Bronchopulmonary 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.

Aim: Previously, we have shown that inhibition of SphK by the SphK inhibitor-II (SKI II) prevents lipopolysaccharide-induced preterm birth in mice. The aim of this study was to develop a vaginal self-nanoemulsifying drug-delivery system (SNEDDS) for SKI II. Materials & methods: A SKI II-loaded SNEDDS was characterized and tested in a murine preterm birth model. Results: The SNEDDS immediately formed a gel and then slowly emulsified to nanoglobules with over 500-fold enhancement of SKI II solubility at vaginal pH. Intravaginal administration of the SKI II SNEDDS significantly decreased lipopolysaccharide-induced preterm birth in mice. Conclusion: A vaginal nanoformulation of SKI II represents a novel, noninvasive approach to prevent preterm birth.

Preterm birth (PTB) is a major cause of infant mortality in the United States and around the globe. Makena®—once-a-week intramuscular injection of 17-α Hydroxyprogesterone caproate (17P)—is the only FDA approved treatment for the prevention of PTB. Invasive delivery of 17P requires hospitalization and expert personnel for injection. Vaginal delivery of 17P would be preferable, because of high patient compliance, reduced systemic exposure, fewer side effects, and no need for hospitalization. The objective of the present study was to prepare and evaluate a self-nanoemulsifying vaginal tablet of 17P. A solid self-nanoemulsifying preconcentrate (S-SNEDDS) of 17P and dimethylacetamide (DMA) was developed using medium chain triglycerides, a non- immunogenic surfactant, and co-processed excipient (PVA-F100). The tablet prepared was characterized for emulsification time, particle size, solid state properties, and drug release. The formulation showed >50% inhibition of TNF-α release from LPS-stimulated RAW 264.7 cells. Importantly, there were significant differences in rates of PTB and average time to delivery between control and vaginal 17P-treated groups in LPS-stimulated timed pregnant E15.5 mice. Considering the lacuna of therapeutic approaches in this area, vaginal delivery of 17P for the prevention of preterm birth has significant clinical relevance.

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The ET-1/SphK/SIP pathway is a potential pharmacotherapeutic target for the prevention of PTB.