Basic Science Research: Circadian Rhythm and Lung Biology

A new preclinical study by researchers in our division has found that side-effects of oxygen therapy in the neonatal period increase susceptibility to influenza infection by eliminating protection via the lung circadian clock. Premature infants are born with very immature lungs, which necessitates lifesaving oxygen therapy. However, the inadvertent side effect of this therapy is hyperoxia, the key risk factor for developing bronchopulmonary dysplasia (BPD). BPD is a chronic condition that results from the lungs not developing appropriately. Patients with BPD are more susceptible to other diseases of the lung—including asthma, COPD, and respiratory infections like influenza—later in life.

Previous research done at our hospital and the University of Pennsylvania has shown that circadian rhythms offer a protection against influenza, with mortality 3 times lower if animal models are infected in the morning rather than in the evening. However, until now, researchers had not established a connection between neonatal hyperoxia, circadian clock disruption, and influenza infection.

To do so, we analyzed adult mice who had been exposed to neonatal hyperoxia and in adulthood were exposed to influenza at different times of day. We found that adult mice exposed to hyperoxia as neonates lose the time-of-day protection from circadian regulation of influenza infection. On the other hand, adult mice exposed to hyperoxia in adulthood did not lose the time-of-day protection. This led us to conclude that the neonatal period represents a uniquely vulnerable window for development of circadian networks and thus exposure to hyperoxia in the neonatal period alters this function.

Although the suprachiasmatic nucleus (SCN) is the master circadian pacemaker in the body, peripheral tissues, including the lungs, also have their own circadian clocks. To identify the location of the clock responsible for the increase in susceptibility to influenza, we knocked out the core clock gene Bmal1 in adult mouse models. We found that disrupting Bmal1 in alveolar type II (AT2) cells, which are critical in maintaining lung function and integrity, produced the same phenotype as mouse models that had been exposed to neonatal hyperoxia, suggesting that early life hyperoxia disrupts the circadian regulation of the pulmonary response to hyperoxia through the AT2 clock.

Our work here suggests that a unique window exists in the lung in the early neonatal period that affects circadian regulation throughout life. Children born prematurely and suffering from even mild BPD have persistent adverse effects on their lung function into adulthood and beyond, so this study could pave the way for novel therapeutics and chronobiological strategies for this vulnerable population.

Reference

Issah Y, Naik A., et al. Loss of circadian protection against influenza infection in adult mice exposed to hyperoxia as neonates. Elife. 2021;10:e61241.