Transforming growth factor-beta(1) overexpression in tumor necrosis factor-alpha receptor knockout mice induces fibroproliferative lung disease

Our plain-English summary of Transforming growth factor-beta(1) overexpression in tumor necrosis factor-alpha receptor knockout mice induces fibroproliferative lung disease, by J.Y. Liu, P.J. Sime, T. Wu, et al (American Journal of Respiratory Cell and Molecular Biology, 2001).

The study

• Authors: J.Y. Liu, P.J. Sime, T. Wu, G.S. Warshamana, D. Pociask, S.Y. Tsai, A.R. Brody
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2001;25(1):3-7
• Cited by: 65 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This was a laboratory experiment in mice. No asbestos was used in it. The authors' earlier work had reported that mice lacking both receptors for tumor necrosis factor-alpha (TNF-alpha receptor knockout mice) were protected from lung scarring caused by inhaled asbestos, silica and bleomycin. Here the authors asked whether making the lungs produce one growth factor, active transforming growth factor-beta1 (TGF-beta1), would cause disease in these resistant mice. Knockout mice and normal hybrid control mice received a virus carrying TGF-beta1, a control virus, or saline into the windpipe, and were examined 7 days later. Saline-treated mice had normal lungs. The control virus caused only mild inflammation around vessels and airways. Both knockout and normal mice given TGF-beta1 developed diffuse inflammation and early scarring (fibrogenesis) in the lung walls, with the same pattern in both. Dividing cells increased in tissue beneath the airways (6.44% versus 1.00% in knockout mice; 6.57% versus 2.50% in hybrids). Dividing cells in the airway lining were not significantly increased. The authors stated that whether disease progresses similarly in both kinds of mice is not yet known.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (gene transfer using a replication-deficient adenovirus vector in mice)
• Who was studied: TNF-alpha receptor knockout mice (both 55- and 75-kD receptors deleted) and B6129 F2 hybrid wild-type control mice, aged 8 to 10 weeks. The article states that groups consisted of 5 hybrid controls and 10 knockout mice per treatment. The work was done at Tulane University Health Sciences Center, New Orleans.
• Exposure: Mice received 50 microliters into the trachea of one of three treatments: an adenovirus carrying active porcine TGF-beta1 (AdTGF-beta1 223/225) at 5 x 10^8 plaque-forming units, the control virus MG3 at the same dose, or saline. They were killed 7 days later. No asbestos exposure was part of this study.
• Main results:
  • Untreated and saline-treated mice always had normal lung tissue.
  • The control virus alone caused mild inflammation around small vessels and bronchioles. This inflammation did not extend into the alveolar walls.
  • At 7 days, normal hybrid mice given the TGF-beta1 virus had developed diffuse interstitial inflammation and fibrogenesis.
  • TNF-alpha receptor knockout mice given the TGF-beta1 virus showed the same pattern of tissue damage as the normal hybrid mice.
  • Trichrome staining, used to detect collagen, showed some early evidence of fibrogenesis in the inflamed lungs, with patches of clearly stained tissue in the interstitium.
  • In knockout mice, the mean percentage of dividing (BrdU-labeled) airway interstitial cells was 6.44% (SEM 1.34) with the TGF-beta1 virus versus 1.00% (SEM 0.62) with the control virus. The table marks this as significantly different, p less than 0.01 by ANOVA.
  • In normal hybrid mice, dividing airway interstitial cells were 6.57% (SEM 0.93) with the TGF-beta1 virus versus 2.50% (SEM 0.27) with the control virus. The table marks this as significantly different, p less than 0.01 by ANOVA.
  • Dividing airway epithelial (lining) cells were not significantly increased. They were 0.88% with TGF-beta1 versus 0.62% with control virus in knockout mice, and 1.28% versus 0.62% in hybrid mice.
  • Dividing parenchymal alveolar cells were 5.23% (SEM 1.11) with TGF-beta1 versus 0.00 with control virus in knockout mice, and 3.90% (SEM 0.81) versus 0.00 in hybrid mice. The text describes these as significantly increased rates in inflamed areas.
  • There were no significant differences between TGF-beta1-treated knockout mice and TGF-beta1-treated hybrid mice.
  • Northern analysis of lung RNA confirmed that both TNF-alpha receptors were deleted in the knockout mice (data not shown).
• The authors' conclusion: The authors concluded that TGF-beta1 overexpression delivered by the adenovirus causes interstitial inflammation and fibrogenesis in TNF-alpha receptor knockout mice. They postulated that TNF-alpha is essential for activating a natural cascade of factors that mediate fibroproliferative lung disease, and suggested this could be a useful model system for studying the role of each growth factor.
• Limitations the authors state:
  • Whether the disease will progress similarly in normal and knockout mice is not yet known. Only the 7-day time point was examined.
  • The inflammatory cells had not yet been characterized.
  • The apparent suppression of airway epithelial cell division needs to be confirmed through further studies of individual cell populations.
  • Trichrome staining was a relatively crude assay for mature collagen.
  • Only one vector dose was used. Whether knockout mice respond differently to other vector concentrations remains to be determined.

Topics

Medical terms in this study, explained in our Lexicon: Transforming Growth Factor-beta (TGF-β), Tumor Necrosis Factor-alpha (TNF-α), Homozygous Deletion, Fibrogenic, Platelet-Derived Growth Factor (PDGF), Cytokine.

Related studies

• Reduced tumor necrosis factor-alpha and transforming growth factor-beta1 expression in the lungs of inbred mice that fail to develop fibroproliferative lesions consequent to asbestos exposure — D.M. Brass, G.W. Hoyle, et al. (1999)
• Susceptibility to asbestos-induced and transforming growth factor-beta1-induced fibroproliferative lung disease in two strains of mice — G.S. Warshamana, D.A. Pociask, et al. (2002)
• TNF-alpha receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers — J.Y. Liu, D.M. Brass, et al. (1998)
• Distribution of transforming growth factor-beta 1, fibronectin, and smooth muscle actin in asbestos-induced pulmonary fibrosis in rats — T.D. Perdue, A.R. Brody (1994)
• Early-passage rat lung fibroblasts do not migrate in vitro to transforming growth factor-beta — A.R. Osornio-Vargas, V.G. Kalter, et al. (1993)
• Immunohistochemical localization of transforming growth factor beta isoforms in asbestos-related diseases — J. Jagirdar, T.C. Lee, et al. (1997)

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