MicroRNAs May Program Premature Lung Disease Before Birth

Bronchopulmonary dysplasia, the most common chronic respiratory complication of extreme prematurity, may begin its molecular life long before a preterm infant takes a first breath. A new educational review argues that the disease should be understood not merely as the consequence of weeks of ventilator support and oxygen therapy, but as the final phenotype of a fetal–neonatal continuum in which antenatal susceptibility and postnatal injury interact over time. At the center of that argument sits a family of tiny gene regulators: microRNAs, short non-coding RNA molecules roughly 20 to 24 nucleotides long that fine-tune gene expression after transcription.

The scale of the clinical problem is substantial. Current estimates indicate that bronchopulmonary dysplasia develops in up to 45 percent of infants born before 29 weeks of gestation, with considerable variability depending on gestational age, clinical characteristics and diagnostic criteria. Contemporary definitions, including a three-grade classification based on the type and intensity of respiratory support required at 36 weeks’ postmenstrual age, identify the disease only when chronic lung disease is already established. By that point, the biological processes driving arrested alveolar and vascular development have been active for weeks, and the affected infants face persistent abnormalities in lung function, recurrent respiratory morbidity, pulmonary vascular disease and adverse neurodevelopmental outcomes.

MicroRNAs regulate gene expression by binding predominantly to complementary sequences within the 3′ untranslated region of target messenger RNAs, promoting mRNA degradation or inhibiting translation. Because a single microRNA can regulate multiple transcripts simultaneously, shifts in microRNA expression can ripple across interconnected pathways controlling cell proliferation and differentiation, inflammation, antioxidant responses, apoptosis, extracellular matrix remodeling, angiogenesis and vascular development. During the embryonic, pseudoglandular, canalicular, saccular and alveolar stages of lung development, dynamic changes in microRNA expression contribute to epithelial differentiation, airway branching, mesenchymal–epithelial interactions, pulmonary vascular development and ultimately alveolarization. Mechanical stretch, hyperoxia, inflammation, infection and metabolic disturbances can subsequently reshape these profiles, and altered microRNA patterns have been reported both in experimental models of hyperoxia-induced neonatal lung injury and in biological specimens from preterm infants with the disease, including peripheral blood, tracheal aspirates, extracellular vesicles and lung tissue.

The review emphasizes that dysregulation is not a simple story of protective microRNAs falling and injurious ones rising. Several microRNAs involved in lung growth, such as members of the miR-17-92 cluster including miR-17 and miR-19b, which participate in pulmonary progenitor cell proliferation and epithelial morphogenesis, appear downregulated in association with impaired lung development, as do miR-206, miR-489, let-7 family members and miR-876-3p. Reduced miR-425 expression has been linked to altered PI3K/Akt signaling and impaired cellular survival responses, potentially increasing the susceptibility of the immature pulmonary epithelium to oxidative injury. Conversely, adverse perinatal exposures can induce microRNAs that suppress pathways needed for normal development: increased miR-34a expression in experimental hyperoxia-induced neonatal lung injury has been associated with disruption of alveolar development, angiogenesis and epithelial cell survival, while miR-421, through regulation of fibroblast growth factor 10-related signaling, has been implicated in altered epithelial development. More recently, transcriptomic analyses identified increased miR-219-5p expression in association with severe disease; through regulation of platelet-derived growth factor receptor-α signaling, miR-219-5p may interfere with secondary septation and pulmonary microvascular development.

That context-dependence is precisely why the authors turn to the placenta. Fetal growth restriction, frequently associated with placental insufficiency and chronic fetal hypoxemia, has emerged as an important antenatal risk factor: clinical studies and meta-analyses have shown that growth-restricted preterm infants, as well as infants born small for gestational age, have an increased risk of bronchopulmonary dysplasia and severe respiratory morbidity compared with appropriately grown preterm infants. Experimental models of fetal growth restriction show reduced angiogenic signaling, including alterations in vascular endothelial growth factor and its receptor pathways, endothelial dysfunction, abnormal extracellular matrix remodeling and impaired alveolarization—abnormalities that resemble key features of contemporary bronchopulmonary dysplasia. The review is careful to distinguish fetal growth restriction, a pathological failure to achieve individual growth potential, from small-for-gestational-age status, which is defined by birth weight relative to gestational age and does not necessarily imply pathological restriction.

