Intermittent Hypoxia-Hyperoxia and Oxidative Stress in Developing Human Airway Smooth Muscle

Abstract

Premature infants are frequently and intermittently administered supplemental oxygen during hypoxic episodes, resulting in cycles of intermittent hypoxia and hyperoxia. The relatively hypoxic in utero environment is important for lung development while hyperoxia during the neonatal period is recognized as detrimental towards the development of diseases such as bronchopulmonary dysplasia and bronchial asthma. Understanding early mechanisms that link hypoxic, hyperoxic, and intermittent hypoxic-hyperoxic exposures to altered airway structure and function are key to developing advanced therapeutic approaches in the clinic. Changes in oxygen availability can be detrimental to cellular function and contribute to oxidative damage. Here, we sought to determine the effect of oxygen on mitochondria in human fetal airway smooth muscle cells exposed to either 5% O2, 21% O2, 40% O2, or cycles of 5% and 40% O2 (intermittent hypoxia-hyperoxia). Reactive oxygen species production, altered mitochondrial morphology, and changes in mitochondrial respiration were assessed in the context of the antioxidant N-acetylcysteine. Our findings show developing airway smooth muscle is differentially responsive to hypoxic, hyperoxic, or intermittent hypoxic-hyperoxic exposure in terms of mitochondrial structure and function. Cycling O2 decreased mitochondrial branching and branch length similar to hypoxia and hyperoxia in the presence of antioxidants. Additionally, hypoxia decreased overall mitochondrial respiration while the addition of antioxidants increased respiration in normoxic and O2-cycling conditions. These studies show the necessity of balancing oxidative damage and antioxidant defense systems in the developing airway.

Tear Proteomics in Infants at Risk of Retinopathy of Prematurity: A Feasibility Study

“…Oxidative stress can be triggered by any imbalance in oxygen levels relative to the local tissue's normal state, such as poorly functional, chaotically organized vasculature (often seen in vessel overgrowth), or from changes in oxygen supply (antenatal air exposure or oxygen therapy). 27 The changes in peroxiredoxin expression observed here suggest a deeper change in oxidative stress and warrant further investigation into oxidation of tear proteins themselves or other markers of ROP.…”

Effects of Hypoxia–Hyperoxia Preconditioning on Indicators of Muscle Damage After Acute Resistance Exercise in Male Athletes

“…For example, preconditioning using hyperthermia ( Nosaka et al, 2007 ), ischemia ( Franz et al, 2018 ), or light exercise ( Nausheen et al, 2017 ) have been shown to reduce RE-induced muscle damage and inflammation. In a previous cell culture study, intermittent hypoxia–hyperoxia treatment elevated oxidative stress production in human airway smooth muscle cells ( Bartman et al, 2021 ). Chronic intermittent hypoxia–hyperoxia also increased oxidative damage in lung tissue of neonatal rodents ( Dylag et al, 2017 ; Mohamed et al, 2020 ).…”

Predictors of recurrent wheezing in late preterm infants

“…However, episodes of hypoxia or respiratory distress requiring supplemental oxygen, and the subsequent exposure to it, may confer risk of wheezing in the first few years of life. Recent studies in newborn mouse and primary human airway smooth muscle cells suggest intermittent hyperoxia and hypoxia has a long‐term detrimental effect on airway function that may involve oxidative stress 17,18 . Again, this remains an area of interest for future prospective studies to better define the role of oxidative stress, coupled with a potentially immature respiratory system in this patient population.…”