Adaptive immune responses are altered in adult mice following neonatal hyperoxia

Abstract

Premature infants with bronchopulmonary dysplasia (BPD), are at risk for frequent respiratory infections and reduced pulmonary function. We studied whether neonatal hyperoxia disrupts adaptive immune responses in adult mice, contributing to higher respiratory‐related morbidities seen in these infants. Newborn mice litters were randomized at 3 days to 85% O2 or room air (RA) for 12 days. Whole lung mRNA was isolated in both the groups at 2 weeks and 3 months. Gene expression for T‐cell and B‐cell adaptive immune response was performed by real‐time PCR and qRT‐PCR; protein expression (p21, IL4, IL10, IL27, cd4) was performed by enzyme immunoassay along with p21 immunohistochemistry. Hyperoxia increased expression of p21 and decreased expression of 19 genes representing T/B‐cell activation by ≥ fourfold; three of them significantly (Rag1, Cd1d1, Cd28) compared to the RA group at 2 weeks. Despite RA recovery, the expression of IFN γ, IL27, and CD40 was significantly reduced at 3 months in the hyperoxia group. Expression of p21 was significantly higher and IL27 protein lower at 2 weeks following hyperoxia. Adult mice exposed to neonatal hyperoxia had lower IL4 and IL10 in the lung at 3 months. Adaptive immune responses are developmentally regulated and neonatal hyperoxia suppresses expression of genes involved in T‐/B‐cell activation with continued alterations in gene expression at 3 months. Dysfunction of adaptive immune responses increases the risk for susceptibility to infection in premature infants.

Clocks, Viruses, and Immunity: Lessons for the COVID-19 Pandemic

“…Many patients would have received oxygen, and it is interesting to consider the potential effects of this therapy on clock-regulated pathways and disease outcomes. Importantly, several reports show that supplemental oxygen given to premature infants associates with a risk of lung dysfunction and susceptibility to respiratory infections in adult life ( Buczynski et al, 2013 ; Yee et al, 2013 ; Kumar et al, 2018 ).…”

Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

“…These data speak for a protective effect of Lpar1 in oxygen-injury in rat lungs. In another study, exposure to hyperoxia in the neonatal period was documented to cause changes in adaptive cellular immunity that persisted into adulthood (286), where exposure of mouse pups to hyperoxia between P3 and P12 impacted both T cell and B cell activation, which was noted during hyperoxia exposure, as well as in adult mice after a 10-week recovery after hyperoxia exposure. No studies on lung structure were undertaken in that study, and the association between alterations to T cell and B cell activation and lung alveolarization remains cor-…”

Mesenchymal Stromal Cell-Derived Extracellular Vesicles Restore Thymic Architecture and T Cell Function Disrupted by Neonatal Hyperoxia

“…In a baboon BPD model, investigations into thymic involution provided evidence that thymic architecture and T cell function are altered leading to autoreactivity and immunodeficiency (11). Further mouse studies of neonatal hyperoxia-induced lung injury demonstrated a dysregulation of thymopoiesis and altered adaptive immune responses which persisted into adulthood (12,13). These data suggest that hyperoxia-induced thymic atrophy during the neonatal period results in long-term complications with an autoimmune component.…”

“…The camera shutter speed was fixed at 30.1 ms and camera gain to 500. The camera sensitivity and detection threshold were set for (11)(12)(13)(14) and (4)(5)(6), respectively. For each sample, three videos of 60 seconds were recorded using the NTA software (version 3.0), and individual samples were run in triplicate.…”