Patterns of inflammation, cell proliferation, and related gene expression in lung after inhalation of chrysotile asbestos

Our plain-English summary of Patterns of inflammation, cell proliferation, and related gene expression in lung after inhalation of chrysotile asbestos, by T.R. Quinlan, K.A. BéruBé, J.P. Marsh, et al (The American Journal of Pathology, 1995).

The study

• Authors: T.R. Quinlan, K.A. BéruBé, J.P. Marsh, Y.M. Janssen, P. Taishi, K.O. Leslie, D. Hemenway, P.T. O'Shaughnessy, P. Vacek, B.T. Mossman
• Journal: The American Journal of Pathology
• Published: 1995;147(3):728-39
• Cited by: 51 articles, as counted by NIH iCite
• Read it: PubMed · Free full text

Abstract

Biochemical and molecular markers of inflammation, cell proliferation, and pulmonary fibrosis were studied in lungs and bronchoalveolar lavage preparations from Fischer 344 rats at time periods from 3 to 20 days after inhalation of two airborne concentrations (0.18 and 8.2 mg/m3 air) of chrysotile asbestos. Additional groups of animals were examined for lung histopathology and cell proliferation with an antibody to 5-bromo-2'-deoxyuridine after exposure to asbestos for 5 and 20 days and after 20 days of exposure followed by an additional 20 days in room air. Exposure to chrysotile at the higher concentration caused protracted increases in steady-state mRNA levels of manganese-containing superoxide dismutase and elevation in glyceraldehyde-3-phosphate dehydrogenase mRNA at 3 days, but levels of mRNAs encoding copper-zinc-containing superoxide dismutase, ornithine decarboxylase, and the proto-oncogene, c-jun were not statistically elevated from levels occurring in lung homogenates from sham control rats. Differential cell counts in bronchoalveolar lavage revealed an early infiltration of neutrophils that correlated with focal areas of increased cellularity and fibrosis in rat lungs at the higher concentrations of asbestos. However, elevations in lung hydroxyproline were not observed. Significant increases in epithelial cells of the bronchi, the interstitial compartment of the lung, and mesothelial cells incorporating 5-bromo-2'-deoxyuridine, an indication of DNA synthesis, were noted in the higher chrysotile group at 5 days, but labeling in all cell compartments was comparable with that occurring in sham controls at later time points. Indicators of inflammation, increased cell proliferation, and pulmonary fibrosis were not observed in the lungs of rats exposed to the lower concentration of chrysotile. Thus, results indicate that cellular and molecular markers of inflammation and proliferation in lung are dose-related and indicative of the histopathological development of asbestosis.

In plain English

This animal experiment exposed male Fischer 344 rats by inhalation to chrysotile asbestos at one of two concentrations, 6 hours a day, 5 days a week, for up to 20 days. The lower concentration was 0.18 mg/m3 air (32 fibers longer than 5 micrometers per cc). The higher was 8.2 mg/m3 air (about 2457 such fibers per cc). Control rats breathed room air. At the higher concentration, lung washings held more neutrophils, a type of inflammatory white blood cell, at all time points. Levels of the antioxidant gene message MnSOD were raised. One cell-growth gene message, GAPDH, rose briefly at 3 days. At 5 days there was a short-lived rise in dividing cells in the airways, lung tissue and pleural lining, which was no longer seen later. Two of eight high-dose rats had small, focal fibrotic lesions at 20 days, but lung hydroxyproline, a collagen marker, was not significantly raised. Rats at the lower concentration showed no inflammation, increased cell division or fibrosis. The authors suggested that the early cell division reflected acute nonspecific effects of the fibers rather than a cause of fibrosis.

