Severe but not moderate hyperoxia of newborn mice causes an emphysematous lung phenotype in adulthood without persisting oxidative stress and inflammation

Abstract

BackgroundPreterm newborns typically require supplemental oxygen but hyperoxic conditions also damage the premature lung. Oxygen-induced lung damages are mainly studied in newborn mouse models using oxygen concentrations above 75% and looking at short-term effects. Therefore, we aimed at the investigation of long-term effects and their dependency on different oxygen concentrations.MethodsNewborn mice were exposed to moderate vs. severe hyperoxic air conditions (50 vs. 75% O2) for 14 days followed by a longer period of normoxic conditions. Lung-related parameters were collected at an age of 60 or 120 days.ResultsSevere hyperoxia caused lower alveolar density, enlargement of parenchymal air spaces and fragmented elastic fibers as well as higher lung compliance with peak airflow limitations and higher sensitivity to ventilation-mediated damages in later life. However, these long-term lung structural and functional changes did not restrict the voluntary physical activity. Also, they were not accompanied by ongoing inflammatory processes, increased formation of reactive oxygen species (ROS) or altered expressions of antioxidant enzymes (superoxide dismutases, catalase) and lung elasticity-relevant proteins (elastin, pro-surfactant proteins) in adulthood. In contrast to severe hyperoxia, moderate hyperoxia was less lung damaging but also not free of long-term effects (higher lung compliance without peak airflow limitations, increased ROS formation).ConclusionsSevere but not moderate neonatal hyperoxia causes emphysematous lungs without persisting oxidative stress and inflammation in adulthood. As the existing fragmentation of the elastic fibers seems to play a pivotal role, it indicates the usefulness of elastin-protecting compounds in the reduction of long-term oxygen-related lung damages.

Hyperoxia-induced bronchopulmonary dysplasia: better models for better therapies

“…Based on our previously published findings, we have shown that exposing mice at PN1 to 75% O 2 for 14 days is sufficient to induce alveolar simplification and septal thickening similar to those seen in a premature infant suffering from BPD ( Fig. 3 ), corroborating findings by others ( Mitchell et al, 2020 ; Popova et al, 2014 ; Kindermann et al, 2019 ; Schmiedl et al, 2017 ). Nardiello et al exposed C57/BL6 mouse pups to 85% O 2 for 14 days and used to analyze lung tissue samples ( Nardiello et al, 2017b ).…”

Regulation of hyperoxia-induced neonatal lung injury via post-translational cysteine redox modifications

“…3 B). A similar observation was made in mouse lung under 75% O 2 using immunoblot [ 79 ]. Other forms of SOD such as SODC and SODE, as well as catalase, do not show significant increases in protein abundance under hyperoxia.…”

An Experimental Model of Bronchopulmonary Dysplasia Features Long-Term Retinal and Pulmonary Defects but Not Sustained Lung Inflammation

“…This suggests that the structural changes apparent in adulthood are most likely the consequences of oxygen exposure during critical lung stages in infancy (49). Concurrently, there may also be changes occurring in other tissue components external to inflammation, such as modifications to extracellular matrix proteins (50).…”