Scientists at UT Southwestern Medical Center may have found a key to understand what causes bronchopulmonary dysplasia (BPD), a lung disease found in premature infants that can be fatal.
According to the new study, the condition might be caused by the inflammatory protein NLRP3 and its action on the protein interleukin 1 beta. The report, “The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia,“ was published in the journal Nature Communications.
Inflammatory proteins, known as growth factors and cytokines, are believed to cause BPD, although the underlying mechanism was unclear until recently. Animal studies demonstrated that the group of proteins (a protein complex) that make up what is called the NLRP3 inflammasome could be involved in causing lung disease.
Researchers led by Jie Liao of the Department of Pediatrics, Center for Pulmonary and Vascular Biology at UT Southwestern Medical Center, used an animal model of lung disease in premature infants by exposing neonatal mice to 85 percent oxygen. They examined mice that had been genetically modified to lack the gene for the NLRP3 inflammasome, and compared the effects of a lack of oxygen in these mice to normal mice with no such genetic change.
The team found that in normal mice, functional levels of the inflammatory cytokine IL1β were increased, but this did not happen in the genetically modified mice. The genetically modified mice also did not show an increase in other measurements of inflammation, specifically Caspase-1 and IL18. Although intermediate forms of the inflammation-causing proteins increased, the mature, functional versions were not detected.
In agreement with these observations, the genetically modified mice did not have apparent damage to the lung, measured by what is called decreased alveolarization. The normal mice did experience decreased alveolarization after exposure to only 85 percent oxygen.
Remarkably, two FDA-approved drugs that block the protein interleukin 1 beta normalized the lungs of mice exposed to 85 percent oxygen. These medictions, which are already in use, are called IL1ra and glyburide.
The researchers found similar results in baboons, noting that prematurely born baboons who were put on ventilators have increased levels of the protein interleukin 1 beta and low levels of IL1ra. The ventilation could be the cause of the problem.
“The same ventilation that ultimately saves their lives damages their lungs,” Dr. Rashmin Savani, the study’s senior author, said in a press release. Savani is professor and chief of Neonatal-Perinatal Medicine, and is the William Buchanan Chair in Pediatrics.
Supporting this observation even further, the study authors took samples from the lungs of premature infants (tracheal aspirates) and measured high the interleukin 1 beta and low ILra.
The measurements in mice, baboons and humans ultimately point toward ways to block the development of BPD in premature infants through the use of treatments that block the protein interleukin 1 beta or the NLRP3 inflammasome, such as IL1ra and glyburide.
“Our findings suggest that if we target premature infants born at less than 28 weeks gestation from three to 10 days after birth with this therapy, we might be able to drastically reduce or even eliminate the development of BPD,” Savani said.