The placenta is highly enriched in microRNAs, and particular attention has focused on the chromosome 19 microRNA cluster, one of the largest primate-specific miRNA clusters, whose members are highly expressed in trophoblastic tissue and participate in regulatory networks governing trophoblast differentiation, cellular proliferation, immune modulation, angiogenesis and adaptation to cellular stress. Quantitative RT-PCR studies have reported reduced expression of miR-518b, miR-1323, miR-516b, miR-515-5p, miR-520h, miR-519d and miR-526b in placentas from pregnancies complicated by fetal growth restriction compared with uncomplicated pregnancies. Because these microRNAs are involved in pathways regulating trophoblast function, vascular remodeling, endothelial homeostasis and cellular responses to hypoxia, their dysregulation may reflect impaired placental adaptation and altered maternal–fetal signaling. The authors stress, however, that direct evidence linking specific chromosome 19 cluster alterations to subsequent bronchopulmonary dysplasia remains limited; whether these microRNAs directly contribute to fetal lung programming, primarily serve as markers of placental dysfunction, or do both, is still unresolved.

Angiogenesis offers the most concrete bridge between antenatal vulnerability and postnatal lung injury, because vascular growth and alveolarization are tightly coupled during fetal and early postnatal development. Clinical observations support the relevance of early angiogenic dysregulation: one research team reported lower circulating vascular endothelial growth factor concentrations during the first week of life in preterm infants who subsequently developed the disease, although circulating concentrations may not directly reflect local pulmonary activity. Among the microRNAs implicated in this axis, miR-203a-3p has the most direct evidence: increased expression has been described in peripheral blood samples from affected infants, vascular endothelial growth factor A has been identified as one of its molecular targets, and complementary experiments in hyperoxia-exposed neonatal rats and alveolar epithelial cells showed that increased miR-203a-3p was associated with reduced VEGFA signaling and increased apoptosis, while inhibition of the microRNA restored VEGFA expression, modulated downstream ERK and PI3K signaling and attenuated hyperoxia-induced lung injury. Experimental studies have also demonstrated that miR-16 can bind the 3′ untranslated region of VEGF mRNA, reducing VEGF expression and suppressing angiogenic activity, although its role in human disease remains biologically plausible rather than established. In a murine model, miR-451 inhibition increased macrophage migration inhibitory factor expression, restored VEGF-A expression, modulated angiopoietin-1, angiopoietin-2 and their receptor Tie2, and was accompanied by improved alveolar and vascular development. Reduced miR-30a expression under hyperoxic conditions has been associated with dysregulated DLL4/Notch signaling and abnormal pulmonary vascular development.

Oxidative stress forms the second great pillar of the proposed mechanism. Preterm infants are particularly vulnerable because antioxidant defense systems mature predominantly during late gestation, and premature birth interrupts that process while simultaneously exposing the immature lung to a rapid increase in oxygen tension, often compounded by supplemental oxygen, mechanical ventilation, inflammation and infection. Oxidative stress and microRNAs are connected through a bidirectional regulatory network: increased oxygen tension and reactive oxygen species accumulation can modify microRNA transcription, processing and stability, while redox-responsive microRNAs can regulate genes controlling mitochondrial function, antioxidant defenses, apoptosis, inflammation and ROS generation. Increased miR-34a expression has been reported in experimental neonatal hyperoxia and in respiratory samples from preterm infants developing the disease, and miR-195, induced by hyperoxic exposure, has been associated with intracellular ROS accumulation, apoptosis and impaired lung development, whereas experimental inhibition of miR-195 reduced oxidative injury and preserved alveolar and microvascular architecture. Reduced miR-3202 expression under experimental hyperoxic conditions has been described, and its restoration decreased RAG1 expression, intracellular ROS accumulation and epithelial apoptosis. Reduced miR-574-3p expression, meanwhile, has been proposed as an adaptive response that could relieve post-transcriptional repression of adrenomedullin, a vasoactive peptide with antioxidant and endothelial-protective properties, although whether this provides effective protection in the human preterm lung remains to be established.

