Decreased asbestos-induced lung inflammation and fibrosis after radiation and bone marrow transplant

Our plain-English summary of Decreased asbestos-induced lung inflammation and fibrosis after radiation and bone marrow transplant, by J. Levis, R. Loi, K.J. Butnor, et al (American Journal of Respiratory Cell and Molecular Biology, 2008).

The study

• Authors: J. Levis, R. Loi, K.J. Butnor, P. Vacek, C. Steele, B.T. Mossman, D.J. Weiss
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2008;38(1):16-25
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The effect of lung irradiation on subsequent inflammatory or fibrotic lung injuries remains poorly understood. We postulated that irradiation and bone marrow transplantation might impact the development and progression of lung remodeling resulting from asbestos inhalation. Our objective was to determine whether irradiation and bone marrow transplantation affected inflammation and fibrosis associated with inhaled asbestos exposure. Inflammation, cytokine production, and fibrosis were assessed in lungs of naïve and sex-mismatched chimeric mice exposed to asbestos for 3, 9, or 40 days. Potential engraftment of donor-derived cells in recipient lungs was examined by fluorescence in situ hybridization and immunohistochemistry. Compared with asbestos-exposed naïve (nonchimeric) mice, chimeric mice exposed to asbestos for 3, 9, or 40 days demonstrated significant abrogation of acute increases in asbestos-associated inflammatory mediators and fibrosis. Donor-derived cells trafficked to lung but did not significantly engraft as phenotypic lung cells. Irradiation and bone marrow transplantation alters inflammatory and fibrotic responses to asbestos, likely through modulation of soluble inflammatory mediators.

In plain English

In this mouse experiment, female C57Bl/6 mice received a single 1,000 cGy dose of total body radiation and then bone marrow from male mice ("chimeric" mice). Untreated ("naive") mice served for comparison. Both groups breathed chrysotile asbestos at approximately 7 mg/m3, or clean air, for 6 hours a day, 5 days a week, over periods of 3, 9 or 40 days. Compared with asbestos-exposed naive mice, asbestos-exposed chimeric mice had lower percentages of eosinophils in lung washings at 3 days, and of lymphocytes, eosinophils and neutrophils at 9 days. They also had smaller rises in several inflammatory signalling proteins at 9 days, although some proteins were higher in them at 40 days. At 40 days, fibrosis averaged 2.9 on a 1-to-4 scale, affecting 65.6% of bronchioles, in asbestos-exposed naive mice (8 mice). In asbestos-exposed chimeric mice (5 mice) the figures were 1.8 and 27.0%. The authors concluded that radiation plus transplant altered the lungs' response to asbestos. They thought this more likely reflected changes in inflammatory and immune responses than donor marrow cells becoming lung cells. They could not include mice given radiation without a transplant.

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 in mice comparing chimeric mice (myeloablative total body irradiation, 1,000 cGy in a single dose, followed by bone marrow transplant) with naive mice in an asbestos inhalation model
• Who was studied: Adult (8 to 12 weeks old) female C57Bl/6 mice at the University of Vermont. Sex-mismatched chimeric mice (given marrow from male GFP transgenic mice) and naive female controls. The figure legend gives 5 to 10 mice per group at each time point.
• Exposure: Inhaled chrysotile asbestos (NIEHS reference sample) at approximately 7 mg/m3 air, or clean air (sham). Exposures ran 6 hours a day, 5 days a week, over periods of 3, 9 or 40 days. Chimeric mice had earlier received total body irradiation (1,000 cGy) and a bone marrow transplant.
• Main results:
  • 14 days after transplant, an average of 87% of blood white cells in the chimeric mice were of donor origin
  • In lung lavage fluid, percentages of lymphocytes, eosinophils and neutrophils were lower in asbestos-exposed chimeric mice than in asbestos-exposed naive mice at 9 days, and eosinophils were also lower at 3 days (p less than 0.05)
  • At 9 days, the rise in IL-4, IL-5, IL-12p70, MIP-1 beta and MCP-1 in asbestos-exposed chimeric mice was significantly smaller than in asbestos-exposed naive mice
  • At 40 days, IL-1 beta, G-CSF and KC were increased in asbestos-exposed chimeric mice but not in asbestos-exposed naive mice
  • Active (acidic) TGF-beta1 was significantly decreased in asbestos-exposed chimeric mice at 9 days, but this decrease was not seen at 40 days
  • At 40 days, asbestos-exposed naive mice (8 mice) had an average fibrosis severity of 2.9 on a scale from 1 (no fibrosis) to 4 (severe fibrosis), with 65.6% of bronchioles affected. Sham naive mice scored 1.0 with 0% affected.
  • At 40 days, asbestos-exposed chimeric mice (5 mice) had an average fibrosis severity of 1.8 with 27.0% of bronchioles affected. This was significantly different from both sham chimeric mice and asbestos-exposed naive mice (p less than 0.05).
  • Neither sham group showed increased peribronchiolar fibrosis or inflammation. The authors took this to suggest that myeloablation and transplant alone did not cause the lung injury or fibrosis in this model.
  • Most donor-derived (Y chromosome-positive) cells found in chimeric mouse lungs stained for CD45, suggesting they were white blood cells
  • Donor-derived cells that were CD45-negative averaged 7.6 to 10% in lungs of sham chimeric mice and 10.8 to 16.3% in lungs of asbestos-exposed chimeric mice
• The authors' conclusion: The authors concluded that myeloablative irradiation followed by bone marrow transplant altered inflammatory and fibrotic lung injury from subsequent chrysotile inhalation. In their view, this was less likely due to marrow-derived cells becoming epithelial or interstitial lung cells, and may instead reflect altered lung inflammatory and immune responses after irradiation and transplantation.
• Limitations the authors state:
  • A group of mice irradiated but not transplanted could not be included, because the radiation dose required marrow rescue
  • Alveolar macrophages may take up to 3 months to fully turn over after irradiation and transplant, longer than the 30-day engraftment period used
  • The mechanisms behind the observed effects are unclear
  • The donor-derived interstitial cells need further characterization of their identity and origin

Topics

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

Medical terms in this study, explained in our Lexicon: Inflammation, Fibrosis, Asbestos Exposure, Cytokine, Fluorescence In Situ Hybridization (FISH), Immunohistochemistry.

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