Lung phenotype of juvenile and adult cystic fibrosis transmembrane conductance regulator-knockout ferrets.
Chronic bacterial lung infections in cystic fibrosis (CF) are caused by defects in the CF transmembrane conductance regulator chloride channel. Previously, we described that newborn CF transmembrane conductance regulator-knockout ferrets rapidly develop lung infections within the first week of life. Here, we report a more slowly progressing lung bacterial colonization phenotype observed in juvenile to adult CF ferrets reared on a layered antibiotic regimen. Even on antibiotics, CF ferrets were still very susceptible to bacterial lung infection. The severity of lung histopathology ranged from mild to severe, and variably included mucus obstruction of the airways and submucosal glands, air trapping, atelectasis, bronchopneumonia, and interstitial pneumonia. In all CF lungs, significant numbers of bacteria were detected and impaired tracheal mucociliary clearance was observed. Although Streptococcus, Staphylococcus, and Enterococcus were observed most frequently in the lungs of CF animals, each animal displayed a predominant bacterial species that accounted for over 50% of the culturable bacteria, with no one bacterial taxon predominating in all animals. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry fingerprinting was used to quantify lung bacteria in 10 CF animals and demonstrated Streptococcus, Staphylococcus, Enterococcus, or Escherichia as the most abundant genera. Interestingly, there was significant overlap in the types of bacteria observed in the lung and intestine of a given CF animal, including bacterial taxa unique to the lung and gut of each CF animal analyzed. These findings demonstrate that CF ferrets develop lung disease during the juvenile and adult stages that is similar to patients with CF, and suggest that enteric bacterial flora may seed the lung of CF ferrets.
Departments of 1 Anatomy and Cell Biology.
Xingshen
X
Sun
Alicia K
AK
Olivier
Bo
B
Liang
Yaling
Y
Yi
Hongshu
H
Sui
Turan I A
TI
Evans
Yulong
Y
Zhang
Weihong
W
Zhou
Scott R
SR
Tyler
John T
JT
Fisher
Nicholas W
NW
Keiser
Xiaoming
X
Liu
Ziying
Z
Yan
Yi
Y
Song
J Adam
JA
Goeken
Joann M
JM
Kinyon
Danielle
D
Fligg
Xiaoyan
X
Wang
Weiliang
W
Xie
Thomas J
TJ
Lynch
Paul M
PM
Kaminsky
Zoe A
ZA
Stewart
R Marshall
RM
Pope
Timothy
T
Frana
David K
DK
Meyerholz
Kalpaj
K
Parekh
John F
JF
Engelhardt
D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D018988:Bacterial Translocation; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000382:microbiology* / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005289:Ferrets / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D007422:Intestines / Q000187:drug effects / Q000382:microbiology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology* / Q000503:physiopathology; D009079:Mucociliary Clearance; D010641:Phenotype; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000382:microbiology* / Q000503:physiopathology
D000900:Anti-Bacterial Agents; D019005:Cystic Fibrosis Transmembrane Conductance Regulator