Comparison of hyperoxia or normoxia resolution of intermittent hypoxia and intermittent hyperoxia episodes on liver histopathology, IGF-1, IGFBP-3, and GHBP in neonatal rats

Abstract

Objective

Extremely low gestational age neonates requiring oxygen therapy for chronic lung disease experience repeated fluctuations in arterial oxygen saturation, or intermittent hypoxia (IH), during the first few weeks of life. These events are associated with a high risk for reduced growth, hypertension, and insulin resistance in later life. This study tested the hypothesis that IH, or intermittent hyperoxia have similar negative effects on the liver; somatic growth; and liver insulin-like growth factor (IGF)-I, IGF binding protein (BP)-3, and growth hormone binding protein (GHBP), regardless of resolution in normoxia or hyperoxia between episodes.

Design

Newborn rats on the first day of life (P0) were exposed to two IH paradigms: 1) hyperoxia (50% O₂) with brief hypoxia (12% O₂); or 2) normoxia (21% O₂) with hypoxia (12% O₂); intermittent hypoxia (50% O₂/21% O₂); hyperoxia only (50% O₂); or room air (RA, 21% O₂). Pups were euthanized on P14 or placed in RA until P21. Controls remained in RA from P0-P21. Growth, liver histopathology, apoptosis, IGFI, IGFBP-3, and GHBP were assessed.

Results

Pathological findings of the liver hepatocytes, including cellular swelling, steatosis, apoptosis, necrosis and focal sinusoid congestion were seen in the IH and intermittent hyperoxia groups, and were particularly severe in the 21–12% O₂ group during exposure (P14) with no significant improvements during recovery/reoxygenation (P21). These effects were associated with induction of HIF_1α, and reductions in liver IGFI, IGFBP-3, and GHBP.

Conclusions

Exposure to IH or intermittent hyperoxia during the first few weeks of life regardless of resolution in RA or hyperoxia is detrimental to the immature liver. These findings may suggest that interventions to prevent frequent fluctuations in oxygen saturation during early neonatal life remain a high priority.