Short-term perinatal oxygen exposure may impair lung development in adult mice

Abstract

Background Hyperoxia at resuscitation increases oxidative stress, and even brief exposure to high oxygen concentrations during stabilization may trigger organ injury with adverse long-term outcomes in premature infants. We studied the long-term effects of short-term perinatal oxygen exposure on cell cycle gene expression and lung growth in adult mice. Methods We randomized mice litters at birth to 21, 40, or 100%O2 for 30 min and recovered in room air for 4 or 12 weeks. Cell cycle gene expression, protein analysis, and lung morphometry were assessed at 4 and 12 weeks. Results The principal component analysis demonstrated a high degree of correlation for cell cycle gene expression among the three oxygen groups. Lung elastin was significantly lower in the 100%O2 groups at 4 weeks. On lung morphometry, radial alveolar count, alveolar number, and septal count were similar. However, the mean linear intercept (MLI) and septal length significantly correlated among the oxygen groups. The MLI was markedly higher in the 100%O2 groups at 4 and 12 weeks of age, and the septal length was significantly lower in the 100%O2 groups at 12 weeks. Conclusion Short-term exposure to high oxygen concentrations lead to subtle changes in lung development that may affect alveolarization. The changes are related explicitly to secondary crest formation that may result in alteration in lung elastin. Resuscitation with high oxygen concentrations may have a significant impact on lung development and long-term outcomes such as BPD in premature infants.

Oxygen Toxicity to the Immature Lung—Part I: Pathomechanistic Understanding and Preclinical Perspectives

“…Several approaches have tested the potential of augmenting Nrf2 activity, including preconditioning of the lung by targeting Keap1 and treatment with rapamycin, which resulted in increased baseline Nrf2 levels and antioxidant capacity. While the inflammatory response to hyperoxia was not altered in Nrf2-augmented mice, hypoalveolarization was markedly reduced [4,55]. In recent years, it has become clear that miRNA regulations constitute key events in the pathogenesis of BPD in hyperoxic injury models, and comparable changes have been documented in infants with BPD [56].…”

“…With preterm, delivery the fetus is exposed to 4-5-fold higher tensions of oxygen measured 2 of 15 in the arterial blood, and the local oxygen concentrations applied to the lungs to meet oxygen saturation targets depend on the capacities for gas exchange [1]. From the available experimental evidence, it becomes clear that brief changes in oxygen tension can have tremendous effects on the balanced in utero situation that extend far beyond the neonatal period [4]. While the HIF family is well suited to counteracting hypoxemic episodes, nature is not prepared to counteract hyperoxic events until shortly before birth.…”

“…Two pioneering studies in rodents displayed the wide range of genes being regulated when animals were exposed to hyperoxia directly after birth, which included central pathways of lung development such as transforming growth factor (TGF)-β and cell cycle control. A recent study demonstrated that even short-term exposure of newborn mice to oxygen for 30 min induced subtle but persistent typical changes in lung structures related to secondary crest formation, which is the critical step of lung development at this stage [4]. In another study using an identical model, it was demonstrated that even lower fractions of oxygen (40% and 65%) than the 80% usually applied in rodent models caused a persistent increase in lung oxidative stress response and immune cell reactivity in the bronchoalveolar lavage that was mainly constituted by macrophages.…”

Oxygen Toxicity to the Immature Lung—Part II: The Unmet Clinical Need for Causal Therapy

“…There, we provided detailed mechanistic insights, including figure illustrations. It has been demonstrated in these models that even short periods of hyperoxia exposure of 30 min can have long-term effects on lung histology [ 10 ]. This second part of our review series is dedicated to summarizing the current knowledge of the consequences of oxygen exposure to preterm infants during their NICU stay.…”

Comparative study of oral versus parenteral crocin in mitigating acrolein-induced lung injury in albino rats

“…The total lung injury score was calculated by adding up the individual scores of each category 22 – 24 . Moreover, Alveolization was estimated at 200 magnification fields by the radial alveolar count (RAC), alveolar number/field, and mean linear intercept (MLI) was calculated by dividing the total length of a line (in micrometers) drawn across the entire field by the total number of alveolar intercepts encountered along the length of the line 25 . In addition, in Masson's trichrome obtained fields, Lung fibrotic score was graded from 0 (normal) to 4 (severe) and the intensity of immunolabelling with the anti- BAX and anti-Bcl2 antibodies for alveolar cells in lung tissues in different studied groups were scored as 0 (normal) to 4 (severe).…”