Loss of Circadian Protection in Adults Exposed to Neonatal Hyperoxia

Adverse early life exposures having a lasting negative impact on health. For examples, neonatal hyperoxia which is a risk factor for chronic lung disease of prematurity or bronchopulmonary dysplasia (BPD) confers susceptibility to respiratory infections like Influenza A (IAV) later in life. Given our previous findings that the circadian clock exerts a protective effect on injury from IAV, we asked if the long-term impact of neonatal hyperoxia includes disruption of circadian rhythms. We show here that neonatal hyperoxia abolishes the circadian clock mediated time of day protection from IAV, not through the regulation of viral burden, but through host tolerance pathways. We further discovered that that this dysregulation is mediated through the intrinsic clock in the lung, rather than through central or immune system clocks. Loss of circadian protein, Bmal1, in AT2 cells of the lung recapitulates the increased mortality, loss of temporal gating and other key features of hyperoxia-exposed animals. Taken together, our data suggest a novel role for the circadian clock in AT2 clock in mediating long-term effects of early life exposures to the lungs.