Role of cystic fibrosis transmembrane conductance regulator in pulmonary clearance of Pseudomonas aeruginosa in vivo.
Cystic fibrosis (CF)2 is a fatal genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) that is commonly associated with chronic pulmonary infections with mucoid Pseudomonas aeruginosa (PA). To test the hypothesis that CFTR plays a direct role in PA adhesion and clearance, we have used mouse lines expressing varying levels of human (h) or mouse (m) CFTR. A subacute intratracheal dose of 3 x 10(6) bacteria was cleared with similar kinetics in control wild-type (WT) and transgenic mice overexpressing hCFTR in the lung from the surfactant protein C (SP-C) promoter (SP-C-hCFTR+/-). In a second series of experiments, the clearance of an acute intratracheal dose of 1.5 x 10(7) PA bacteria was also similar in WT, hemizygous SP-C-hCFTR+/-, and bitransgenic gut-corrected FABP-hCFTR+/+-mCFTR-/-, the latter lacking expression of mCFTR in the lung. However, a small but significant decrease in bacterial killing was observed in lungs of homozygote SP-C-hCFTR+/+ mice. Lung pathology in both WT and SP-C-hCFTR+/+ mice was marked by neutrophilic inflammation and bacterial invasion of perivascular and subepithelial compartments. Bacteria were associated primarily with leukocytes and were not associated with alveolar type II or bronchiolar epithelial cells, the cellular sites of SP-C-hCFTR+/+ transgene expression. The results indicate that there is no direct correlation between levels of CFTR expression and bacterial clearance or association of bacteria with epithelial cells in vivo.
Chroneos
Z C
ZC
Children's Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, OH 45229, USA.
Wert
S E
SE
Livingston
J L
JL
Hassett
D J
DJ
Whitsett
J A
JA
D000818:Animals; D001422:Bacterial Adhesion / Q000235:genetics / Q000276:immunology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007375:Interleukin-1 / Q000378:metabolism; D007442:Intubation, Intratracheal; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D011510:Proteolipids / Q000096:biosynthesis / Q000235:genetics; D011552:Pseudomonas Infections / Q000235:genetics / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000502:physiology; D011663:Pulmonary Surfactants / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007375:Interleukin-1; D011510:Proteolipids; D011663:Pulmonary Surfactants; D014409:Tumor Necrosis Factor-alpha; D019005:Cystic Fibrosis Transmembrane Conductance Regulator