Lung biological clock fracture may explain the risk of influenza in adults who survived premature birth

Disruption of circadian rhythms in lung cells may explain why premature adults are more often at risk of serious disease, suggests a study in mice published today in an eLife.

Dramatic improvements in the care of premature babies have allowed many more to live as adults. But ex-preemies can have a number of long-term side effects from the life-saving care they received. The study suggests potential new approaches to treating chronic lung problems in those born prematurely.

Many premature babies cannot breathe on their own and need oxygen to survive. But getting too much oxygen can cause permanent damage to the lungs which makes them more susceptible to severe flu disease later in life. In a previous study, senior author and neonatologist Shaon Sengupta, and her colleagues at the Children’s Hospital Research Institute of Philadelphia, Pennsylvania, USA, found that susceptibility to influenza in mice depended on the time of day when they took the disease.

Mice that caught the disease when they became active at night were more likely to die, and those that became infected when they went to bed at break of day were more likely to survive. This suggests that the circadian clock, which controls day and night activity in the body, may provide some protection against influenza.

“Taking into account the previous findings, we wanted to see if the severity of influenza infection in premature infants is caused by a breakdown in their circadian clock,” said Yasmine Issah, a former Research Technician at the Philadelphia Children ‘s Hospital Research Institute, and co – author of the current study with Postdoctoral Researcher Amruta Naik.

The team began by showing that the time of day when the flu appeared did not affect infectious vulnerability in adult mice exposed to high levels of oxygen as a newborn. This gives the impression that these mice had lost their clock-based flu protection.

However, when the team tested the animals’ ability to adjust to a normal daytime schedule after living in dim light for several weeks, they found that there were no problems at the animals – suggesting that they had the central circadian clock in the brain, which is controlled by it was exposed to daylight.

To determine if the circadian problems were confined to lung cells, which have their own circadian clocks separate from the brain clock, the team removed a key circadian clock gene called Bmal1 in cells lungs of normal adult mice. They removed the gene in the same lung cells that are damaged in newborn mice due to high levels of oxygen. Like the mice that had been exposed to high oxygen as a newborn, the adult animals with the deleted gene were just as susceptible to influenza at dusk or dusk.

Our findings suggest that adverse early life exposures can disturb the lung circadian clock. Those born prematurely are vulnerable to this defective development of their circadian network, and this is a new paradigm for understanding the lung problems that lead to adulthood in exememies. These findings could pave the way for new therapies that may work to improve circadian health in prematurely born adults. “

Shaon Sengupta, Attending Neonatologist, Philadelphia Children’s Hospital Research Institute