Inhalation of Asbestos Fibers and Consequent Expression of Peptide Growth Factors

Our plain-English summary of Inhalation of Asbestos Fibers and Consequent Expression of Peptide Growth Factors, by A.R. Brody (Inhalation Toxicology, 2000).

The study

• Author: A.R. Brody
• Journal: Inhalation Toxicology
• Published: 2000;12 Suppl 3:245-50
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

It would be impossible to completely review this broad topic in the space and time allowed, lust as we must make choices when focusing on a research topic, this brief overview of particles and fibrosis deals with a small corner of our current thinking on the molecular mechanisms through which inhaled particles mediate fibroproliferative lung disease. At some point, there must be a common pathway of action because the fundamental process after any exposure involves fibroblast proliferation and production of extracellular matrix, that is, scar tissue. Thus, if we can understand how to control the fibroblast cell cycle and those genes that code for matrix components, it may be possible to develop effective therapeutic modalities for pulmonary fibrosis where none now exist. To control cell cycle and matrix genes that are expressed due to particle exposure, investigators have focused on certain peptide growth factors. The genes that code for these factors as well as the genes and oncogenes that are expressed when the peptides bind to their cognate receptors offer the best opportunities for understanding the molecular mechanisms of particle-induced lung fibrosis. As an example, mice with the genes knocked out for both the 55- and 75-kD receptors for tumor necrosis factor-alpha (TNF-α) are protected from the fibrogenic effects of inhaled asbestos and silica. Expression of other peptide growth factors in these animals is reduced, leading to a central working hypothesis, that TNF-α is a "master switch" that controls the expression of other more downstream factors that mediate components of the fibrogenic process. There is ample evidence of TNF-α expression in animal models and in populations of dust-exposed workers to support this postulate. In addition, it appears that transforming growth factor beta (TGF-β) is the primary peptide that controls production of extracellular matrix. Blocking of TGF-β expression in animal models prevents fibrosis, and the use of specific antisense RNA blocks both TGF-β and collagen gene expression in primary lung fibroblasts. Conversely, an adenovirus vector that transduces expression of TGF-β to the bronchiolar-alveolar epithelium induces diffuse fibrogenesis in rats and mice. Thus, particle-induced pulmonary fibrosis is a complex process that will be understood only after we dissect and elucidate the signal transduction pathways that control growth factor and matrix gene expression. The emerging technologies for developing transgenic and knockout mice, viral vectors for gene transduction, antisense approaches, and microarray gene analysis will finally allow us to accomplish these goals.

In plain English

This article was a brief review in which the author summarized earlier experiments from the author's own laboratory. It did not report a new study. In those experiments, rats and mice breathed an aerosol of chrysotile asbestos fibers for 1 to 5 hours. Four growth factors (PDGF, TGF-alpha, TGF-beta and TNF-alpha) were all produced within hours of the initial injury, by cells in the scar-forming (fibroproliferative) lesions that developed where fibers first landed. These lesions persisted for at least 6 months after exposure ended. Mice lacking the genes for both TNF-alpha receptors were protected from these lesions after a single 5-hour asbestos exposure. Their expression of the other three growth factors, measured by in situ hybridization, was significantly lower than in control mice. Mice of the 129 strain also did not develop the lesions. The author concluded that the findings supported the hypothesis that TNF-alpha acts as a "master switch" over the other growth factors. The author also stated that the precise role of each factor remained to be established. No animal counts were given.

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: Brief review (overview) of the author's laboratory's earlier animal experiments; no new study reported
• Who was studied: Rats and mice, including normal animals, TNF-alpha receptor knockout mice (both 55- and 75-kD receptors), C57Bl/6 and C57-129 hybrid control mice, and the 129 mouse strain; numbers of animals not given
• Exposure: Inhaled aerosol of chrysotile asbestos fibers for 1 to 5 hours; in the knockout experiments, a single 5-hour aerosol exposure, with air-exposed mice as negative controls
• Main results:
  • In normal rats and mice, PDGF, TGF-alpha, TGF-beta1 and TNF-alpha were all expressed within hours of initial injury, by cells of the developing fibroproliferative lesions
  • The asbestos-induced lesions contained mature collagen and persisted for at least 6 months after exposure ceased
  • TNF-alpha receptor knockout mice were protected from the fibroproliferative effects of inhaled asbestos fibers
  • In the knockout mice, expression of PDGF, TGF-alpha and TGF-beta, as determined by in situ hybridization, was significantly reduced compared with the C57 and hybrid control mice
  • Mice of the 129 strain did not develop fibroproliferative lesions at sites of fiber deposition after asbestos exposure
• The authors' conclusion: The author concluded that the mouse experiments supported the hypothesis that TNF-alpha serves as a "master switch" controlling other growth factors. The author also held that sorting out the many interacting cytokines will require transgenic, knockout and gene-vector technologies.
• Limitations the authors state:
  • The author stated that the topic could not be completely reviewed in the space available
  • The author stated that it still had to be determined whether any or all of these growth factors play a role in the disease process, and that the precise roles remain to be established

Topics

Medical terms in this study, explained in our Lexicon: Fibrosis, Fibroblast, Pulmonary Fibrosis, Tumor Necrosis Factor-alpha (TNF-α), Fibrogenic, Collagen, Epithelium.

Related studies

• Analyzing the genes and peptide growth factors expressed in lung cells in vivo consequent to asbestos exposure and in vitro — A.R. Brody, J.Y. Liu, et al. (1997)
• 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)
• Occupational lung disease and the role of peptide growth factors — A.R. Brody (1997)
• Role of peptide growth factors in asbestos-related human lung cancer — B. Guillemin, Y. Zhang, et al. (1991)
• Chrysotile asbestos upregulates gene expression and production of alpha-receptors for platelet-derived growth factor (PDGF-AA) on rat lung fibroblasts — J.C. Bonner, A.L. Goodell, et al. (1993)
• Up-regulated expression of transforming growth factor-alpha in the bronchiolar-alveolar duct regions of asbestos-exposed rats — J.Y. Liu, G.F. Morris, et al. (1996)

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