Dose-responsive increases in pulmonary fibrosis after inhalation of asbestos

Our plain-English summary of Dose-responsive increases in pulmonary fibrosis after inhalation of asbestos, by T.R. Quinlan, J.P. Marsh, Y.M. Janssen, et al (American Journal of Respiratory and Critical Care Medicine, 1994).

The study

• Authors: T.R. Quinlan, J.P. Marsh, Y.M. Janssen, K.O. Leslie, D. Hemenway, P. Vacek, B.T. Mossman
• Journal: American Journal of Respiratory and Critical Care Medicine
• Published: 1994;150(1):200-6
• Cited by: 47 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

We focused here on steady-state mRNA levels of genes involved in antioxidant defense, i.e., manganese superoxide dismutase and copper-zinc superoxide dismutase, and in cell proliferation, i.e., ornithine decarboxylase, c-jun, and glyceraldehyde-3-phosphate-dehydrogenase in whole-lung homogenates from Fischer 344 rats at 3 h to 20 d after exposure to crocridolite asbestos. Changes in gene expression were correlated with histopathologic findings, total and differential cell counts in bronchoalveolar lavage, and levels of hydroxyproline in lung. Dosage-dependent increases in mRNA levels of antioxidant enzymes and proliferation-related genes were observed. Differential cell counts revealed a dose-related infiltration of neutrophils that preceded elevations in gene expression. Neutrophil infiltration into lung and focal lesions of fibrosis as well as increased levels of hydroxyproline were observed only at high concentrations of asbestos. These results indicate that high airborne concentrations of asbestos cause molecular changes in lung that may be related to antioxidant defense and the triggering of cell proliferation, a feature of asbestosis and lung cancer.

In plain English

This was an animal experiment. Male Fischer 344 rats breathed crocidolite asbestos at one of three levels: a low concentration (about 0.1 mg per cubic meter of air, roughly 60 fibers longer than 5 micrometers per milliliter), a high concentration (7 to 10 mg per cubic meter, roughly 2,800 fibers longer than 5 micrometers per milliliter), or room air. In two experiments, rats were exposed 6 hours a day, 5 days a week, for up to 10 or 20 days, with four rats per group at each time point (three for Experiment 1 lung-washing counts). Changes were seen only in the high-concentration rats. In both experiments they had statistically significant increases at all time points in neutrophils, a type of inflammatory white blood cell, in lung washings. At 20 days they had hydroxyproline (a collagen marker) about 1.5-fold above controls, along with inflammation and focal fibrotic lesions. Messenger RNA from antioxidant and cell-proliferation genes also rose. Lungs of low-concentration rats at 20 days looked like those of unexposed rats. The authors concluded that this low-dose exposure was insufficient to produce inflammatory and fibrotic changes in rat lung.

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 (two experiments in rats, compared with sham-exposed controls)
• Who was studied: Male Fischer 344 rats weighing 200 to 250 g. The Methods state 4 rats per exposure group per time point, but the Figure 1 caption reports n = 3 for the Experiment 1 lavage differential counts. Experiment 1 examined rats at 3 hours and 1, 3, 6 and 9 days, plus a group exposed 10 days and then kept 14 days in clean air. Experiment 2 examined rats at 3, 9 and 20 days.
• Exposure: Inhaled crocidolite asbestos (National Institute of Environmental Health Sciences reference samples) at about 0.1 mg per cubic meter (about 60 fibers longer than 5 micrometers per milliliter) or 7 to 10 mg per cubic meter (about 2,800 fibers longer than 5 micrometers per milliliter), 6 hours a day, 5 days a week, for 10 days (Experiment 1) or 20 days (Experiment 2). Sham controls breathed room air.
• Main results:
  • Neither the low nor the high asbestos concentration changed total cell numbers in bronchoalveolar lavage compared with sham rats, in either experiment.
  • In both experiments, high-concentration rats had statistically significant increases in polymorphonuclear leukocytes (neutrophils) in lavage fluid at all time points.
  • Lung hydroxyproline was significantly increased at 20 days (about 1.5-fold above sham controls) in the high-concentration group. It was not increased at any time point in Experiment 1, and no changes were found at the low concentration.
  • After 20 days at the low concentration, no pleural or interstitial fibrosis was seen, and lung slides were indistinguishable from those of sham rats.
  • Rats exposed to the high concentration showed inflammation and focal fibrotic lesions at 20 days, with slight thickening of alveolar septa.
  • At the high concentration, MnSOD mRNA was significantly increased from 1 day of exposure onward. The increase ranged from 1.4-fold above sham controls at 1 day to about 5-fold, peaking at 3 days.
  • In Experiment 1, MnSOD mRNA remained elevated in rats kept 14 days in room air after exposure stopped.
  • In the high-concentration group, CuZnSOD mRNA peaked at 3 days at about two-fold above sham controls and was also significantly elevated at 9 days.
  • Changes in proliferation-related genes occurred only in the high-exposure group. ODC mRNA was significantly increased at 9 days in Experiment 1 and at 20 days in Experiment 2, about 4.4-fold above controls at 20 days. ODC was not elevated after exposure stopped.
  • c-jun mRNA was elevated at 20 days but not at day 9.
  • GAPDH mRNA was elevated as early as 3 days, with about threefold increases over sham values at 9 days.
  • In Experiment 2, MnSOD protein showed statistically significant increases of about 2.2-fold at 20 days. No increase in CuZnSOD protein was detected at 9 or 20 days.
• The authors' conclusion: The authors concluded that subchronic exposure of rat lungs to low doses of crocidolite (approximately 100-fold lower than concentrations previously examined by others) is insufficient to produce inflammatory and fibrotic changes in the lung.
• Limitations the authors state:
  • The authors observed some variation between the two experiments in the size and timing of inflammatory changes and gene expression.
  • The authors suggested that the lack of gene expression increases at 6 days may reflect that rats were not exposed over the weekend, so much of the inhaled fiber burden may have been cleared.
  • The authors noted that the very high concentrations used in their earlier rodent models (5 to 10 mg per cubic meter) exceed levels encountered in past and current occupational and environmental situations. The high dose in this study (7 to 10 mg per cubic meter) was in this range.

Topics

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

Medical terms in this study, explained in our Lexicon: Pulmonary Fibrosis, Superoxide, Bronchoalveolar Lavage (BAL), Fibrosis, Lung Cancer.

Related studies

• Patterns of inflammation, cell proliferation, and related gene expression in lung after inhalation of chrysotile asbestos — T.R. Quinlan, K.A. BéruBé, et al. (1995)
• 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)
• 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)
• Similar and Differential Canonical Pathways and Biological Processes Associated With Multiwalled Carbon Nanotube and Asbestos-Induced Pulmonary Fibrosis: A 1-Year Postexposure Study — J.M. Dymacek, B.N. Snyder-Talkington, et al. (2018)
• Comparative proliferative and histopathologic changes in rat lungs after inhalation of chrysotile or crocidolite asbestos — K.A. BéruBé, T.R. Quinlan, et al. (1996)
• Mesothelial cell proliferation: a nonspecific response to lung injury associated with fibrosis — I.Y. Adamson, J. Bakowska, et al. (1994)

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