 0.0001), with sex differences noted due to lack of SP-A in RAC (Fig 2A and B) (n= 3-10 mouse per sex per group). Increased septal wall thickness was noted in SP-A KO lungs exposed to hyperoxia (Fig 3A). Spatial proteomic profiling of hyperoxic SP-A-deficient lungs showed increased expression of gammaH2Ax (a marker for DNA injury) (n=2, fold >4, p< 0.05) compared to normoxia (Fig 3B).

Conclusion(s): Our findings demonstrate that a lack of SP-A significantly enhances hyperoxia-induced alveolar simplification. Furthermore, SP-A contributes to sex differences in susceptibility to BPD. These results support the notion that lack of SP-A contributes to the development of BPD.