Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth.
Lung disease causes most of the morbidity and mortality in cystic fibrosis (CF). Understanding the pathogenesis of this disease has been hindered, however, by the lack of an animal model with characteristic features of CF. To overcome this problem, we recently generated pigs with mutated CFTR genes. We now report that, within months of birth, CF pigs spontaneously developed hallmark features of CF lung disease, including airway inflammation, remodeling, mucus accumulation, and infection. Their lungs contained multiple bacterial species, suggesting that the lungs of CF pigs have a host defense defect against a wide spectrum of bacteria. In humans, the temporal and causal relations between inflammation and infection have remained uncertain. To investigate these processes, we studied newborn pigs. Their lungs showed no inflammation but were less often sterile than controls. Moreover, after introduction of bacteria into their lungs, pigs with CF failed to eradicate bacteria as effectively as wild-type pigs. These results suggest that impaired bacterial elimination is the pathogenic event that initiates a cascade of inflammation and pathology in CF lungs. Our finding that pigs with CF have a host defense defect against bacteria within hours of birth provides an opportunity to further investigate CF pathogenesis and to test therapeutic and preventive strategies that could be deployed before secondary consequences develop.
Stoltz
David A
DA
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Meyerholz
David K
DK
Pezzulo
Alejandro A
AA
Ramachandran
Shyam
S
Rogan
Mark P
MP
Davis
Greg J
GJ
Hanfland
Robert A
RA
Wohlford-Lenane
Chris
C
Dohrn
Cassie L
CL
Bartlett
Jennifer A
JA
Nelson
George A
GA
Chang
Eugene H
EH
Taft
Peter J
PJ
Ludwig
Paula S
PS
Estin
Mira
M
Hornick
Emma E
EE
Launspach
Janice L
JL
Samuel
Melissa
M
Rokhlina
Tatiana
T
Karp
Philip H
PH
Ostedgaard
Lynda S
LS
Uc
Aliye
A
Starner
Timothy D
TD
Horswill
Alexander R
AR
Brogden
Kim A
KA
Prather
Randall S
RS
Richter
Sandra S
SS
Shilyansky
Joel
J
McCray
Paul B
PB
Zabner
Joseph
J
Welsh
Michael J
MJ
D000818:Animals; D000831:Animals, Newborn; D003550:Cystic Fibrosis / Q000150:complications / Q000000981:diagnostic imaging / Q000382:microbiology* / Q000473:pathology*; D004195:Disease Models, Animal; D045823:Ileus / Q000601:surgery; D007249:Inflammation / Q000150:complications / Q000473:pathology; D008168:Lung / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000382:microbiology* / Q000473:pathology*; D008470:Meconium; D009093:Mucus / Q000378:metabolism; D010182:Pancreatic Diseases / Q000473:pathology; D013902:Radiography, Thoracic; D016019:Survival Analysis; D013552:Swine / Q000254:growth & development* / Q000382:microbiology*; D013997:Time Factors