By Will Boggs, MD

NEW YORK (Reuters Health) - Cystic fibrosis transmembrane conductance regulator Cl- channel (CFTR) plays a key role in phagosome acidification in alveolar macrophages and thereby enhances bactericidal activity, according to a report in the August 20th advance online publication of Nature Cell Biology.

"Alveolar macrophages and circulating neutrophils contribute to the innate immunity in the lung -- first and foremost due to their phagocytic and microbicidal activity," principal investigator Dr. Deborah J. Nelson, from University of Chicago, told Reuters Health. "A link between the macrophage and neutrophil function and cystic fibrosis lung infection has not been well studied."

Dr. Nelson and colleagues investigated the role of CFTR in the normal functioning of alveolar macrophages using normal and CFTR-deficient mice. CFTR is expressed in mouse and human alveolar macrophages, but not in mouse or human neutrophils, the authors report.

CFTR was present in the plasma membrane and within phagosomes, lysosomes, and other intracellular compartments of macrophages, the results indicate.

Alveolar macrophages from CFTR-null mice were deficient in both microbicidal capacity and phagosomal acidification, the researchers note.

Phagosomes from wild-type alveolar macrophages had a pH of around 4.7 after fusion with the lysosomal compartment, the report indicates, whereas phagosomes from CFTR-null alveolar macrophages had a pH of around 6.5 after fusion.

"These findings demonstrate that the loss of subcellular acidification in CFTR-deficient alveolar macrophages is a key factor that contributes to the enhanced survival of bacterial loads within the phagosomal compartment," the investigators conclude. "However, the relationship of these data to the etiology of cystic fibrosis is unclear."

"We are currently carrying out studies to address the question of whether there is a link between macrophage function in individuals with genetic mutations in the protein responsible for the disease and cystic fibrosis lung infection," Dr. Nelson said. "A better understanding of potentially altered macrophage and neutrophil killing may lead to the development of new therapies that ameliorate the course of cystic fibrosis lung disease."

"Conventional gene therapy has not been very successful," she added. "Modifying CFTR in macrophages could be a possible route or therapeutic modality in the future."

Nature Cell Biology 2006. 

http://www.nature.com/ncb/press_release/ncb0806.html

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