332 - Tau is a Novel Mediator of Neonatal Lung Injury and Bronchopulmonary Dysplasia

Publication Number: 1316.332

Althea deWeever, University of South Alabama College of Medicine, MOBILE, AL, United States; Saminathan Anbalagan, University of South Alabama Children's and Women's Hospital, Mobile, AL, United States; Chung-sik Choi, University of South Alabama College of Medicine, Mobile, AL, United States; Allison Bauman, University of South Alabama College of Medicine, Mobile, AL, United States; Mike lin, University of South Alabama, Mobile, AL, United States; Manimaran Ramani, University of Alabama School of Medicine, Birmingham, AL, United States; Troy Stevens, University of South Alabama College of Medicine, Mobile, AL, United States; Kalsang Dolma, University of South Alabama Children's and Women's Hospital, Mobile, AL, United States

Background: Hyperoxia and infection trigger lung inflammation that drives bronchopulmonary dysplasia (BPD) in very preterm infants, but the mechanisms linking these insults to impaired lung development remain unclear. Tau protein is expressed in lung endothelial cells as early as the pseudoglandular stage. In adults, infection induces toxic tau variants that contribute to end-organ dysfunction. We have detected toxic tau variants in tracheal aspirates of mechanically ventilated preterm neonates exposed to hyperoxia; however, the role of endothelial tau in BPD pathogenesis is unknown

Objective: We hypothesized that postnatal hyperoxia and/or infection generate cytopathic tau variants that contribute to lung injury and developmental arrest, resulting in a BPD-like phenotype in mice.

Design/Methods: Wild-type (WT) and tau-knockout (KO) mice were exposed to normoxia (21% FiO₂) or hyperoxia (85% FiO₂) from postnatal days 3–14, with intranasal PBS or LPS on PND 3, 5, 7, and 10. On PND 14, pulmonary arterial hypertension was assessed by echocardiography (PAT/PET ratio), lung mechanics by compliance, and alveolar and vascular development by mean linear intercept (MLI), radial alveolar count (RAC), and CD31 staining. Lung homogenates were assessed using BiFC seeding assays for toxic tau variants.

Results: Hyperoxia caused alveolar simplification and decreased vascularization in WT mice (↓RAC p< 0.001; ↑MLI p=0.002; ↓CD31 p=0.0493), accompanied by pulmonary hypertension (↓PAT/PET p=0.0069) and a trend toward reduced compliance (p=0.0594). These effects were attenuated in KO mice. LPS under normoxia did not alter alveolar or vascular indices or compliance but worsened PAT/PET in WT mice (p < 0.001), an effect absent in KO animals. Combined hyperoxia and LPS caused additive injury in both genotypes, with KO mice showing less severe pathology.

Conclusion(s): Tau may act as a key regulator of pulmonary vascular development and injury in neonatal lungs. Reduced CD31 staining in WT but not KO mice under hyperoxia and/or infection indicates tau mediates impaired angiogenesis, which may contribute to pulmonary hypertension by altering vascular structure and compliance. These findings highlight tau as a potential modulator of pulmonary vascular growth and remodeling in BPD. Ongoing studies of cytokines, toxic tau variants, and lung mechanics aim further to define tau’s mechanistic role in neonatal lung injury.

Alveolar and Vascular Development After Hyperoxia, LPS, and Combined Hyperoxia + LPS Exposure in Wild-Type and Tau KO Mice”
Hyperoxia led to vascular rarefaction in WT mice, evidenced by decreased CD31+ vessel density (p=0.0493), along with alveolar simplification (↓RAC p<0.001; ↑MLI p=0.002), pulmonary hypertension (↓PAT/PET p=0.0069), and a trend toward reduced compliance (p=0.0594). These effects, particularly the loss of CD31 expression, were attenuated in Tau KO mice. LPS alone did not affect alveolarization or CD31 levels but worsened PAT/PET in WT mice (p < 0.001), an effect absent in Tau KO animals. Combined hyperoxia and LPS exposure produced additive vascular and alveolar injury in both genotypes, with Tau KO mice showing relative preservation of CD31 expression and less severe pathology.