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 inhalation experiment comparing two airborne concentrations of chrysotile with sham (room air) controls
• Who was studied: Male Fischer 344 rats weighing 200 to 250 g, 4 per group per time period. High-dose experiments were run in duplicate. Rats were examined after 3, 9 and 20 days of exposure, and for histology and cell division after 5 and 20 days of exposure and after 20 days of exposure plus 20 days in clean air. University of Vermont; dates not stated.
• Exposure: National Institute of Environmental Health Sciences reference samples of chrysotile asbestos. Exposure was 6 hours a day, 5 days a week, for a total of 20 days. The lower concentration was 0.18 mg/m3 air (32 fibers longer than 5 micrometers per cc). The higher concentration averaged 8.21 and 8.26 mg/m3 air in two experiments (about 2457 fibers longer than 5 micrometers per cc).
• Main results:
  • High-dose group: significant increases in polymorphonuclear leukocytes (neutrophils) in lung lavage at all time points, highest after 20 days. Total lavage cell numbers did not change at either dose.
  • Neither exposed group showed a statistically significant increase in lung hydroxyproline compared with sham controls.
  • At 20 days, two of eight high-dose rats had focal fibrotic lesions (grade 1) starting at bronchoalveolar duct junctions, involving less than 10% of units. Lungs of sham control and low-dose rats were unremarkable.
  • High-dose group: cell division (BrdU uptake) increased significantly in all compartments examined (lung tissue, bronchial and bronchiolar lining, and mesothelial cells) at 5 days, but not at 20 days or at 20 days after the 20-day exposure. No increases were seen at any time in the low-dose group.
  • High-dose group: MnSOD mRNA was significantly increased at all time periods. MnSOD was not raised in the low-dose group, and CuZnSOD was unchanged in both asbestos groups.
  • The only rise in cell-growth-related gene messages was a transient increase in GAPDH in the high-dose group at 3 days. There were no statistically significant increases in c-jun or ODC at either concentration or any time point.
  • After 5 days, the high-dose group had 5.52 plus or minus 0.6 x 10^6 fibers (longer than 5 micrometers) per lung lobe, compared with 2.3 plus or minus 0.6 x 10^4 in the low-dose group. No asbestos fibers were found in sham controls.
• The authors' conclusion: The authors concluded that the early, reversible increases in cell division reflected acute nonspecific effects of the fibers rather than causal events in the development of pulmonary fibrosis. They also wrote that the lack of effects at the lower chrysotile concentration supported other experimental data indicating dose-response relationships.
• Limitations the authors state:
  • The fibrotic lesions were focal, so increases in lung hydroxyproline may not have been detectable.
  • Gene messages were measured in whole lung homogenates, so subtle and transient changes in individual cells may have been missed.
  • Chronic studies at several concentrations would be needed to establish no-observed-adverse-effect levels for disease.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Chrysotile.

Medical terms in this study, explained in our Lexicon: Inflammation, Chrysotile, Pulmonary Fibrosis, Bronchoalveolar Lavage (BAL), Histopathology, Superoxide, Fibrosis, Bronchus.

Related studies

• Dose-responsive increases in pulmonary fibrosis after inhalation of asbestos — T.R. Quinlan, J.P. Marsh, et al. (1994)
• Comparative proliferative and histopathologic changes in rat lungs after inhalation of chrysotile or crocidolite asbestos — K.A. BéruBé, T.R. Quinlan, et al. (1996)
• Inhibition of lung injury, inflammation, and interstitial pulmonary fibrosis by polyethylene glycol-conjugated catalase in a rapid inhalation model of asbestosis — B.T. Mossman, J.P. Marsh, et al. (1990)
• Increased phosphorylated extracellular signal-regulated kinase immunoreactivity associated with proliferative and morphologic lung alterations after chrysotile asbestos inhalation in mice — R.F. Robledo, S.A. Buder-Hoffmann, et al. (2000)
• Patterns of c-fos and c-jun proto-oncogene expression, apoptosis, and proliferation in rat pleural mesothelial cells exposed to erionite or asbestos fibers — C.R. Timblin, G.D. Guthrie, et al. (1998)
• Inhalation and Oropharyngeal Aspiration Exposure to Rod-Like Carbon Nanotubes Induce Similar Airway Inflammation and Biological Responses in Mouse Lungs — P. Kinaret, M. Ilves, et al. (2017)

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