title: Pseudomonas aeruginosa-induced apoptosis is defective in respiratory epithelial cells expressing mutant cystic fibrosis transmembrane conductance regulator.
abstract: 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.
authors.affiliation: Channing Laboratory, Brigham And Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. cannon_c@kids.wustl.edu
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cannon
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kowalski
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Stopak
authors.forename: Gerald B
authors.initials: GB
authors.lastname: Pier
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D053178:Caspase 6; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis / Q000235:genetics*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000382:microbiology* / Q000473:pathology*; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D013997:Time Factors; D019014:fas Receptor / Q000096:biosynthesis
chemical_list: C505032:CFTR protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D019014:fas Receptor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C505407:CASP3 protein, human; C505514:CASP6 protein, human; C505409:Casp3 protein, mouse; C505516:Casp6 protein, mouse; D053148:Caspase 3; D053178:Caspase 6; D020169:Caspases