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American Journal of Respiratory Cell and Molecular Biology. Vol. 29, pp. 188-197, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.4898

Pseudomonas aeruginosa–Induced Apoptosis Is Defective in Respiratory Epithelial Cells Expressing Mutant Cystic Fibrosis Transmembrane Conductance Regulator

Carolyn L. Cannon, Michael P. Kowalski, Kimberly S. Stopak and Gerald B. Pier

Channing Laboratory, Brigham and Women's Hospital, and Children's Hospital, Harvard Medical School, Boston, Massachusetts

Address correspondence to: Carolyn L. Cannon, M.D., Ph.D., Washington University School of Medicine, Department of Pediatrics, Campus Box 8208, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail: cannon_c{at}kids.wustl.edu

Chronic lung infection with Pseudomonas aeruginosa constitutes the most severe manifestation of cystic fibrosis, a scenario that results from defects in early clearance of the microbe. Early clearance involves epithelial cell ingestion of bacteria, rapid activation of nuclear factor-{kappa}B and cellular desquamation within minutes of P. aeruginosa infection, processes that are deficient in cells with mutant alleles of Cftr. Analyzing the effect of Cftr genotype on the apoptotic response of airway epithelial cells to P. aeruginosa, we found that human bronchial epithelial cells expressing {Delta}F508 cystic fibrosis transmembrane conductance regulator (CFTR) underwent significantly delayed apoptosis compared with cells expressing wild-type (WT) CFTR. Mice with a WT Cftr allele had apoptotic cells in their lungs after P. aeruginosa infections, whereas mice homozygous for the {Delta}F508 or G551D Cftr alleles showed little apoptosis in response to acute infection. Pseudomonal infection induced expression of CD95 and CD95 ligand, a response that was also delayed in cells homozygous for mutant Cftr alleles. Thus, WT CFTR expression promotes a rapid expression of CD95/CD95 ligand and apoptotic response to P. aeruginosa infection. Prompt apoptosis of infected epithelial cells may be critical for clearance of P. aeruginosa, and CFTR-associated defects in apoptosis may contribute to the pathogenesis of the lung disease in cystic fibrosis.

Abbreviations: cystic fibrosis transmembrane conductance regulator, CFTR • colony-forming units, CFU • fetal bovine serum, FBS • lipopolysaccharide, LPS • phosphate-buffered saline, PBS • wild-type, WT




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