339 - Preterm birth followed by mechanical ventilation at different lung developmental stages changes the trajectory of markers of alveolarization in lambs

Publication Number: 1323.339

Andrew Rebentisch, University of Utah School of Medicine, Salt Lake City, UT, United States; Jakob D. Van Boerum, University of Utah School of Medicine, Salt Lake City, UT, United States; Linden Carter, UNIVERSITY OF UTAH, West Des Moines, IA, United States; Haixia Yang, uofu, Salt Lake City, UT, United States; Reagan Cathcart, University of Utah Health, Salt Lake City, UT, United States; Rachael S. Peel, University of Utah School of Medicine, Salt Lake City, UT, United States; Tegan Kett-Eubanks, University of Utah, Salt Lake City, UT, United States; Chiara Veneroni, Politecnico di Milano, Milan, Lombardia, Italy; Davide Bizzotto, Restech srl, Milano, Lombardia, Italy; Raffaele Dellaca', Politecnico di Milano, Milano, Lombardia, Italy; Anna Lavizzari, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardia, Italy; Kurt H. Albertine, University of Utah, Salt Lakr City, UT, United States; Yasmine White, University of Utah School of Medicine, Salt Lake City, UT, United States; Matthew Douglass, University of Utah School of Medicine, Salt Lake City, UT, United States; Mar Janna Dahl, University of Utah School of Medicine, Salt Lake City, UT, United States

Background: Throughout gestation, the lung undergoes a complex process of proliferation, apoptosis, and vascularization that ensures efficient gas exchange after birth. Preterm birth interrupts the development process and increases the need for invasive mechanical ventilation (IMV).

Objective: The study aimed to assess the trajectories of markers of alveolarization after preterm birth in the canalicular, saccular, and alveolar stages of lung development, followed by IMV in preterm lambs.

Design/Methods: Two groups of lambs were delivered by Cesarean-section at each of the following gestations: 1) 110d (canalicular, 22-23wk human equivalent; n=4/group); 2) 115d (canalicular/saccular, 24-25wk ; n=4/group); 3) 120d (saccular, ~26wk; n=8/group); or 4) 130d (saccular/alveolar, ~28-; n=4/group) gestation. The IMV groups were exposed to antenatal steroids, intubated, given surfactant, caffeine, and resuscitated by IMV followed by 3d continued IMV respiratory support. The fetal control groups were not ventilated and euthanized after delivery. Quantitative histology assessed indices of alveolar formation. Real-time RT-PCR assessed mRNA levels of markers of proliferation, apoptosis, surfactant, and vascularization. Simple linear regression examined the effect of gestational age and ventilation.

Results: Distal airspace walls (gas exchange location) became thinner with increased gestational age in both groups (IMV: R²=0.3673, p=0.0036; Fetal: R²=0.5440, p=0.0003). Secondary septal volume density, an indicator of alveolarization, increased with gestational age in both groups (IMV: R²=0.3717, p=0.0033; Fetal:R²=0.6546, p< 0.0001). c-myc (proliferation) mRNA decreased with gestational age in IMV lambs (R²=0.2824, p=0.0232) but increased in fetal lambs (R²=0.6095, p< 0.0001). p53 (apoptosis) mRNA increased with gestational age in both groups (IMV:R²=0.3570, p=0.0088; Fetal:R²=0.1723, p=0.0437). Surfactant protein B mRNA increased with gestational age in fetal (R²=0.7672, p< 0.0001) but not in the IMV lambs (R²=0.0581, p=0.3355). VEGF and VEGF-R2 mRNA increased with gestational age in both IMV (VEGF: R²=0.4637, p=0.0019; VEGF-R2: R²=0.3764, p=0.0068) and Fetal (VEGF: R²=0.5679, p< 0.0001; VEGF-R2: R²=0.8102, p< 0.0001) lambs.

Conclusion(s): Preterm birth followed by IMV delayed progression of indices of alveolarization compared to uninterrupted development. IMV lambs delivered earlier in gestation had more evidence of alveolar simplification than those delivered later in gestation. Understanding how preterm birth and IMV alter the trajectory of lung maturation may help guide treatments to minimize neonatal chronic lung disease.