Abstract
ABSTRACTBronchopulmonary dysplasia (BPD) is a chronic lung disease caused by exposure to high levels of oxygen (hyperoxia) and is the most common complication that affects preterm newborns. At present, there is no cure for BPD. Infants can recover from BPD; however, they will suffer from significant morbidity into adulthood in the form of neurodevelopmental impairment, asthma and emphysematous changes of the lung. The development of hyperoxia-induced lung injury models in small and large animals to test potential treatments for BPD has shown some success, yet a lack of standardization in approaches and methods makes clinical translation difficult. In vitro models have also been developed to investigate the molecular pathways altered during BPD and to address the pitfalls associated with animal models. Preclinical studies have investigated the efficacy of stem cell-based therapies to improve lung morphology after damage. However, variability regarding the type of animal model and duration of hyperoxia to elicit damage exists in the literature. These models should be further developed and standardized, to cover the degree and duration of hyperoxia, type of animal model, and lung injury endpoint, to improve their translational relevance. The purpose of this Review is to highlight concerns associated with current animal models of hyperoxia-induced BPD and to show the potential of in vitro models to complement in vivo studies in the significant improvement to our understanding of BPD pathogenesis and treatment. The status of current stem cell therapies for treatment of BPD is also discussed. We offer suggestions to optimize models and therapeutic modalities for treatment of hyperoxia-induced lung damage in order to advance the standardization of procedures for clinical translation.
Highlights
Bronchopulmonary dysplasia (BPD) is a chronic lung disease that is multifactorial in nature
Data from our laboratory has shown that induced pluripotent stem cells (iPSCs), when administered intraorally after exposing mice to hyperoxic conditions (75% O2 for 14 days), attenuate alveolar simplification (Fig. 2A) and restore lung morphology to that seen in normoxic control animals (Fig. 2B) (Mitchell et al, 2020)
Considerable differences in animal models and methodologies used to analyze the effects of hyperoxia-induced lung damage exist, hampering the potential to develop reliable and effective therapies for the treatment of BPD in neonates
Summary
Bronchopulmonary dysplasia (BPD) is a chronic lung disease that is multifactorial in nature. It is the most common complication of preterm birth, occurring in 43% of infants born at or before 28 weeks gestation (Lignelli et al, 2019; Willis et al, 2018). BPD is characterized by arrested lung growth, alveolar simplification, impaired blood vessel development and abnormal pulmonary function (Baraldi and Filippone, 2007). It is associated with significant morbidity and mortality in premature infants, and survivors often exhibit persistent long-term effects into adulthood (Silva et al, 2015). Lung damage can range from early developmental arrest in patients diagnosed with new BPD to structural damage of the immature lung in neonates diagnosed with classic BPD (Mosca et al, 2011)
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