Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis.
BACKGROUND
Ineffective repair of a damaged alveolar epithelium has been postulated to cause pulmonary fibrosis. In support of this theory, epithelial cell abnormalities, including hyperplasia, apoptosis, and persistent denudation of the alveolar basement membrane, are found in the lungs of humans with idiopathic pulmonary fibrosis and in animal models of fibrotic lung disease. Furthermore, mutations in genes that affect regenerative capacity or that cause injury/apoptosis of type II alveolar epithelial cells have been identified in familial forms of pulmonary fibrosis. Although these findings are compelling, there are no studies that demonstrate a direct role for the alveolar epithelium or, more specifically, type II cells in the scarring process.


OBJECTIVE
To determine if a targeted injury to type II cells would result in pulmonary fibrosis.


METHODS
A transgenic mouse was generated to express the human diphtheria toxin receptor on type II alveolar epithelial cells. Diphtheria toxin was administered to these animals to specifically target the type II epithelium for injury. Lung fibrosis was assessed by histology and hydroxyproline measurement.


RESULTS
Transgenic mice treated with diphtheria toxin developed an approximately twofold increase in their lung hydroxyproline content on Days 21 and 28 after diphtheria toxin treatment. The fibrosis developed in conjunction with type II cell injury. Histological evaluation revealed diffuse collagen deposition with patchy areas of more confluent scarring and associated alveolar contraction.


CONCLUSIONS
The development of lung fibrosis in the setting of type II cell injury in our model provides evidence for a causal link between the epithelial defects seen in idiopathic pulmonary fibrosis and the corresponding areas of scarring.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, 1150 West Medical Center Drive, 6301 MSRB III, Ann Arbor, MI 48109-5642, USA. tsisson@umich.edu
Thomas H
TH
Sisson
Michael
M
Mendez
Karen
K
Choi
Natalya
N
Subbotina
Anthony
A
Courey
Andrew
A
Cunningham
Aditi
A
Dave
John F
JF
Engelhardt
Xiaoming
X
Liu
Eric S
ES
White
Victor J
VJ
Thannickal
Bethany B
BB
Moore
Paul J
PJ
Christensen
Richard H
RH
Simon
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation; D005838:Genotype; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D037721:Pulmonary Surfactant-Associated Protein C; D012313:RNA / Q000235:genetics; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D037721:Pulmonary Surfactant-Associated Protein C; C489680:Sftpc protein, mouse; D012313:RNA