351 - Fetal Lung Injury in a Maternal ARDS Model: Implications for Neonatal Respiratory Dysfunction

Publication Number: 1335.351

Xiaohan Li, University of California, Davis, School of Medicine, Davis, CA, United States; Jocelyn Livezey, University of California, Davis, School of Medicine, Davis, CA, United States; Deepika Sankaran, University of California Davis Children's Hospital, Sacramento, CA, United States; Evan M. Giusto, UC Davis Health, Sacramento, CA, United States; Evan Maher, University of California, Davis, School of Medicine, Woodland, CA, United States; Rebecca Valdez, University of California Davis Children's Hospital, Sacramento, CA, United States; Payam Vali, University of California, Davis, School of Medicine, sacramento, CA, United States; Sylvia Bowditch, University of California Davis Children's Hospital, Sacramento, CA, United States; Amy Lesneski, UC Davis, Davis, CA, United States; Victoria Hammitt, UC Davis Stem Cell Research, Davis, CA, United States; Nicholas Burke, University of California Davis Children's Hospital, Davis, CA, United States; Kent E. Pinkerton, University of California, Davis, Davis, CA, United States; Satyan Lakshminrusimha, UC Davis, Sacramento, CA, United States; Michelle J. Lim, University of California, Davis, School of Medicine, Sacramento, CA, United States

Background: Higher rates of perinatal complications and increased neonatal respiratory distress syndrome (RDS) were reported among infants born to mothers with COVID-19 infection, despite the absence of widespread in-utero transmission. The underlying mechanisms remain uncertain and may reflect the effects of prematurity itself, which occurred frequently among COVID-19-infected mothers. Alternative mechanisms include severity of maternal disease and maternal-fetal inflammation leading to surfactant deficiency and/or fetal hypoxia with disrupted alveolar and vascular development, increasing susceptibility to bronchopulmonary dysplasia (BPD), similar to patterns seen with maternal chorioamnionitis.

Objective: We sought to characterize fetal lung development in a novel maternal ovine model of Acute Respiratory Distress Syndrome, characterized by maternal hypoxia and systemic inflammation.

Design/Methods: Lung injury was induced in pregnant ewes at preterm gestation (132-135 days; term ≈147 days) using the combined acid and small gastric particle (CASP) model (1mL/kg). This validated model produced moderate-to-severe hypoxemia within 30 minutes of CASP instillation, accompanied by IL-6- and IL-8-mediated inflammatory lung injury consistent with ARDS. Right cranial lobes were collected 4 hours after injury, inflation fixed by formalin, and stained with H&E. Lung injury was scored semi-quantitatively and compared to an age-matched control. Cytokine were measured using a commercially available Luminex assay.

Results: Maternal ewes showed significant increase in plasma IL-6 and IL-8 following induction of the lung injury. However, there was no significant increase in fetal plasma levels of IL-6 and IL-8 (Figure 1). Fetal lungs of those with maternal ARDS were characterized with increased cell infiltrates in the parenchyma compared to the age-matched control (Figure 2). Further, using a validated semi-quantitative histopathology scoring system, fetus from the ARDS ewes showed moderate inflammation (8.5 ± 3.0) in the parenchyma compared to the age-matched surgical control with minimal inflammation (Figure 3).

Conclusion(s): Maternal ARDS induces localized fetal lung inflammation and disrupts alveolarization, associated with mild systemic fetal cytokine elevation. This injury may reflect direct effects of maternal respiratory failure on fetal lung development and may contribute to the increased risk of neonatal respiratory dysfunction in affected preterm infants. In inflammatory lung disease causing maternal respiratory failure, fetal lung inflammation may negatively impact respiratory outcomes in preterm infants.

Relationship of Maternal and Fetal Inflammatory Profiles
Serum IL-6 and IL-8 levels of the ewe and lamb at baseline compared to 4 hours following induction of acute lung injury. *p < 0.05, ***p < 0.001

Lung Histology in Lambs following Maternal Acute Lung Injury
FIgure 3. Representative H&E images of alveoli, airways, perivascular cuff and pleura of control and ALI lambs. Lambs in the ALI group displays increased cell infiltrates in the alveolar space.

Semi-quantitative Scores of Total Lung Injury in Control and Maternal ALI Lambs
Lung injury was semi-quantitatively scored in right cranial lobe in control and maternal ALI lamb. Total injury score was the sum of score in alveoli, airways, perivascular cuff and pleura, respectively. Each region was evaluated with extent and severity from 1 to 3. The injury score of each region was calculated from the product of extent times severity. The total score was calculated from the sum of scores of all four regions.