186 - Increasing Intermittent Hypoxia Episodes and Biomarkers of Lung Alveolarization and Microvascular Maturation in Neonatal Rats.

Poster Number: 186
Publication Number: 186.3077

Background: Extremely preterm infants experience frequent apnea with brief intermittent hypoxia (IH) cycling, predisposing them to bronchopulmonary dysplasia (BPD. Biomarkers that regulate microvascular maturation and alveolarization, such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs), respectively, are adversely affected by IH and may contribute to the development and severity of BPD.

Objective: We tested the hypothesis that: 1) increasing daily IH episodes result in significant alterations in VEGF and MMPs, causing dysregulated microvascular maturation and alveolarization; and 2) there is a critical number of daily IH episodes that render the immature lungs irreparable despite reoxygenation/reperfusion in room air (RA).

Design/Methods: Neonatal rats at birth were exposed to hyperoxia (50% O2) with 2, 4, 6, 8 10, or 12 brief IH (12% O2) episodes per day (EPD) until day 14 (P14). Littermates exposed to 50% O2 only served as hyperoxia (Hx) controls, and littermates raised in RA served as RA controls. Body and lung weight accretion; lung histopathology; and lung VEGF, HIF1α, MMPs, and their tissue inhibitors (TIMPs) were assessed. Data are mean±SEM.

Results: Weight accretion was higher in the Hx group (241.0±13.4, p< 0.01) vs. RA (216.0±8.6). However, pups exposed to 8-10 IH EPD had lower weight accretion ranging from 198.9±6.6 to 210.1±6.1, p< 0.01), with significant reductions in body length in all groups (p < 0.01). All exposed groups showed evidence of pulmonary hemorrhage, reduced alveolarization, thickened septae, reduced secondary crest formation, and overall lung damage. HIF1α, VEGF, and MMP-9 increased as a function of increasing IH episodes (p < 0.01), peaking with 8-12 IH EPD. In contrast, MMP-2 declined in all exposed groups compared to RA (p < 0.01), while MMP-8 increased with hyperoxia and declined with 8-12 IH EPD. TIMP-1 levels declined in all groups, while TIMP-2 increased with hyperoxia and 2-6 IH EPD (p < 0.01).

Conclusion(s): Exposure to daily IH cycles >6 EPD may represent a degree of hypoxia that induces VEGF over-secretion causing vascular permeability and hemorrhage, suggesting a maximum number of daily IH EPD that the immature lungs can sustain. The imbalance of increased MMPs to TIMPs, particularly MMP-9/TIMP-1, may indicate in part, a mechanism involved in IH-induced disruptions in lung alveolarization.