Pathogenesis of Fibrosis Produced by Asbestos and Man-Made Mineral Fibers: What Makes a Fiber Fibrogenic?

Our plain-English summary of Pathogenesis of Fibrosis Produced by Asbestos and Man-Made Mineral Fibers: What Makes a Fiber Fibrogenic?, by A. Churg, J. Wright, B. Gilks, et al (Inhalation Toxicology, 2000).

The study

• Authors: A. Churg, J. Wright, B. Gilks, J. Dai
• Journal: Inhalation Toxicology
• Published: 2000;12 Suppl 3:15-26
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Recent studies have revealed a wide array of molecular and cellular changes in cells and whole lungs exposed to asbestos fibers, changes that are presumed to be related to asbestos-induced fibrogenesis. These include generation of reactive oxygen species (ROS), induction of cell signaling factors and proinflammatory cytokines, and induction of fibrogenic mediators. Tumor necrosis factor-alpha (TNFα) appears to play a crucial role, since mice with TNFα receptor genes knocked out are resistant to asbestos-induced fibrosis. However, many man-made mineral fibers (MMVF) are able to generate ROS, cell signaling factors, and proinflammatory cytokines (probably every fiber causes expression of TNFα), but there is no clear correlation between the ability of MMVF to initiate these events and their ability to produce fibrosis. Moreover, asbestos produces fibrosis in tracheal explant systems without increasing TNFα expression, and nonfibrogenic dusts induce fibrogenic mediators such as transforming growth factor-beta (TCFβ) and platelet-derived growth factor (PDGF) but not procollagen in such systems. It remains uncertain whether alveolar macrophages are central to fibrosis, as is often assumed, or whether fibers penetrating tissue are the real effector agents. Fiber length, biopersistence, and dose clearly do play a very important role in fibrogenesis, since short fibers, readily degraded fibers, and small numbers of fibers of any type are nonfibrogenic. There is some evidence to suggest that short and nonpersistent fibers produce quantitatively less of the mediators just described, but the ability of macrophages to clear fibers is probably crucial to preventing fibrosis. Thus, molecular and cellular events must combine in as yet uncertain ways with abnormalities at a more "'macroscopic" level before fibrosis can become established.

In plain English

This article was a short narrative review, not a new study. It examined selected published experimental research, mostly in cells and in rats and mice, on how asbestos (amosite, crocidolite, chrysotile) and man-made mineral fibers (MMVF) cause lung fibrosis. The authors found no clear correlation between a fiber's ability to generate reactive oxygen species and its ability to cause fibrosis. They also found that inflammatory signals such as TNF-alpha were not specific markers of fibrosis-causing fibers. They cited studies in which mice lacking TNF-alpha receptors were protected from asbestos fibrosis. Yet in the authors' own earlier work with rat windpipe tissue, amosite raised procollagen (a collagen building block) after 1 week with no change in TNF-alpha. The review reported that long fibers caused fibrosis while short ones caused only a passing response. Fibers that dissolved readily caused little response, and asbestosis required very high doses. Chrysotile left the lung faster than amosite or crocidolite but still caused fibrosis at greater doses. The authors concluded that these events combine in still uncertain ways with larger-scale factors before fibrosis is established.

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: Narrative review of selected experimental literature on how fibers cause lung fibrosis, including some of the authors' own published and unpublished tracheal explant data
• Who was studied: Published experimental studies in cultured cells, rat tracheal explants, and rats, mice and hamsters. No number of studies is given. Written by authors at the Department of Pathology, University of British Columbia.
• Exposure: Asbestos (amosite, crocidolite, chrysotile) and man-made mineral fibers, including refractory ceramic fibers (RCF1), silicon carbide, glass fibers (code 100, MMVF10, X607), potassium octatitanate and titanium dioxide whiskers. Silica was used for comparison.
• Main results:
  • Across asbestos and MMVF, measures of reactive oxygen species generation or iron release did not clearly correlate with ability to cause fibrosis.
  • Cited studies found that mice with the p55 and p75 TNF-alpha receptor genes knocked out were protected from the inflammatory and fibrosis-causing effects of asbestos.
  • From the data on MMVF and asbestos, the authors judged that NF-kappaB activation and TNF-alpha induction are not, in themselves, specific markers of fibrosis-causing fibers.
  • In the authors' own rat tracheal explants exposed to amosite, PDGF-A, PDGF-B, TGF-beta1 and procollagen expression all increased after 1 week in organ culture, with no change in TNF-alpha at any time.
  • In the same explant model, iron oxide and titanium dioxide particles increased PDGF and TGF-beta expression but did not increase procollagen expression.
  • Reviewed animal experiments with sized crocidolite preparations showed that long fibers caused fibrosis, while short fibers caused only a transient inflammatory and cell-proliferation response.
  • In MMVF inhalation studies, biopersistent glass caused fibrosis, but glass of ordinary solubility (MMVF10) or high-solubility glass (X607) did not.
  • Chrysotile disappeared from the lung more readily than amosite or crocidolite but still caused fibrosis. In humans and experimental animals, relatively greater doses of chrysotile were required.
  • Epidemiologic, human fiber burden and animal studies were described as showing that asbestosis requires very high fiber doses and that there is a dose threshold for fiber-induced fibrosis.
  • Asbestos and silica appeared to act almost identically at the molecular level, yet asbestosis and silicosis differ in lung location and in pattern of scarring.
• The authors' conclusion: The authors concluded that molecular and cellular events must combine in as yet uncertain ways with abnormalities at a more 'macroscopic' level before fibrosis becomes established. They also concluded that the most important role of alveolar macrophages may be removing fibers before they enter tissue.
• Limitations the authors state:
  • Exact comparisons between fiber studies are difficult because different investigators used different fibers sharing the same generic name, across a very broad range of sizes.
  • Because of space limits, references were kept to a minimum.

Topics

Medical terms in this study, explained in our Lexicon: Fibrosis, Mineral Fiber, Fibrogenic, Reactive Oxygen Species (ROS), Cytokine, Tumor Necrosis Factor-alpha (TNF-α), Transforming Growth Factor-beta (TGF-β), Platelet-Derived Growth Factor (PDGF).

Related studies

• Mineral dusts directly induce epithelial and interstitial fibrogenic mediators and matrix components in the airway wall — J. Dai, B. Gilks, et al. (1998)
• Man-made respirable-sized organic fibers: what do we know about their toxicological profiles? — D.B. Warheit, K.L. Reed, et al. (2001)
• Mortality among a cohort of US man-made mineral fiber workers: 1985 follow-up — G.M. Marsh, P.E. Enterline, et al. (1990)
• Silica, asbestos, man-made mineral fibers, and cancer — K. Steenland, L. Stayner (1997)
• Solubility of asbestos and man-made mineral fibers in vitro and in vivo: its significance in lung disease — A. Morgan, A. Holmes (1986)
• A trial on the quantitative risk assessment of man-made mineral fibers by the rat intraperitoneal administration assay using the JFM standard fibrous samples — S. Adachi, K. Kawamura, et al. (2001)

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