Susceptibility to asbestos-induced and transforming growth factor-beta1-induced fibroproliferative lung disease in two strains of mice

Our plain-English summary of Susceptibility to asbestos-induced and transforming growth factor-beta1-induced fibroproliferative lung disease in two strains of mice, by G.S. Warshamana, D.A. Pociask, P. Sime, et al (American Journal of Respiratory Cell and Molecular Biology, 2002).

The study

• Authors: G.S. Warshamana, D.A. Pociask, P. Sime, D.A. Schwartz, A.R. Brody
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2002;27(6):705-13
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Pulmonary fibrosis (PF) is caused by a number of inhaled agents, as well as by some drugs and toxic particles. The elaboration of certain peptide growth factors is thought to be key to the development of this disease process. In addition, genetic susceptibility plays a role in the development of PF. For instance, we have previously shown that the 129J strain of mice is resistant, whereas the C57BL/6 strain is highly susceptible, to asbestos-induced fibrosis. To pursue this further, in one mouse model, we crossed the 129J strain to the C57BL/6 strain to produce an F1 generation and subsequently backcrossed the F1 mice to the inbred founders. This backcross to the 129 inbred strain produced reverse similar 25% of the offspring with a phenotype that was protected from the fibrogenic effects of inhaled asbestos fibers. In the second model, both strains of mice were treated intratracheally with an adenovirus vector (AdV), which transduces expression of active transforming growth factor (TGF)-beta(1) in the lungs, producing fibroproliferative lung disease. Compared with C57 mice, a significant number of 129 strain mice exhibited at least a 1-wk delay in the fibroproliferative response to TGF-beta(1) expression at three concentrations of virus. These findings suggest that certain sequences in a gene or a cluster of genes in the 129 mouse strain impart a phenotype in which there is a delay in, or protection from, the development of lung fibrogenesis.

In plain English

This was an animal experiment in mice, not a study of people. The authors had previously found that 129 strain mice were resistant, and C57BL/6 mice susceptible, to asbestos-induced lung fibrosis. In this study they crossed the two strains and bred the offspring back to each parent strain. They then exposed the mice to a chrysotile asbestos aerosol and scored lung lesions under the microscope 48 hours later. Among offspring bred back to the 129 strain, 5 of 19 (26.3%) had no apparent asbestos-induced lesions, compared with one of 21 (4.7%) offspring bred back to C57BL/6. In a second experiment, a virus was used to make the lungs produce the growth factor TGF-beta1. At 7 days, 8 of 13 129 mice at the lowest dose showed no disease, while all 25 C57BL/6 mice at the two lower doses scored 2 or higher. By day 14, nearly all mice had disease. The authors concluded that a gene or gene cluster appears to control a degree of susceptibility to asbestos disease in some 129 mice. That gene remains unknown.

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: crossbreeding and backcrossing of two inbred mouse strains with asbestos inhalation, plus adenovirus-delivered TGF-beta1 overexpression in the lungs
• Who was studied: C57BL/6 and 129 inbred mice from Jackson Laboratories, their F1 offspring, and backcrosses of F1 mice to each parent strain. Intercross and backcross groups had 19 to 40 animals; unexposed control groups had 3 to 5 mice.
• Exposure: Aerosol of chrysotile asbestos: either a single 5-hour exposure at 16.3 mg/m3, or 5 hours a day on two consecutive days (12.8 and 17.5 mg/m3). Lungs were examined 48 hours after exposure. Separately, an adenovirus vector expressing active TGF-beta1 was instilled into the trachea at 5 x 10^7, 10^8 or 10^9 pfu.
• Main results:
  • After asbestos exposure, the inbred C57BL/6 mice all had lesion scores of 2 or more. Most inbred 129 mice (4 of 5) had scores of 2 or less.
  • Unexposed mice rarely (2 of 18) had a score greater than 1.
  • The F1 offspring (C57BL/6 crossed with 129) showed a broad range of lesion scores, from 0 to 3.
  • Among F1 mice backcrossed to the C57 strain, only one of 21 (4.7%) offspring had no clear asbestos lesions.
  • Among F1 mice backcrossed to the 129 strain, 5 of 19 (26.3%) offspring had no apparent asbestos-induced lesions. The authors reported the difference between the two backcross groups as highly significant (P less than 0.0009).
  • TGF-beta1 vector, day 7, 5 x 10^7 pfu: 8 of 13 129 mice showed no evidence of disease (score of 0).
  • TGF-beta1 vector, day 7, 10^8 pfu: 4 of 11 129 mice were essentially normal (score of 1 or less).
  • At both of these virus doses, all 25 C57 mice had scores of 2 or greater at day 7.
  • By day 14, all but two of the mice in both strains had scores greater than 1.
  • The highest dose, 10^9 pfu, was lethal for most of the 129 mice.
  • The control vector did not produce scores greater than 1 in any animal at any time point.
  • Cell proliferation (BrdU labeling) was significantly higher in C57 mice in every lung region at day 7. By day 14, the 129 mice appeared to have more disease.
  • Lavage fluid contained significantly more TGF-beta1 protein in C57 mice than in 129 mice at day 4. At day 7, the difference between strains did not reach statistical significance.
  • Both strains expressed a test gene (LacZ) delivered by the same type of vector at comparable levels.
• The authors' conclusion: The authors concluded that, in the 129 mouse strain they used, a gene or gene cluster appears to segregate well enough to control a degree of susceptibility to asbestos disease in some of the animals. They stated that the gene and its products remain unknown.
• Limitations the authors state:
  • The authors state that they do not know what the gene or gene cluster is.
  • The authors state that the reversal of disease severity between the strains at day 14 in the TGF-beta1 model is unexplained.
  • The authors state it is not known whether the same genetic influence reduces the early response to TGF-beta expression in some inbred 129 mice.

Topics

Medical terms in this study, explained in our Lexicon: Pulmonary Fibrosis, Fibrosis, Fibrogenic.

Related studies

• Transforming growth factor-beta(1) overexpression in tumor necrosis factor-alpha receptor knockout mice induces fibroproliferative lung disease — J.Y. Liu, P.J. Sime, et al. (2001)
• 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)
• 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)
• Immunohistochemical localization of transforming growth factor beta isoforms in asbestos-related diseases — J. Jagirdar, T.C. Lee, et al. (1997)
• 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 and insulin-like growth factor-I in asbestosis in the sheep model — T.C. Lee, L.I. Gold, et al. (1997)

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