Inhibition of lung injury, inflammation, and interstitial pulmonary fibrosis by polyethylene glycol-conjugated catalase in a rapid inhalation model of asbestosis

Our plain-English summary of Inhibition of lung injury, inflammation, and interstitial pulmonary fibrosis by polyethylene glycol-conjugated catalase in a rapid inhalation model of asbestosis, by B.T. Mossman, J.P. Marsh, A. Sesko, et al (The American Review of Respiratory Disease, 1990).

The study

• Authors: B.T. Mossman, J.P. Marsh, A. Sesko, S. Hill, M.A. Shatos, J. Doherty, J. Petruska, K.B. Adler, D. Hemenway, R. Mickey
• Journal: The American Review of Respiratory Disease
• Published: 1990;141(5 Pt 1):1266-71
• Cited by: 148 articles, as counted by NIH iCite
• Read it: PubMed · Publisher
• In J-M's library: Johns-Manville's company medical library held a copy (J-M no. 004181).

Abstract

Several in vitro studies suggest the involvement of active oxygen metabolites in cell damage caused by asbestos. To determine if lung injury, inflammation, and asbestosis could be inhibited in vivo in a rapid-onset, inhalation model of disease, a novel method of chronic administration of antioxidant enzymes was developed. In brief, Fischer 344 rats were treated with polyethylene glycol-conjugated (PEG-) superoxide dismutase or catalase in osmotic pumps over a 10-day (5 days/wk for 2 wk) or 20-day (5 days/wk for 2 wk) period of exposure to crocidolite asbestos. Control rats included sham-exposed animals and those exposed to asbestos but receiving chemically inactivated enzymes. After 10 days of exposure to asbestos, lactic dehydrogenase (LDH), alkaline phosphatase, and total protein in bronchoalveolar lavage (BAL) were measured in one group of rats. Total and differnetial cell counts in BAL also were assessed. After 20 days of exposure, lungs of an additional group of rats were evaluated by histopathology and by measurement of hydroxyproline. Asbestos-associated elevations in LDH, protein, and total cell numbers in BAL were reduced in rats receiving PEG-catalase. Decreases in numbers of alveolar macrophages, polymorphonuclear leukocytes, and lymphocytes occurred in these animals. Exposure to asbestos for 20 days caused significant increases in both the amount of hydroxyproline in lung and the severity and extent of fibrotic lesions as determined by histopathology. These indicators of asbestosis were inhibited in a dosage-dependent fashion in rats receiving PEG-catalase. Use of inactivated PEG-catalase failed to boost serum levels of catalase and did not inhibit asbestos-induced elevation of hydroxyproline in lung.(ABSTRACT TRUNCATED AT 250 WORDS)

In plain English

This animal experiment had male Fischer 344 rats inhale crocidolite asbestos (10 mg per cubic metre, 6 hours daily, 5 days weekly) for 10 or 20 days. Controls included clean-air rats and asbestos-exposed rats given saline or inactivated enzymes. Pumps under the skin delivered polyethylene glycol-linked antioxidant enzymes: PEG-superoxide dismutase (PEG-SOD) or PEG-catalase. In asbestos-exposed rats, lung-washing markers of cell injury and inflammation rose at 10 days. Lung hydroxyproline (a collagen marker) and fibrosis grades rose at 20 days. With PEG-catalase, total cells in lung washings fell as dose rose, and the cell-damage enzyme LDH was lower at all doses. Fibrosis grades also fell with dose. In the three-dose experiment, hydroxyproline was significantly lower only at the highest dose; an earlier single-dose experiment also found it lower. Alkaline phosphatase stayed raised at all but the highest dose; the protein effect was not statistically significant. PEG-SOD was not effective, and inactivated PEG-catalase did not lower hydroxyproline. The authors concluded that the results confirm the importance of active oxygen species in asbestos-associated lung injury and suggest a possible future therapeutic approach to clinical asbestosis.

