White Blood Cells May Be to Blame for CF-Related Lung Damage

In individuals with cystic fibrosis (CF), white blood cells called "neutrophils" actually work against patients, releasing large quantities of human neutrophil elastase, the enzyme that destroys the elastic fiber of lung tissue. This according to new research published in the Proceedings of the National Academy of Sciences by investigators at the Stanford University School of Medicine and Lucile Packard Children's Hospital.

"Cystic fibrosis patients have a problem with turning down the inflammatory response in the lungs," said senior study author Rabindra Tirouvanziam, PhD, an instructor in pediatric pulmonary medicine. "We've found that patients' neutrophils become kind of schizophrenic, doing a number of things that are opposite to the textbook view of neutrophils' role."

Until now, the consensus has been that lung problems associated with CF were a result of bacteria trapped in excess mucus in the lungs and that any neutrophils that appeared in the lungs were killed quickly, releasing destructive human neutrophil elastase. In healthy individuals, neutrophils never release these tissue-destroying enzymes into nearby tissue.

"This paradigm makes sense in a superficial way, but it has very little to do with clinical reality," Tirouvanziam said. Careful clinical testing in infants with cystic fibrosis indicates that lung inflammation with neutrophils occurs even in the absence of detectable infection. Tirouvanziam's earlier research showed further that the immune cells stay alive in the lung for quite a while after they arrive.

For this research, the team analyzed fresh neutrophils in the sputum of CF patients, discovering that signals from the patients' lung tissue were reprogramming live neutrophils with conflicting messages. The first was what Tirouvanziam calls "an ancient happiness pathway," which tells the neutrophils that nutrients are plentiful, and that it is a good time to translate the cell's library of genes into new protein. The second pathway is a cellular alarm system associated with inflammation and stress.

"They're receiving a lot of signals at the same time, and we think the happiness signals are messing them up completely," Tirouvanziam said. His team now suspects the inappropriate activation of the "happiness signal"—the molecular target of rapamycin, or mTOR, cell signaling pathway—may trigger neutrophils to release the elastase.

Tirouvanziam added that understanding the sequence of events could help researchers find new disease therapies, because drugs now given to improve patients' lung function target symptoms do not do anything to alter neutrophils' behavior.