TNF-alpha receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers

Our plain-English summary of TNF-alpha receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers, by J.Y. Liu, D.M. Brass, G.W. Hoyle, et al (The American Journal of Pathology, 1998).

The study

• Authors: J.Y. Liu, D.M. Brass, G.W. Hoyle, A.R. Brody
• Journal: The American Journal of Pathology
• Published: 1998;153(6):1839-47
• Cited by: 119 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

We have demonstrated that C57BL/6-129 hybrid mice with genes for both the 55kd and 75kd receptors for TNF-alpha knocked out (TNF-alphaRKO) fail to develop fibroproliferative lesions after asbestos exposure. There is good evidence that TNF-alpha plays a major role in mediating interstitial pulmonary fibrosis. Our findings support this view and we present here new data obtained by in situ hybridization showing that expression of the genes coding for transforming growth factor alpha (TGF-alpha) and platelet-derived growth factor A-chain (PDGF-A) is reduced in the TNF-alphaRKO mice compared with control animals. In accordance with this observation, data on bromodeoxyuridine (BrdU) incorporation in the lungs of the TNF-alphaRKO mice show no increases over unexposed control animals. In contrast, wild-type control mice exposed to asbestos exhibit 15- to 20-fold increases in BrdU uptake and consequently develop fibrogenic lesions. Even though the levels of TNF-alpha gene expression and protein production were increased in the asbestos-exposed TNF-alphaRKO mice, the lack of receptor signaling protected the mice from developing fibroproliferative lesions. We agree with the view that TNF-alpha is essential for the development of interstitial pulmonary fibrosis and postulate that TNF-alpha mediates its effects through activation of other growth factors such as PDGF and TGF-alpha that control cell growth and matrix production.

In plain English

This was an animal inhalation experiment. Mice lacking the genes for both the 55kd and 75kd TNF-alpha receptors (TNF-alpha receptor knockouts, on a mixed C57BL/6 and 129 background) were exposed nose-only for a single 5-hour period to an aerosol of California chrysotile asbestos at 10 mg per cubic metre respirable mass, or to room air; C57BL/6 and B6129 F2 hybrid mice were exposed at the same time as controls. Five animals per group were killed at 0 hours, 48 hours and 2 weeks. Asbestos-exposed C57 and B6129 mice developed the expected hypercellular lesions at bronchiolar-alveolar duct junctions, with BrdU labelling increases approaching 15- to 20-fold that remained elevated for at least 2 weeks, and with expression of TNF-alpha, TGF-alpha and PDGF-A messenger RNA. The knockout mice developed no fibroproliferative lesions, though a few had increased alveolar macrophages at those junctions; they showed no BrdU increase above air-exposed controls and reduced TGF-alpha and PDGF-A expression, while TNF-alpha gene and protein expression remained increased. The authors concluded that TNF-alpha receptor signalling is essential for asbestos-induced fibroproliferative disease.

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: controlled animal inhalation experiment using TNF-alpha receptor knockout and wild-type mice
• Who was studied: Mice with both p55 and p75 TNF receptor genes knocked out, maintained on a mixed C57BL/6 and 129 background, with B6129 F2 hybrid and C57BL/6 wild-type controls; five animals per group killed at 0 hours, 48 hours and 2 weeks
• Exposure: A single 5-hour nose-only inhalation of California chrysotile asbestos aerosol at 10 mg/m3 respirable mass, or room air (sham)
• Main results:
  • Asbestos-exposed knockout mice did not develop fibroproliferative lesions; a blinded histopathologist classed most of them as normal, though a few had increased alveolar macrophages at the bronchiolar-alveolar duct junctions
  • In asbestos-exposed C57 and B6129 wild-type mice, BrdU incorporation increases approached 15- to 20-fold and remained significantly elevated for at least 2 weeks
  • Knockout mice exposed to asbestos had significantly fewer BrdU-labelled cells than B6129 hybrid controls and did not differ significantly from air-exposed B6129 mice
  • Statistical significance of the BrdU increases in C57 and B6129 mice versus air-exposed controls and asbestos-exposed knockouts: p less than 0.01 and p less than 0.05
  • PDGF-A and TGF-alpha messenger RNA were markedly reduced in asbestos-exposed knockout mice, while TNF-alpha messenger RNA hybridized densely in both knockout and wild-type asbestos-exposed mice
  • Immunohistochemistry showed TNF-alpha protein staining in both knockout and B6129 mice after asbestos exposure, mainly in bronchiolar-alveolar epithelial cells and alveolar macrophages
• The authors' conclusion: The authors concluded that mice lacking both TNF-alpha receptors are protected from the fibrogenic effects of inhaled asbestos, and postulated that TNF-alpha acts through growth factors such as PDGF, TGF-alpha and TGF-beta
• Limitations the authors state:
  • The authors stated that the central question of TNF-alpha's role cannot be answered definitively from these data
  • The authors stated that further experiments are needed to establish whether TNF-alpha expression is necessary for the elaboration of other key growth factors

Topics

Medical terms in this study, explained in our Lexicon: Asbestos Exposure, Interstitial, Pulmonary Fibrosis, Platelet-Derived Growth Factor (PDGF), 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)
• Activated TNF-alpha/NF-kappaB signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice — D.A. Altomare, C.W. Menges, et al. (2009)
• 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)
• Asbestos-induced pulmonary fibrosis is augmented in 8-oxoguanine DNA glycosylase knockout mice — P. Cheresh, L. Morales-Nebreda, et al. (2015)
• Upregulation of the PDGF-alpha receptor precedes asbestos-induced lung fibrosis in rats — J.A. Lasky, B. Tonthat, et al. (1998)

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