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: a rapid-onset inhalation model of asbestosis in rats, testing antioxidant enzymes delivered continuously by implanted osmotic pumps
• Who was studied: Male Fischer 344 rats weighing 200 to 250 g, 4 per time point per experiment, with each experiment done in duplicate or triplicate. Controls included sham-exposed (clean-air) rats and asbestos-exposed rats given saline (PBS) or chemically inactivated enzymes. Location and dates of the experiments are not stated, apart from the authors' affiliations (University of Vermont; Georgetown University).
• Exposure: Inhalation of NIEHS crocidolite asbestos at a time-weighted average of 10 mg per cubic metre of air, 6 hours a day, 5 days a week, for 10 or 20 days. Sham rats breathed clean air. Treatments were delivered by subcutaneous osmotic pumps: saline (PBS), PEG-SOD (4,130 IU/day), PEG-catalase (5,585 IU/day, then 8 x 10^2, 4 x 10^3 and 8 x 10^3 IU/day), and chemically inactivated PEG-catalase (8 x 10^3 IU/day).
• Main results:
  • In asbestos-exposed rats at 10 days, LDH, alkaline phosphatase, protein and total cell numbers in lung washings (BAL) rose. In control rats more than 98% of BAL cells were alveolar macrophages. In asbestos-exposed rats, polymorphonuclear leukocytes and lymphocytes made up about 25% and 5% of cells.
  • In the first series, PEG-catalase (5,585 IU/day) significantly reduced total lung hydroxyproline in asbestos-exposed rats after 20 days, compared with asbestos plus saline (999 ± 78 vs 1,275 ± 129, p less than 0.005; n = 4 per group). It also reduced total BAL cells (p less than 0.001) and the percentage of polymorphonuclear leukocytes.
  • PEG-SOD did not reduce asbestos-associated cell injury, inflammation or fibrosis.
  • In the dose-response studies, the asbestos-induced rise in LDH in BAL was inhibited (p less than 0.001) at all three PEG-catalase doses.
  • Alkaline phosphatase was increased in the BAL of PEG-catalase-treated rats at all but the highest dose tested. The authors referred to a lack of inhibition of alkaline phosphatase or total protein by PEG-catalase.
  • Total protein in BAL appeared lower in asbestos-exposed rats given PEG-catalase, but the changes were neither dose-dependent nor statistically significant.
  • Total BAL cell counts fell significantly with increasing PEG-catalase dose. At the highest dose (8 x 10^3 IU/day), alveolar macrophages (p less than 0.01), polymorphonuclear leukocytes (p less than 0.001) and lymphocytes (p less than 0.001) decreased. Each cell type showed a significant linear decrease with dose (p less than 0.01).
  • In the dose-response studies at 20 days, the asbestos-induced rise in lung hydroxyproline was inhibited (p less than 0.05) in rats receiving the highest PEG-catalase dose.
  • On histopathology, the development of fibrotic lesions was inhibited in a dose-dependent fashion in asbestos-exposed rats treated with PEG-catalase. The scrambled Table 1 lists mean scores of 0.19 ± 0.12 (no asbestos) and 2.42 ± 0.58 (asbestos). It lists 1.63 ± 0.32, 0.94 ± 0.17 and 1.03 ± 0.17 for the three increasing doses (n = 8 per group; significant linear trend, p less than 0.01). These group assignments follow the order in which the scores appear in the table.
  • In a specificity experiment, asbestos significantly increased lung hydroxyproline (p less than 0.01). Active PEG-catalase reduced it (p less than 0.02), but chemically inactivated PEG-catalase did not.
  • In rats receiving PEG-catalase, serum catalase rose with dose at the start of exposure and at 10 days. It was not raised in any PEG-catalase group after 20 days of exposure.
• The authors' conclusion: The authors concluded that the results confirm the importance of active oxygen species in asbestos-associated lung injury and suggest the possible future use of a therapeutic approach to clinical asbestosis.
• Limitations the authors state:
  • The pump method of giving the enzymes does not target the lung specifically.
  • Circulating catalase levels fell back to control levels by Day 20 of exposure.

Topics

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

Medical terms in this study, explained in our Lexicon: Inflammation, Interstitial, Pulmonary Fibrosis, Superoxide, Crocidolite, Bronchoalveolar Lavage (BAL), Histopathology, Alveolar Macrophage.

Related studies

• Approaches to prevention of asbestos-induced lung disease using polyethylene glycol (PEG)-conjugated catalase — B.T. Mossman, J.P. Marsh, et al. (1986)
• Development and characterization of a rapid-onset rodent inhalation model of asbestosis for disease prevention — B.T. Mossman, Y.M. Janssen, et al. (1991)
• Dose-responsive increases in pulmonary fibrosis after inhalation of asbestos — T.R. Quinlan, J.P. Marsh, et al. (1994)
• 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)
• Polyethylene glycol-superoxide dismutase, a conjugate in search of exploitation — F.M. Veronese, P. Caliceti, et al. (2002)
• 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)

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