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Transforming growth factor-beta(1) overexpression in tumor necrosis factor-alpha receptor knockout mice induces
1Department of Pathology and Laboratory Medicine and the Lung Biology Program, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112-2699.
Abstract:
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.
Insights
Tumor necrosis factor-alpha receptor knockout mice resist fibrotic lung disease. However, transforming growth factor-beta 1 overexpression still causes lung fibrosis in these mice, revealing TGF-beta 1
Area of Science:
- Pulmonary fibrosis research
- Immunology and inflammation
- Molecular biology of lung disease
Background:
- Tumor necrosis factor-alpha receptor knockout (TNF-alphaRKO) mice are protected from lung fibrotic agents like asbestos.
- These mice show reduced expression of key growth factors (TGF-alpha, PDGF, TGF-beta) after asbestos exposure.
- The specific role of individual growth factors in fibroproliferative lung disease pathogenesis remains unclear.
Purpose of the Study:
- To investigate whether transforming growth factor-beta 1 (TGF-beta 1) can induce lung fibrogenesis in fibrogenic-resistant TNF-alphaRKO mice.
- To explore the role of TGF-beta 1 in fibroproliferative lung disease, particularly in the context of TNF-alpha receptor deficiency.
Main Methods:
- Overexpression of TGF-beta 1 in the lungs of TNF-alphaRKO mice and background controls using a replication-deficient adenovirus vector.
- Assessment of fibrogenic lesion development and cell proliferation (bromodeoxyuridine incorporation) at 7 days post-induction.
- Observation of airway epithelial cell proliferation in response to TGF-beta 1.
Main Results:
- TGF-beta 1 overexpression successfully induced fibrogenic lesions in both TNF-alphaRKO mice and background controls.
- Similar bromodeoxyuridine incorporation rates were observed in both groups, indicating comparable cell proliferation.
- Airway epithelial cell proliferation was suppressed, likely due to TGF-beta 1's known inhibitory effects on epithelial mitogenesis.
Conclusions:
- Transforming growth factor-beta 1 can overcome the fibrogenic resistance conferred by TNF-alpha receptor knockout.
- This study demonstrates that TGF-beta 1 is a potent inducer of lung fibrogenesis, even in resistant animal models.
- The findings highlight the critical role of TGF-beta 1 in lung fibrosis pathogenesis, independent of TNF-alpha signaling.