Each year, thousands of premature infants battle to breathe. Thanks to life-saving interventions developed in the past couple decades - steroids given to their mothers to stall pre-term labor, mechanical ventilation, air enriched with extra oxygen, and surfactant, a crucial wetting agent that makes breathing less work - most of these newborns survive with enough lung function to grow and go home.
But as the eldest of this new survivor population now embarks into young adulthood, research suggests that the same miraculous interventions that kept them alive in their first weeks of life may haunt them later on. University of Rochester Medical Center researcher Michael O'Reilly, Ph.D., unveils new research probing just how one such intervention - breathing oxygen-enriched air in those first weeks - may warp signaling pathways that rev up the body to fight respiratory infections, like flu.
The article appeared in the May edition of the American Journal of Respiratory Critical Care Medicine.
"The scope of this problem really begins to register when you consider that, as a nation, we spend a total $26.2 billion each year caring for health needs associated with all children born prematurely," said O'Reilly, an associate professor of Pediatrics and Environmental Medicine who works closely with neonatologists. "Many of today's 'survivor kids' once relied on high oxygen as babies, so a piece of that money represents the cost of their continued care. And that's just the financial burden; other sacrifices associated with poorer health just can't be given a price tag."
Broncopulmonary dysplasia, or BPD, is the most common form of chronic lung disease in infants; 5,000 to 10,000 newborns earn this diagnosis each year. Unfortunately, the ventilators that help such babies' immature lungs must deliver air with a higher-than-normal oxygen concentration (hyperoxia), often under greater pressure than tiny lungs are ready for. Together, the extra pressure and oxygen strain alveoli - the small, balloon-like, gas-exchange structures that compose the lung - throwing a wrench in normal lung development.
"Premature babies develop fewer and more simplified alveoli over time," O'Reilly said. "Their lungs are only partially developed at birth, and in the presence of oxygen, maturation can stall."
Rather than becoming small and plentiful as they should, fed by a rich web of tiny, oxygen-carrying capillaries, these under-developed structures remain bloated, fewer in number, and sometimes laced with less vessels. Children with such lungs wheeze, have difficulty running or rising to aerobic challenges, and are at greater risk for asthma; but that's just the start.
It also seems that these changes last a lifetime, said O'Reilly: These children are more easily sidelined by routine infections and respiratory diseases, like flu, and in many cases, need more frequent hospitalization, especially in the preschool years.
To begin to understand why, O'Reilly and colleagues studied two groups of full-term mice - the only distinction being that, for the first four days of life, one set breathed 100-percent oxygen, and the other breathed normal room air. After they had grown to adulthood (eight weeks), both groups were exposed to influenza A virus, and their susceptibility to infection, immune response, and lung structure was analyzed.
"We realized, as we expected, that mice born in pure oxygen had simplified alveoli, making it harder for them to take in oxygen," O'Reilly said. "Imagine that normal lung alveoli look like a cluster of grapes. Compared to that, these mice's lungs looked like bunches of plums, kiwis, even oranges."
The team also found that such mice had a more difficult time fighting off infection. Though both groups lost significant weight while battling the virus, mice born in pure oxygen took four days longer to regain their healthy weight. They also were more likely to die of the infection - 15 of 18 room-air mice lived, compared to nine of 21 beginning life in pure oxygen.
"We looked to the immune response for an explanation, but we found that both groups were producing the expected amount of virus-specific antibodies. Helper T cells were swarming to differentiate and fight infection, expanding at virtually the same levels in both groups," O'Reilly said. "It seemed mysterious; if both groups marshaled the same response, why was one still struggling to fight the virus?"
But a clue soon surfaced. In the pure oxygen group, some other white blood cells -macrophages, neutrophils and lymphocytes - were rushing in exceptionally large numbers to ward off the infection.
"We know, in some cases, that an immune response on overdrive can harm more than it helps," O'Reilly said. "In fact, that's the almost ironic reason why a number of people with flu die - the body's excessive response, not necessarily the virus - and that's precisely what we were seeing in these mice."
But why? Upon closer look, MCP-1 - a cytokine, or chemical messenger in the body - was running on hyperdrive. Though typically, MCP-1 serves as a chemical magnet, drawing other immune cells to battle and then waning after the demand is met, in the pure-oxygen mice, MCP-1 kept relentlessly recruiting.
"On day five and nine after infection, there were twice as many of these recruiter messengers in the blood of pure-oxygen mice," O'Reilly said. "What's troublesome is that drafting too many helpers to the fight leads to fibrosis - or scarring and further lung damage - making for stiff, inflexible alveoli, and eventually, weakening the lungs even further."
O'Reilly's team also realized that mice born in pure oxygen didn't experience across-the-board immune deregulation; other signaling mechanisms still existed at expected levels in both groups.
"For now, it seems that just the MCP-1 mechanism had run amok. And really, this is just one of the first pieces in a complex puzzle of how too much oxygen might be hurtful in the long term," O'Reilly said.
"As medicine advances, and we learn to wrangle the disease, we then have the luxury of finding less troublesome ways of imparting the same desired benefit," he added. "It's not unlike the state of cancer care today - as we become more proficient at wiping out malignancies, we turn our attention to finding ways to do so that have fewer repercussions in later life."
O'Reilly admits there is much research yet to do, but his hope is to find some way to improve lung function in our first generation of survivors. The next step, then, is to learn how to start saving these babies in ways that afford them the healthiest possible futures.
The study is funded in part by a grant from the March of Dimes Birth Foundation, and in part by grants from the National Institutes of Health.