A particularly important intersection involves nuclear factor erythroid 2-related factor 2, a master transcriptional regulator of cellular antioxidant defense that is normally kept at low intracellular levels through KEAP1-mediated ubiquitination and proteasomal degradation. In response to oxidative stress, NRF2 accumulates and translocates to the nucleus, where it binds antioxidant response elements and promotes transcription of cytoprotective genes including heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. NRF2 has been experimentally validated as a direct target of miR-144 in redox-sensitive cellular systems, meaning increased miR-144 expression can reduce NRF2 abundance and attenuate antioxidant responses, while reduced expression could theoretically relieve repression and facilitate adaptation. miR-34a may also influence antioxidant responses through regulation of SIRT1, which can modulate NRF2 activity through deacetylation-dependent mechanisms, although evidence for the complete miRNA–SIRT1–NRF2 axis derives from different experimental systems and direct demonstration in human disease remains limited. The review frames oxidative stress and microRNA dysregulation as a potential self-reinforcing feedback loop: oxidative stress modifies microRNA expression, altered profiles can weaken antioxidant defenses or enhance ROS-generating pathways, and the resulting redox imbalance may further reshape microRNA expression, contributing to epithelial and endothelial dysfunction, apoptosis, inflammation, impaired angiogenesis and ultimately arrested alveolarization.

Translational implications follow in two directions. As biomarkers, microRNAs are detectable in multiple biological fluids, relatively stable because of their association with proteins or encapsulation within extracellular vesicles, and quantifiable with highly sensitive molecular techniques, yet no microRNA-based biomarker has been incorporated into routine risk assessment. Most available studies include relatively small, frequently single-center cohorts with substantial heterogeneity in gestational age, respiratory management, sampling time points and diagnostic definitions; normalization strategies, hemolysis and pre-analytical processing can substantially influence measured expression, and a microRNA associated with the disease may reflect developmental immaturity or treatment exposure rather than disease-specific biology. As therapeutic targets, preclinical proof of principle exists—targeting the miR-34a/PDGFRα axis partially restored alveologenesis in experimental disease, and miR-451 inhibition in a murine model preserved MIF expression and attenuated the cardiopulmonary phenotype with improved lung morphometry, vascular density and pulmonary vascular remodeling—but a single microRNA may influence numerous transcripts across several organs, raising the risk of unintended developmental effects in extremely preterm infants. The authors conclude that microRNA-based therapy should currently be regarded as a promising preclinical strategy rather than an immediately translatable intervention, and that the field’s future lies in longitudinal, multi-compartment profiling—from placenta and cord blood through serial circulating and respiratory samples—integrated with clinical phenotyping and complementary omics approaches to identify biologically distinct disease endotypes before conventional clinical manifestations become apparent.

Subject of Research: MicroRNA dysregulation across the fetal–neonatal continuum in bronchopulmonary dysplasia development

Article Title: Bronchopulmonary Dysplasia Starts in Utero: MicroRNA Dysregulation Across the Fetal–Neonatal Continuum in the Bronchopulmonary Dysplasia Development

Article References: Perrone, S., Carloni, S., Beretta, V., Raitano, V., Leuratti, P., Buttarelli, L., Caselli, E., Gerevini, S., Albertini, M. C., Benedetti, S., Nonnis‐Marzano, F., Maffei, G., Gitto, E., & Vento, G. (2026). Bronchopulmonary Dysplasia Starts in Utero: MicroRNA Dysregulation Across the Fetal–Neonatal Continuum in the Bronchopulmonary Dysplasia Development. Journal of Cellular and Molecular Medicine, 30(21), Article e71427. https://doi.org/10.1111/jcmm.71427

Image Credits: AI Generated

DOI: 10.1111/jcmm.71427

Keywords: bronchopulmonary dysplasia, microRNAs, prematurity, placental dysfunction, fetal growth restriction, angiogenesis, VEGF signaling, oxidative stress, NRF2, lung development, biomarkers, therapeutic targets