In the delicate and high-stakes world of neonatal medicine, the fight against lung inflammation in preterm infants has taken a promising turn with recent advances in steroid therapy. Researchers have begun to delve deep into the nuanced effects of two potent corticosteroids, budesonide and hydrocortisone, revealing their distinct influences on the vulnerable lungs and developing brains of ventilated preterm lambs—an animal model that closely replicates human premature infants. This line of inquiry not only illuminates potential new avenues for reducing lung injury but also raises critical questions about the safety and long-term neurodevelopmental outcomes of these treatments, especially when administered alongside the well-established antenatal steroids.
Preterm birth often precipitates a cascade of inflammatory events that impair lung development and function, frequently necessitating mechanical ventilation and surfactant therapy. However, while surfactant replacement has revolutionized respiratory outcomes, it does not sufficiently address the underlying inflammatory processes that contribute to chronic lung disease, including bronchopulmonary dysplasia (BPD). Consequently, postnatal corticosteroids have emerged as therapeutic candidates given their potent anti-inflammatory properties. Yet, their potential neurotoxic effects have limited their widespread use, rendering the search for safer steroid regimens both urgent and complex.
Emerging evidence now suggests that budesonide, when added to surfactant therapy, may offer distinct advantages in mitigating lung inflammation without the overt neurodevelopmental risks traditionally associated with corticosteroids. Budesonide’s high topical potency and rapid clearance from systemic circulation make it a particularly appealing agent, theoretically allowing for localized pulmonary effects without systemic exposure that could negatively impact the developing brain. This targeted approach, if validated, could revolutionize the standard of care for managing preterm infants with respiratory distress.
In parallel, prophylactic administration of hydrocortisone—typically known for its broader systemic effects—has also shown promise in decreasing the incidence and severity of lung inflammation. Hydrocortisone, with its glucocorticoid and mineralocorticoid actions, might modulate inflammation while supporting cardiovascular stability, an important consideration given the cardiovascular challenges faced by extremely premature neonates. However, understanding its differential impact compared to budesonide on both lung and brain tissues remains critical to fine-tuning its clinical application.
A pivotal component of current research explores how these postnatal steroid therapies interact with antenatal steroid regimens, which have long been standard interventions aimed at promoting fetal lung maturation. Antenatal corticosteroids, administered to mothers at risk of preterm delivery, significantly reduce neonatal mortality and respiratory distress syndrome. Nonetheless, their cumulative effect when combined with subsequent postnatal steroid treatments remains uncertain. Determining whether such combinations are safe or if they might exacerbate risks such as neurodevelopmental impairments is essential before clinicians can confidently implement these therapies in concert.
The recent study involving ventilated preterm lambs provides much-needed clarity by carefully dissecting the distinct pulmonary and cerebral responses to budesonide and hydrocortisone treatments. Lambs, due to their physiological similarities to human infants, particularly in lung development and brain maturation trajectories, serve as an excellent translational model. This research employed sophisticated ventilatory support systems and rigorous histopathological analyses to unravel how these steroids modulate inflammation and injury at tissue and cellular levels.
Interestingly, the findings highlight that budesonide, when delivered with surfactant, more effectively reduces lung inflammation markers and structural lung injury compared to hydrocortisone. The localized anti-inflammatory effect resulted in improved alveolar architecture and decreased inflammatory cell infiltration, suggesting better preservation of lung function. Conversely, while hydrocortisone showed some attenuation of inflammatory markers, its systemic exposure appeared to exert less pronounced benefits on pulmonary outcomes, pointing to a potentially narrower therapeutic window or differing mechanisms of action.
Beyond pulmonary effects, the neurological data from this study are equally compelling, shedding light on steroid-induced brain changes during a critical window of neurodevelopment. Budesonide’s minimal systemic absorption corresponded with a lower incidence of neuroinflammation and fewer alterations in key markers of brain injury, such as microglial activation and white matter integrity. Hydrocortisone, however, displayed more variable cerebral effects, warranting cautious interpretation given the delicate balance required to mitigate lung inflammation without sacrificing neurodevelopmental safety.
The distinction between these two steroids’ pharmacokinetics further elucidates their divergent profiles. Budesonide’s lipophilicity and rapid hepatic metabolism minimize systemic circulation, implying that the drug predominantly acts within the lungs. Hydrocortisone’s systemic disparities may expose the developing brain to glucocorticoid receptor-mediated effects that can have lasting ramifications. Such pharmacological nuances underscore the importance of dosage form, timing, and delivery routes in optimizing neonatal steroid therapy.
Alongside tissue-specific assessments, the study also integrated a suite of biomolecular analyses, including cytokine profiling, gene expression assays, and imaging modalities, to provide a holistic view of the inflammatory milieu and tissue remodeling processes. These comprehensive approaches enable a deeper mechanistic understanding, furnishing the groundwork for precision medicine interventions tailored to the unique vulnerabilities and therapeutic needs of preterm infants.
Despite encouraging results, the research community remains vigilant. The complexity of steroid responses, influenced by timing of administration, dose adjustments, and individual variability, necessitates extensive clinical trials before firm practice recommendations can be established. Moreover, the potential additive or synergistic effects when layered onto existing antenatal steroid protocols require careful longitudinal evaluation, incorporating neurodevelopmental follow-up and respiratory outcomes extending well into childhood.
The translational impact of this work is profound. It paves the way toward safer, more effective strategies to combat chronic lung disease in preterm neonates—a condition that not only impacts immediate survival but also shapes lifelong health trajectories. Optimizing steroid therapy could radically reduce the burden of BPD, fostering better quality of life and developmental potential in one of the most vulnerable patient populations.
The nuanced differences between budesonide and hydrocortisone use also open new investigative vistas regarding receptor-specific corticosteroid signaling, pulmonary drug delivery systems, and the intersection of immune modulation with neonatal neurobiology. Such multidisciplinary endeavors will be crucial to unraveling the full therapeutic potential while mitigating risks.
In conclusion, the differential effects of budesonide and hydrocortisone on lung and brain highlight the exciting possibilities but also the cautious path ahead in neonatal care innovation. Early evidence favors budesonide as a potentially safer, more targeted postnatal steroid adjunct to surfactant therapy, whereas hydrocortisone may offer systemic benefits but necessitates additional scrutiny regarding neurodevelopmental safety and optimal dosing strategies.
As ongoing research advances, clinicians and scientists alike anticipate the emergence of refined, evidence-based protocols that integrate the best of antenatal and postnatal steroid therapies. Such integration holds promise not only for improved pulmonary outcomes but also for safeguarding the neurological futures of preterm infants worldwide, ultimately transforming neonatal critical care.
Subject of Research: Differential effects of budesonide and hydrocortisone on lung and brain inflammation in ventilated preterm lambs.
Article Title: Budesonide and hydrocortisone have differential effects on lung and brain in ventilated preterm lambs.
Article References:
Grzych, H., Fee, E., Kemp, M.W. et al. Budesonide and hydrocortisone have differential effects on lung and brain in ventilated preterm lambs. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04172-0
Image Credits: AI Generated
