Quick Study: Research identifies new pathway to lung damage in cystic fibrosis

THE QUESTION: What is responsible for the lung damage experienced by people with cystic fibrosis?

Cystic fibrosis is an inherited lung and digestive disorder that affects about 30,000 children and adults in the United States. The condition is characterized by a thick, sticky mucous that clogs the airways and leads to damaging lung infections. At one time most people with the disease died before they reached adulthood, but the median life expectancy has increased to about 37 years.

Previous research has indicated that a certain type of white blood cell, an immune cell called a neutrophil, is recruited in large numbers from the blood to the airways of cystic fibrosis patients. Under normal conditions, activated neutrophils engulf and destroy bacteria. However, in cystic fibrosis patients, it was believed that the arriving neutrophils were killed by encountering huge colonies of resident bacteria. It was thought that the dead cells then passively released components such as neutrophil elastase that perpetuate the airway inflammation, damage and obstruction that is the hallmark of cystic fibrosis.

THIS STUDY compared the characteristics of neutrophils collected from the blood and airways of 33 cystic fibrosis patients and from healthy controls. The researchers examined what types of molecules the cells expressed on their surface and secreted into their surroundings. They also investigated the activation status of signaling pathways within the cells.

THE RESULTS: Contrary to conventional wisdom, the researchers found a significant number of living neutrophils in the airways of people with cystic fibrosis. When they examined these cells closely, they discovered many differences between the cells from the airways and those from the blood. Compared with airway neutrophils from healthy controls, airway neutrophils from cystic fibrosis patients released more damaging elastase, and lacked expression of cell surface molecules necessary to engulf bacteria. Conversely, the airway neutrophils expressed unusual cell surface molecules that may allow them to interact with T lymphocytes - other immune cells that are also recruited to the lungs of cystic fibrosis patients.

These functional changes may allow the unusual neutrophils to survive in clogged airways of cystic fibrosis patients. They also explain why airway neutrophils are unable to kill bacteria in the lung. Significantly, the researchers found that the airway neutrophils released elastase regardless of the disease state of the person from whom they were isolated. They also exhibited changes in intracellular signaling pathways that may play a role in lung neutrophil dysfunction in cystic fibrosis patients. These findings suggest that the inflammation and damage associated with the condition cannot be completely blamed on the bacteria that infect the lungs as the disease progresses.

About 10 million U.S. people are carriers of the defective gene that causes cystic fibrosis and 1,000 cases are diagnosed each year.

The fact that neutrophils are actively releasing elastase suggests that compounds interfering with this process may limit or slow lung damage in cystic fibrosis. Although it is clear the contents of dead and dying cells do contribute to the cycle of damage, the presence of living neutrophils gives cystic fibrosis researchers another possible therapeutic target. The results also suggest interactions between neutrophils and lymphocytes may be more important in cystic fibrosis than previously thought.

Rabindra Tirouvanziam, PhD, instructor, is the first author on the study. Other researchers include Yael Gernez, PhD; Carol Conrad, MD; Richard Moss, MD; Iris Schrijver, MD; Colleen Dunn; Zoe Davies; Leonore Herzenberg, PhD, and Leonard Herzenberg, PhD. Tirouvanziam, Gernez, Conrad, Moss, Dunn and Davies are part of Packard Children's Center for Excellence in Pulmonary Biology. Schrijver is part of the Department of Pathology, and the remaining authors are part of the Department of Genetics.

It was published online in the Proceedings of the National Academy of Sciences on March 11.