Asbestos fibers and silica particles stimulate rat alveolar macrophages to release tumor necrosis factor. Autoregulatory role of leukotriene B4

Our plain-English summary of Asbestos fibers and silica particles stimulate rat alveolar macrophages to release tumor necrosis factor. Autoregulatory role of leukotriene B4, by C.M. Dubois, E. Bissonnette, M. Rola-Pleszczynski (The American Review of Respiratory Disease, 1989).

The study

• Authors: C.M. Dubois, E. Bissonnette, M. Rola-Pleszczynski
• Journal: The American Review of Respiratory Disease
• Published: 1989;139(5):1257-64
• Cited by: 160 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Alveolar macrophages (AM) can play a crucial role in the pathogenesis of pulmonary disease via their ability to produce potent inflammatory and fibrogenic mediators. We found that rat AM cultured with 1 to 100 micrograms/ml of silica particles or asbestos fibers produced tumor necrosis factor (TNF) and leukotriene B4 (LTB4) in a concentration-dependent fashion, whereas latex beads, an inert phagocytic stimulus, failed to induce significant augmentation of either TNF or LTB4. In a time course study, AM stimulated for 2 h with silica or asbestos produced an increased amount of LTB4, which preceded the rise in TNF activity detected 7 and 24 h after culture initiation. The induction appears to involve the synthesis of new protein since actinomycin D and cycloheximide abrogate the majority of the stimulatory effect. We next examined the role of LTB4 in mineral-dust-induced TNF production. The lipoxygenase inhibitors nordihydroguaiaretic acid (NDGA) and AA861 used at 1 to 50 micrograms/ml reduced in a concentration-dependent fashion asbestos- or silica-stimulated TNF release. On the other hand, "reconstitutive" experiments in which we added exogenous LTB4 (10(-14) to 10(-8) M) to AM treated with lipoxygenase inhibitors showed partial restoration of TNF production induced by chrysotile or silica, with peak effect at 10(-10)M LTB4. The present study demonstrated that AM incubated in the presence of chrysotile A or silica can produce both LTB4 and TNF and that endogenous lipoxygenase metabolites as well as exogenous LTB4 can act to amplify TNF production. These observations suggest a common mechanism by which asbestos and silica may modulate the production of inflammatory and fibrogenic cytokines.

In plain English

This was a laboratory study of rat cells, not of people. The authors collected alveolar macrophages (lung immune cells) from male Wistar rats and grew them with chrysotile A asbestos fibers or silica particles at 1 to 100 micrograms per ml. Both dusts raised the cells' output of tumor necrosis factor (TNF), an inflammatory signaling protein, and of leukotriene B4 (LTB4), a related messenger. Inert latex beads did not significantly raise either. At 50 micrograms per ml, the article's table gave mean TNF of 18 units per ml without dust, 69.8 with silica and 201.6 with chrysotile A, unlike the text's stated fold increases. LTB4 rose by 2 hours, before TNF rose at 7 and 24 hours. Endotoxin in the dusts was 65 and 130 times below the amount needed for such TNF levels. Drugs that block LTB4 production reduced dust-induced TNF. Adding LTB4 back partly restored it: 73 and 86 percent recovery of the original asbestos and silica stimulation at the best dose. The authors concluded that these cells can make both substances and that LTB4 can act to amplify TNF production.

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: In vitro laboratory experiment on rat alveolar macrophages
• Who was studied: Alveolar macrophages obtained by lung lavage from male Wistar rats weighing 200 to 250 g, bought from Charles River Canada. The number of rats is not given. Each culture held 0.5 x 10^6 cells, and experiments were typically repeated 3 to 6 times.
• Exposure: Chrysotile A asbestos fibers (a standard reference preparation) and silica particles at 1 to 100 micrograms per ml, mostly 50 micrograms per ml, for 30 minutes to 24 hours. Latex beads, MDP and LPS (endotoxin) were used for comparison. Leukotriene and cyclooxygenase inhibitors and added LTB4 were used to study the mechanism.
• Main results:
  • In Table 3, at 50 micrograms per ml for 24 hours, mean TNF was 18 U/ml for medium alone, 20.5 for latex, 69.8 for silica and 201.6 for chrysotile A. The Results text instead describes a 3- and 4-fold enhancement for silica and chrysotile A, which does not match the ratios of these tabulated means.
  • In Table 3, mean LTB4 was 88 pg per 0.5 x 10^6 cells for medium alone, 107 for latex, 1,070 for silica and 2,550 for chrysotile A. The text states a 13- and 32-fold augmentation, which also does not exactly match the ratios of these tabulated means.
  • Latex beads, an inert particle that macrophages engulf, did not significantly increase TNF or LTB4 production. Their Table 3 means were slightly above those for medium alone.
  • LTB4 and TNF production were positively correlated in macrophages stimulated with chrysotile A (r = 0.80, p less than 0.001) and with silica (r = 0.72, p less than 0.01)
  • LTB4 rose significantly after 2 hours, when there was not yet any detectable effect on TNF
  • TNF stimulation became significant after 7 hours and was greatest at 24 hours
  • Actinomycin D and cycloheximide, which block new protein production, abolished most of the dust-induced TNF increase
  • TNF from chrysotile A at 50 micrograms per ml (201.6 plus or minus 29.1 U/ml) was not different from that induced by an optimal dose of MDP (172 plus or minus 19.2 U/ml). LPS induced four times more TNF than chrysotile A.
  • The endotoxin measured in the asbestos and silica preparations was 65 and 130 times, respectively, less than the amount needed to produce the TNF levels seen with the dusts
  • The lipoxygenase inhibitors NDGA and AA861 reduced asbestos- or silica-induced TNF production in a concentration-dependent way
  • The cyclooxygenase inhibitors indomethacin and ibuprofen further increased dust-stimulated TNF production
  • Adding LTB4 to cells treated with AA861 gave 73 percent (asbestos) and 86 percent (silica) recovery of the original dust stimulation of TNF production. The maximal effect was at 10 to the minus 10 molar LTB4.
• The authors' conclusion: The authors concluded that rat alveolar macrophages cultured with chrysotile A or silica can produce both LTB4 and TNF. They also concluded that LTB4, whether made by the cells or added from outside, can act to amplify TNF production.
• Limitations the authors state:
  • The authors could not exclude that other arachidonic acid metabolites, besides LTB4, contribute to dust-induced TNF stimulation

Topics

Medical terms in this study, explained in our Lexicon: Alveolar Macrophage, Necrosis, Fibrogenic, Chrysotile, Cytokine.

Related studies

• Alveolar macrophages from patients with asbestos exposure release increased levels of leukotriene B4 — J.G. Garcia, D.E. Griffith, et al. (1989)
• Asbestos-stimulated tumour necrosis factor release from alveolar macrophages depends on fibre length and opsonization — K. Donaldson, X.Y. Li, et al. (1992)
• Asbestos stimulates alveolar macrophages to release a factor causing human lung fibroblasts to replicate — P. Bitterman, S. Rennard, et al. (1981)
• Iron and reactive oxygen species in the asbestos-induced tumor necrosis factor-alpha response from alveolar macrophages — P.P. Simeonova, M.I. Luster (1995)
• Asbestos fibres and man made mineral fibres: induction and release of tumour necrosis factor-alpha from rat alveolar macrophages — A.G. Ljungman, M. Lindahl, et al. (1994)
• Pulmonary reaction to long and short asbestos fibers is independent of fibroblast growth factor production by alveolar macrophages — I.Y. Adamson, D.H. Bowden (1990)

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