Transforming growth factor-beta(1) overexpression in tumor necrosis factor-alpha receptor knockout mice induces fibroproliferative lung disease.
Tumor necrosis factor-alpha receptor knockout (TNF-alphaRKO) mice have homozygous deletions of the genes that code for both the 55- and 75-kD receptors. The mice are protected from the fibrogenic effects of bleomycin, silica, and inhaled asbestos. The asbestos-exposed animals exhibit reduced expression of other peptide growth factors such as transforming growth factor (TGF)-alpha, platelet-derived growth factors, and TGF-beta. In normal animals, these and other cytokines are elaborated at high levels during the development of fibroproliferative lung disease, but there is little information available that has allowed investigators to establish the role of the individual growth factors in disease pathogenesis. Here, we show that overexpression of TGF-beta(1) by means of a replication-deficient adenovirus vector induces fibrogenesis in the lungs of the fibrogenic-resistant TNF-alphaRKO mice. The fibrogenic lesions developed in both the KO and background controls within 7 d, and both types of animals exhibited similar incorporation of bromodeoxyuridine. Interestingly, airway epithelial cell proliferation appeared to be suppressed, perhaps due to the presence of the TGF-beta(1), a well-known inhibitor of epithelial mitogenesis. Before these experiments, there was no information available that would provide a basis for predicting whether or not TGF-beta(1) expression induces fibroproliferative lung disease in fibrogenic-resistant TNF-alphaRKO mice, an increasingly popular animal model.
Liu
J Y
JY
Department of Pathology and Laboratory Medicine and the Lung Biology Program, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112-2699.
Sime
P J
PJ
Wu
T
T
Warshamana
G S
GS
Pociask
D
D
Tsai
S Y
SY
Brody
A R
AR
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001973:Bromodeoxyuridine; D005822:Genetic Vectors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D018124:Receptors, Tumor Necrosis Factor; D016212:Transforming Growth Factor beta; D001973:Bromodeoxyuridine