Tim Blackwell, M.D., left, and Lance Prince, M.D., Ph.D., and are researching interventions to halt inflammation in the lungs of premature infants. (photo by Mary Donaldson)
Grant bolsters research into premature infant lung disease
An exposure to infection in the womb can lead to premature birth and pose a serious threat to developing lungs. But it may also set the stage for an increasingly common and potentially deadly lung disease, triggered by the body's own defenses when called into action too soon.
That's the theory that Lance Prince, M.D., Ph.D., assistant professor of Pediatrics, and Tim Blackwell, M.D., chief of the division of Allergy, Pulmonary and Critical Care, are examining in the search for an intervention to save tiny lungs.
The two have received a $1.75 million, five year RO1 grant from the National Heart Lung and Blood Institute (NHLBI) to examine a theory involving the role of macrophages and inflammation in the development of bronchopulmonary dysplasia, or BPD, in premature infants.
Prince and Blackwell are crafting a theory that early infections, even in the womb, may “prime” babies for a reaction that halts the normal development of their lungs, freezing the airways in a primitive stage of development.
They are seeking evidence that macrophages continue to have a role in preventing proper development of the lungs in babies after premature birth.
Blackwell has studied the role of macrophages in acute respiratory distress syndrome, pneumonia and sepsis. His lab has become specialized in manipulating the inflammatory signals emanated from macrophages, and is searching for ways to kill them in hopes of reducing lung damage in adults.
“But when we reviewed the literature, we found almost nothing is known about what macrophages do in early lung development, except that they clean up debris left over during the remodeling process,” Blackwell said.
Prince has collected evidence that — so far — indicates macrophages are right in the middle of the complex orchestration of lung development; at least in fetal mice.
Specifically, Prince has evidence that when triggered by an infectious agent, macrophage signaling chemicals like interleukin one (IL-1) and tumor necrosis factor (TNF) kick in and inadvertently switch off an important conductor in orchestrating lung development — a chemical called fgf10.
While it is not possible to see this happen inside the developing human lungs, Prince theorizes that infants born prematurely because of an intrauterine infection may still have macrophages that can be documented to be “primed,” or at least different in some way from macrophages in a baby not exposed to early infection. With this grant, Prince will work with respiratory therapists to collect evidence of this in the NICU.
“We will collect the fluid from the airways of preterm babies that is obtained in routine ventilator care. It should contain macrophages, and we can see if they are overactive or in some way different,” Prince said.
The babies will be followed from birth to see how the macrophages continue to react if the baby remains on a ventilator for an extended period.
“Extra oxygen, tubes in the airways, bacteria, all those things that are part of mechanical ventilation may continue to drive inflammation, perhaps continuing the cycle that prevents lung development from starting up again,” Prince said.
If there is evidence macrophages are really the culprits, Prince said it's possible drugs could be specifically targeted to prevent devastating cases of BPD, a leading killer of premature infants in the NICU.