The Lung Alveolar Lipofibroblast: An Evolutionary Strategy Against Neonatal Hyperoxic Lung Injury

摘要

>Significance: Oxygen, the main mode of support for premature infants with immature lungs, can cause toxicity by producing reactive oxygen species (ROS) that disrupt homeostasis; yet, these same molecules were entrained to promote vertebrate lung phylogeny. By providing a deeper understanding of this paradox, we propose physiologically rational strategies to prevent chronic lung disease (CLD) of prematurity. >Recent Advances: To prevent neonatal hyperoxic lung damage biologically, we have exploited the alveolar defense mechanism(s) that evolutionarily evolved to combat increased atmospheric oxygen during the vertebrate water to land transition. >Critical Issues: Over the course of vertebrate lung evolution, ROS promoted the formation of lipofibroblasts, specialized adepithelial cells, which protect the alveoli against oxidant injury; peroxisome proliferator-activated receptor gamma (PPARγ), the master switch for lipofibroblast differentiation, prevents such oxidant lung injury, both by directly promoting mesodermal differentiation and its antioxidant defenses, and indirectly by stimulating the developmental epithelial–mesenchymal paracrine interactions that have physiologically determined lung surfactant production in accord with the lung's phylogenetic adaptation to atmospheric oxygen, preventing Respiratory Distress Syndrome at birth. >Future Directions: The molecular strategy (PPARγ agonists) to prevent CLD of prematurity, proposed by us, although seems to be robust, effective, and safe under experimental conditions, it awaits detailed pharmacokinetic and pharmacodynamic studies for its safe and effective clinical translation to human infants. Antioxid. Redox Signal. 21, 1893–1904.

“I have procured air [oxygen]…between five and six times as good as the best common air that I have ever met with.”—Joseph Priestley, 1775

class="head no_bottom_margin" id="s001title">IntroductionOxygen therapy is one of the main supportive modalities that is instituted to keep premature infants alive. In view of the compelling experimental and clinical evidence for the involvement of oxidant and antioxidant imbalance in many morbidities associated with prematurity, for example, the chronic lung disease (CLD) of prematurity or bronchopulmonary dysplasia (BPD), retinopathy of prematurity, intra/periventricular hemorrhage, and necrotizing enterocolitis, the safety of this practice has recently been called into question yet again (). The mechanistic basis for free radical involvement in these disorders is that free oxidant radicals are formed too rapidly to be detoxified by the limited antioxidant defenses of the premature infant, with resultant tissue-specific damage. In contrast to the conventional approach to this problem, we will focus on the dyshomeostasis of the preterm alveolus as a failed evolutionary mechanism (), which allows us to consider interventions based on phylogenetic adaptations of the lung to atmospheric oxygen.The fetus develops in a relatively hypoxic environment in utero, its adaptive responses well suited to the relatively low fetal oxygen saturation state, but ill-suited for a smooth and safe transition of the prematurely delivered infant to extrauterine life in a relatively hyperoxic environment. Although there are plenty of animal data suggesting the developmental increases in the expression of antioxidant enzymes during fetal lung development, with the exception of limited data supporting a developmental increase in the expression of lung catalase activity, there are very few human studies that have directly examined the expression of antioxidant enzymes during human lung development (). In fact, some studies have failed to demonstrate any late fetal surges in pulmonary superoxide dismutase and glutathione peroxidase activities in human tissues (). On the other hand, there is no doubt that significantly lower levels of antioxidant enzymes have been observed in many studies in premature infants, and their impaired ability to adequately upregulate antioxidant enzymes in response to oxidant stresses, making them highly susceptible to oxidant injury. Therefore, premature infants are almost certainly developmentally unprepared for extrauterine life in an oxygen-rich environment, and exhibit a unique sensitivity to oxidant injury. Furthermore, the greater the prematurity, the higher is the associated risk of oxidant injury.