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Modern molecular approaches to the ancient problem of surfactant deficiency of prematurity

Pediatric Research (2025)Cite this article

The challenge of maturing the preterm lungs so they can function outside the womb while attempting to maintain the pregnancy inside it has existed since Dr. Mary Ellen Avery first described surfactant deficiency as the cause of hyaline membrane disease in 1959.1 Antenatal corticosteroids, currently the most effective stimulate for fetal maturation, were first reported by Sir “Mont” Liggins in 1972, but some of the corticosteroid effects are transient and corticosteroids may have long-term effects on infants that do not deliver preterm.2,3,4 In their current manuscript, “Combined Transamniotic Delivery of Surfactant Proteins B and C mRNA Enhances Preterm Fetal Surfactant Production is a Rodent Model”, Moskowitzova et al. attempt to provide more localized lung maturation through the application of human surfactant mRNA into the amniotic sacs of fetal rats. The research team performed fetal surgeries at E17 to inject encapsulated human mRNA into the amniotic sacs, then collected the pups between E18 to E21 (term) to evaluate for lung maturation. They demonstrated, in a lab not far from Dr. Avery’s original lab at Harvard, a transient improvement in surfactant proteins and phosphatidyl-choline (PC) preterm rat lungs.

The study compares the effects of modified mRNA for human surfactant protein B (SP-B), surfactant protein C (SP-C), or the combination SP-B and SP-C to nanoparticle vehicle alone on lung maturation. The combination seems to affect the SP-B protein levels and not the SP-C protein levels, but all the mRNA combinations have some effect on the amniotic fluid PC levels. There is not a clear explanation for the benefits of combined mRNA for SP-B and SP-C on lung maturation, but minimal effect of SP-C or SP-B mRNA when given alone. It may be that the higher concentration of the mRNA in the combined groups (2 ÎĽg/injection) caused more of an inflammatory response than a single mRNA alone (1 ÎĽg/injection). Lipopolysaccharide (LPS) has been utilized in preterm sheep models to mimic chorioamnionitis, and the lung inflammation present from the LPS causes increases in surfactant proteins and phospholipids.5 Even lung inflammation from a very brief mechanical stretch can mature the fetal lung and increase surfactant proteins.6 It is unclear if inflammation from the mRNA might be a cause for lung maturation since lung inflammation was not assessed, and the use of mRNA that did not code for surfactant proteins was not utilized as a second control. The cross-reactivity of ELISA for the human surfactant protein and rat surfactant proteins also makes interpretation of the results more difficult. The fetal rat type 2 cells may be translating the human mRNA into stable protein, or the processing of the human mRNA may be priming the cells to produce additional rat mRNA. The increase in phospholipids (PC) found in the amniotic fluid is explained by authors as likely due to priming of the type 2 cells by the mRNA. This could be correct, but direct translation by type 2 cells would require the encapsulated mRNA to migrate down the airways against both a flow and pressure gradient created by the fetal lung fluid and fetal breathing that typically moves from the distal lungs up into the larynx. Although we do not fully understand the mechanism of the increases in protein and phospholipids, it does appear that the rats had some transient increases after transamniotic administration of surfactant mRNA. The effects are short-lived and only occur at some of the time points, so the dosage and encapsulation ratios would need to be further optimized.

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  1. Division of Neonatology, Cardinal Glennon Children’s Hospital, Saint Louis University, Saint Louis, MO, USA

    Noah H. Hillman

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  1. Noah H. Hillman
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Correspondence to Noah H. Hillman.

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Hillman, N.H. Modern molecular approaches to the ancient problem of surfactant deficiency of prematurity. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04694-7

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