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Neonatal Pulmonology

Neonatal Pulmonology 4: Exosomes, Stem Cells, Maternal and Fetal Environmental Effects

130 - Antenatal Endotoxin Impairs Airway and Parenchymal Lung Growth and Function in Infant Rats: A Potential Role for Dysanapsis

Monday, May 1, 2023

9:30 AM – 11:30 AM ET

Poster Number: 130
Publication Number: 130.436

Elizabeth McGinn, University of Colorado School of Medicine, Denver, CO, United States; Elisa Bye, University of Colorado School of Medicine, Aurora, CO, United States; Tania Gonzalez, University of Colorado School of Medicine, Aurora, CO, United States; Jill Bilodeaux, University of Colorado School of Medicine, Denver, CO, United States; Alexander Sosa, Department of Bioengineering, University of Colorado Denver | Anschutz Medical Campus, Denver, CO, United States; Gregory Seedorf, University of Colorado School of Medicine, Aurora, CO, United States; Bradford J. Smith, University of Colorado Denver | Anschutz Medical Campus, Aurora, CO, United States; Steven Abman, University of Colorado School of Medicine, Denver, CO, United States; Erica W. Mandell, University of Colorado School of Medicine, Aurora, CO, United States

Presenting Author(s)

Elizabeth McGinn, MD (she/her/hers)

Resident Physician
University of Colorado School of Medicine
Denver, Colorado, United States

Background: Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is a disease spectrum characterized by impaired lung development with sustained functional abnormalities into adulthood. We have previously shown that a single injection of intra-amniotic endotoxin (IA ETX) causes abnormal distal lung structure in a rat model of BPD. Common to most BPD phenotypes are heterogeneous changes in both airways and distal parenchyma that contribute to chronic respiratory failure. Dysanapsis is the concept of disproportionate airways and parenchyma size, clinically defined as low FEV₁/FVC with normal FEV₁ and FVC.

Objective: To evaluate whether dysanapsis contributes to abnormal lung function in BPD after an antenatal stress.

Design/Methods: Fetal rats were exposed to IA ETX (10 μg) or saline (CTL) at embryonic day 20 (E20) and delivered at E22. At day 14, lung structural analysis was performed using stereology to quantify distal lung components and alveolar complexity, and micro-computed tomography (mCT) to measure conducting airways diameters. Lung function was assessed at baseline, in response to methacholine challenge and albuterol, and using negative forced expiratory maneuvers for spirometry.

Results: Compared to CTL, ETX-exposed pups had decreased body weight and crown-rump length, decreased radial alveolar counts, increased mean linear intercepts, and decreased alveolar surface area and alveolar-airway attachments (p< 0.05). Tracheal, 2^nd, and 3^rd airway generation diameters were decreased in ETX-exposed pups when measured at 5 cmH₂O inflation pressure (p< 0.01), but there were no differences in 2^nd-3^rd gen diameters at 20 cmH₂O. ETX increased respiratory system resistance (Rrs) and decreased lung compliance (Crs) (p< 0.01). There was no bronchial hyper-reactivity to MCh as assessed by Rrs or Crs. However, Newtonian resistance (Rn) increased at lower MCh doses in ETX-exposed pups. ETX-exposed but not CTL pups had decreased FEV_0.1/FVC with normal FEV_0.1 and FVC, meeting the clinical definition of dysanapsis.

Conclusion(s): Antenatal ETX exposure impairs lung structure and function in infant rats, including reduced alveolarization and surface area in the distal lung, and smaller upper airway diameters. We speculate that decreased tethering forces, suggested by decreased alveolar-airway attachments, contribute to airway diameter differences at lower inflation pressure and increased sensitivity of Rn to MCh. We further speculate that antenatal injury to both airways and distal lung with subsequent postnatal dysanaptic growth contribute to abnormalities of late lung function in BPD.