LAUSR

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that occurs at high rates in survivors of premature birth (1). BPD was originally described in 1967 by Northway and colleagues as an airway and parenchymal lung injury in preterm infants with a history of respiratory distress syndrome concurrent with exposures to oxygen andmechanical ventilation (2). More than 50 years later, the clinical features of BPD have evolved, together with abilities to care for extremely premature and low birthweight infants born in the late canalicular/early saccular phases of lung development. Th ebaud and colleagues recently highlighted the complex intersection of lung development, plasticity, injury, and repair in the clinical disease BPD (1). Despite marked advances in our understanding of the disease, no significant progress has been made in reducing its prevalence (3), and therapeutic options remain limited. Hyperoxia-induced neonatal lung injury (4) is used to model BPD, as supraphysiologic oxygen exposure is a common source of lung injury in premature infants (5, 6) and the pathophysiology induced by early oxygen exposure parallels that seen with BPD. Murine models also offer unique opportunities to evaluate early effects of oxygen exposure, as newborn mice exhibit immature morphometry resembling the saccular phase of lung development (7). Understanding how hyperoxia inflicts injury and compromises ongoing alveolar and vascular (8, 9) development is paramount to understanding BPD pathogenesis. Distal airspace alveoli are lined by alveolar epithelial type I and II (ATI and ATII) cells. ATI cells are squamous epithelial cells that facilitate gas exchange and serve barrier functions. ATII cells, which normally cover 5% of the alveolar surface area, produce surfactants that decrease surface tension and thereby protect against atelectasis. ATII cells normally proliferate in the healthy mouse lung from Postnatal day 0 (PN0) to PN14, with a peak of proliferation at PN7. After lung injury, ATII cells become both proliferative and resistant to apoptosis, with increased telomerase activity (10–12). These characteristics, in addition to their ability to repopulate ATI cells lost after lung injury (13), identify ATII cells as a critical progenitor population and a key contributor to the developmental phenotype observed with BPD. A significant knowledge gap remains in understanding the contribution of neonatal hyperoxia to the number and complement of alveolar epithelial cells in simplified alveoli that are pathognomonic for modern BPD (1). Multiple studies have demonstrated oxygeninduced alterations of alveolar epithelial proliferation, apoptosis, and/ or cell-cycle regulation (14–16). Using Sftpc-EGFP transgenic mice, Yee and colleagues previously demonstrated that mice exposed to a fraction of inspired oxygen of 1.0 during PN0–4 exhibited increased proliferating (Bromodeoxyuridine) ATII cells starting at PN1, with rapid expansion of the ATII cell population by PN4 (17, 18). This expanded ATII population is not static, as they identified fewer ATII cells in lungs of adult mice 8 weeks after neonatal hyperoxia exposure (19). In this issue of the Journal, Yee and colleagues (pp. 402–414) now identify a novel—and targetable—mechanism by which hyperoxia causes atypical proliferation of ATII cells in the newborn mouse lung (20). First, the authors demonstrate that an early and aberrant wave of ATII cell proliferation (PN1–4) after neonatal hyperoxia exposure is associated with genetic programs directing serine synthesis and one-carbon–coupled folate metabolism. These metabolic pathways affect cell proliferation throughmultiple mechanisms, nicely outlined by the authors to include redox defense, epigenetic maintenance, and biosynthesis. Second, they show that these gene expression pathways were also associated with the normal wave of postnatal ATII proliferation that peaks at PN7. Narrowing in onmechanism, the authors focused onMthfd2 (methylenetetrahydrofolate dehydrogenase 2), an enzyme in mitochondrial folate metabolism expressed by proliferative cells (21), and the ATII mitogen Fgf7/Kgf (22–24). In this study, Mthfd2 is found to be a central mediator of alveologenesis, induced in aberrant (hyperoxia-treated) and normal (room air) proliferating neonatal ATII cells and in Fgf7/Kgf-treated proliferating adult ATII cells. Third, the authors identify a mechanism of serine/onecarbon–coupled folate metabolism gene expression through mitochondrial stress–related expression of Atf4 (activating transcription factor 4).Mthfd2 is required for Fgf7/Kgf-induced ATII proliferation and Atf4 induction. An exciting finding is that the early and aberrant ATII proliferation during hyperoxia exposure was mitigated by concurrent administration of the SOD (superoxide dismutase) mimetic/antioxidant mitoTEMPO. MitoTEMPO did not affect normal ATII proliferation in control experiments. These results strengthen previous studies showing preservation of lung development during neonatal hyperoxia using transgenic expression of human extracellular SOD or treatment with mitoTEMPO (25, 26). Interestingly, a recent study also showed the therapeutic potential of mitoTEMPO to attenuate cardiac injury after nicotine exposure associated with mitochondrial oxidative stress in rats (27). Finally, the authors identified increased ATII proliferation and increased expression of ATF4 andMTHFD2 in lungs of human patients with severe type 2 BPD. Though not specified, these patients, by definition, had histories of significant hyperoxia exposure associated with a diagnosis of severe disease (28). These translational findings mirror those in premature baboons, where oxygen and mechanical ventilation treatments were associated with ATII proliferation (Reference 29 and current manuscript).