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

Our plain-English summary of 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, by D.M. Brass, G.W. Hoyle, H.G. Poovey, et al (The American Journal of Pathology, 1999).

The study

• Authors: D.M. Brass, G.W. Hoyle, H.G. Poovey, J.Y. Liu, A.R. Brody
• Journal: The American Journal of Pathology
• Published: 1999;154(3):853-62
• Cited by: 53 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta mRNA and protein expression and the degree of fibroproliferative response to inhaled asbestos fibers are clearly reduced in the 129 inbred mouse strain as compared with typical fibrogenesis observed in the C57BL/6 inbred strain. The C57BL/6 mice showed prominent lesions at bronchiolar-alveolar duct (BAD) junctions where asbestos fibers deposit and responding macrophages accumulate. The 129 mice, however, were generally indistinguishable from controls even though the numbers of asbestos fibers deposited in the lungs of all exposed animals were the same. Quantitative morphometry of H&E-stained lung sections comparing the C57BL/6 and 129 mice showed significantly less mean cross-sectional area of the BAD junctions in the 129 animals, apparent at both 48 hours and 4 weeks after exposure. In addition, fewer macrophages had accumulated at these sites in the 129 mice. Nuclear bromodeoxyuridine immunostaining demonstrated that the number of proliferating cells at first alveolar duct bifurcations and in adjacent terminal bronchioles was significantly reduced in the 129 strain compared with C57BL/6 mice at 48 hours after exposure (P < 0.01). TNF-alpha and TGF-beta1 gene expression, as measured by in situ hybridization, was reduced in the 129 mice at 48 hours after exposure, and expression of TNF-alpha and TGF-beta1 protein, as measured by immunohistochemistry, was similarly reduced or absent in the 129 animals. We postulate that the protection afforded the 129 mice is related to reduction of growth factor expression by the bronchiolar-alveolar epithelium and lung macrophages.

In plain English

This was an animal experiment at Tulane University Medical Center comparing two inbred mouse strains, C57BL/6 and 129. The mice breathed either chrysotile asbestos (10 mg/m3 respirable mass) or room air for a single 5-hour, nose-only exposure. Five male mice per group were examined at each of five times, from immediately after exposure to 4 weeks. The same numbers of fibers were deposited in the lungs of both strains, which cleared them at similar rates. C57BL/6 mice developed lesions at the junctions between the small airways and the alveolar ducts. Exposed 129 mice had significantly smaller lesion areas than exposed C57BL/6 mice. At 48 hours, dividing cells and macrophages at these sites rose less in 129 mice. Macrophages rose to 2.5 times control levels in 129 mice, against 5 times in C57BL/6 mice. Two growth factors, TNF-alpha and TGF-beta1, were reduced or largely absent in 129 mice. The authors suggested that reduced growth factor expression plays some role in the lack of disease, and said ongoing experiments would test this. They also noted that the lower expression might instead reflect smaller lesions with fewer cells.

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 (inhalation exposure comparing two inbred mouse strains)
• Who was studied: Specific-pathogen-free 6-week-old male C57BL/6 and 129 mice from Jackson Laboratories. Five animals per group were sacrificed at each of five times: 0 hour, 48 hours, 1 week, 2 weeks and 4 weeks after exposure. The work was done at Tulane University Medical Center, New Orleans.
• Exposure: A single 5-hour, nose-only exposure to an aerosol of California chrysotile asbestos at 10 mg/m3 respirable mass. Controls were exposed to room air for 5 hours.
• Main results:
  • The numbers of fibers deposited in the lungs were the same in both strains, and both strains cleared fibers at similar rates.
  • Mean bifurcation (lesion) area in exposed 129 mice was significantly less than in exposed C57BL/6 mice at 48 hours and 4 weeks. In exposed 129 mice it was elevated over controls at 48 hours but not at 4 weeks.
  • At bronchiolar-alveolar duct junctions at 48 hours, the percentage of BrdU-labeled (dividing) cells in C57BL/6 mice was significantly increased over unexposed mice and over 129 mice. In 129 mice the increase over controls was smaller, and labeling had returned to control levels by 1 week.
  • In terminal bronchioles at 48 hours, the increase in dividing cells in C57BL/6 mice was significantly greater than in 129 mice.
  • At 48 hours, mean macrophage numbers at first alveolar duct bifurcations were elevated 2.5 times over controls in exposed 129 mice and 5 times over controls in exposed C57BL/6 mice.
  • At 48 hours, TNF-alpha gene expression in 129 mice stayed limited to the terminal bronchiole epithelium, as seen immediately after exposure. In C57BL/6 mice it was abundant at the junctions. TNF-alpha protein in 129 mice never exceeded minimal levels.
  • 129 mice showed essentially no increase in TGF-beta1 gene expression at the fiber deposition sites at any time after exposure. C57BL/6 mice showed a strong signal at 48 hours.
• The authors' conclusion: The authors concluded that the 129 strain fails to develop fibroproliferative lesions after asbestos exposure. They suggested that reduced growth factor expression plays some role in this, a postulate their ongoing experiments are designed to test.
• Limitations the authors state:
  • The authors noted it is unclear whether the growth factors are reduced because of genetic programming, or because smaller lesions leave fewer cells available to express them.

Topics

Medical terms in this study, explained in our Lexicon: Tumor Necrosis Factor-alpha (TNF-α), Asbestos Exposure, Necrosis, Macrophage, Immunohistochemistry, Epithelium.

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)
• 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)
• Hyaluronate activation of CD44 induces insulin-like growth factor-1 expression by a tumor necrosis factor-alpha-dependent mechanism in murine macrophages — P.W. Noble, F.R. Lake, et al. (1993)
• 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)

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