Bidirectional modulation of TNF-alpha production by alveolar macrophages in asbestos-induced pulmonary fibrosis

Our plain-English summary of Bidirectional modulation of TNF-alpha production by alveolar macrophages in asbestos-induced pulmonary fibrosis, by S. Ouellet, H. Yang, R.A. Aubin, et al (Journal of Leukocyte Biology, 1993).

The study

• Authors: S. Ouellet, H. Yang, R.A. Aubin, R.G. Hawley, G.F. Wenckebach, I. Lemaire
• Journal: Journal of Leukocyte Biology
• Published: 1993;53(3):279-86
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Bronchoalveolar lavage (BAL) cells were isolated from rats 1, 3, and 6 weeks after a single intratracheal instillation of saline, UICC chrysotile asbestos (5 mg), or silica (5 mg). In asbestos-exposed rats, the pulmonary response was characterized by a significant increase in the number of alveolar macrophages (AMs) and the appearance of fibrotic lesions within 1 week. By contrast, mixed macrophage and neutrophil accumulations were observed in the silica group without evidence of fibrosis. Tumor necrosis factor-alpha (TNF-alpha) production by lipopolysaccharide (LPS)-stimulated BAL cells from asbestos-treated rats was significantly lower than controls 1 and 3 weeks after exposure. However, by 6 weeks higher levels of TNF-alpha production were noticeable in this group. Decreases in LPS-induced TNF-alpha production were also observed with BAL cells from silica-treated animals at all time points studied. Lower levels of TNF-alpha were not related to decreased BAL cell viability or the presence of a significant proportion of neutrophils in the silica group. Furthermore, biphasic changes in TNF-alpha production seen in the asbestos group were correlated with concomitant decreases (3 weeks) and increases (6 weeks) in levels of TNF-alpha mRNA in AMs. These data indicate that lower levels of TNF-alpha resulted from inhibition at the gene expression level and provide evidence for bidirectional modulation of TNF-alpha production by AMs during inflammatory reactions.

In plain English

This was an animal experiment in male Wistar rats. Each rat received a single injection into the windpipe of saline, 5 mg of UICC chrysotile B asbestos, or 5 mg of silica. Cells washed from the lungs were studied 1, 3 and 6 weeks later. The authors measured how much tumor necrosis factor-alpha (TNF-alpha), an inflammation signal, these cells released when stimulated with a bacterial product. In chrysotile-exposed rats, fibrotic lesions appeared within 1 week and appeared to progress. Silica caused a granulomatous reaction, with no fibrosis detected at 6 weeks. Lung cells from chrysotile-exposed rats released less TNF-alpha than controls at 1 and 3 weeks (43 and 71 U/ml versus 106 and 145 U/ml) but more at 6 weeks (264 versus 152 U/ml). TNF-alpha mRNA was lower at 3 weeks and higher at 6 weeks in this group. Cells from silica-exposed rats released less TNF-alpha at all times. Cell viability stayed above 92%, and neutrophils did not explain the silica result. The authors concluded that in the chrysotile group the drop was reversible and consistent with reduced gene expression; in the silica group it persisted at 6 weeks.

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 (single intratracheal instillation in rats, with lung lavage cells studied at set intervals)
• Who was studied: Male Wistar rats weighing 250 to 300 g from Charles River Canada; at least four animals per group were sacrificed at each of 1, 3 and 6 weeks in each experimental protocol (figures report nine animals per group for some measurements)
• Exposure: A single 5 mg dose of UICC chrysotile B asbestos, compared with 5 mg silica (Min-U-Sil) and with saline controls
• Main results:
  • In chrysotile-exposed rats, fibrotic lesions were detectable 1 week after exposure and appeared to progress with time
  • In silica-exposed rats, a granulomatous reaction was seen but no fibrosis was detectable 6 weeks after exposure; neutrophils were significantly increased at all time points
  • LPS-stimulated lung lavage cells from chrysotile-exposed rats released significantly (P<.05) less TNF-alpha than controls at 1 and 3 weeks: 43 and 71 U/ml versus 106 and 145 U/ml
  • At 6 weeks, cells from chrysotile-exposed rats released significantly (P<.001) more TNF-alpha than controls: 264 U/ml versus 152 U/ml
  • Cells from silica-exposed rats released lower TNF-alpha at 1 and 3 weeks (58 and 48 U/ml)
  • Unlike the chrysotile group, the reduced TNF-alpha production in the silica group was still present at 6 weeks
  • In alveolar macrophages from chrysotile-exposed rats, TNF-alpha mRNA was lower than controls at 3 weeks and significantly higher than controls at 6 weeks; mRNA was examined only in saline- and asbestos-exposed rats
  • The authors judged the lower TNF-alpha at 3 weeks in asbestos-exposed rats consistent with down-regulation of the TNF-alpha gene
  • Lavage cell viability was over 92% in every group at all times
  • At 3 weeks, LPS-induced IL-1 activity was higher in cells from asbestos-exposed rats (17.7 U/ml) and silica-exposed rats (36.4 U/ml) than in saline-treated rats (8.5 U/ml)
  • Neutrophil-enriched cells from silica-exposed rats, cultured with normal alveolar macrophages, had no significant effect on TNF-alpha production
• The authors' conclusion: The authors concluded that, in the asbestos model, inhibition of TNF-alpha production was reversible and was followed by enhanced production at 6 weeks, and that the 3-week decrease was consistent with down-regulation of the TNF-alpha gene. In the silica group the reduction persisted at 6 weeks.
• Limitations the authors state:
  • Interstitial lung lymphocytes were not assessed, so a role for lymphocyte-derived cytokines could not be fully ruled out
  • The mechanisms behind the increase in TNF-alpha at 6 weeks were not determined

Topics

Medical terms in this study, explained in our Lexicon: Alveolar Macrophage, Pulmonary Fibrosis, Bronchoalveolar Lavage (BAL), UICC, Chrysotile, Macrophage, Fibrosis, Tumor Necrosis Factor-alpha (TNF-α).

Related studies

• Alveolar macrophage cytokine and growth factor production in a rat model of crocidolite-induced pulmonary inflammation and fibrosis — K.E. Driscoll, J.K. Maurer, et al. (1995)
• Iron and reactive oxygen species in the asbestos-induced tumor necrosis factor-alpha response from alveolar macrophages — P.P. Simeonova, M.I. Luster (1995)
• Relative release of interleukin-1 beta and interleukin-1 receptor antagonist by alveolar macrophages. A study in asbestos-induced lung disease, sarcoidosis, and idiopathic pulmonary fibrosis — J.N. Kline, D.A. Schwartz, et al. (1993)
• 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)
• Synergistic effects of mineral fibres and cigarette smoke on the production of tumour necrosis factor by alveolar macrophages of rats — Y. Morimoto, M. Kido, et al. (1993)
• Distinctive profile of alveolar macrophage-derived cytokine release induced by fibrogenic and nonfibrogenic mineral dusts — I. Lemaire, S. Ouellet (1996)

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