Osteopontin modulates inflammation, mucin production, and gene expression signatures after inhalation of asbestos in a murine model of fibrosis

Our plain-English summary of Osteopontin modulates inflammation, mucin production, and gene expression signatures after inhalation of asbestos in a murine model of fibrosis, by T. Sabo-Attwood, M.E. Ramos-Nino, M. Eugenia-Ariza, et al (The American Journal of Pathology, 2011).

The study

• Authors: T. Sabo-Attwood, M.E. Ramos-Nino, M. Eugenia-Ariza, M.B. Macpherson, K.J. Butnor, P.C. Vacek, S.P. McGee, J.C. Clark, C. Steele, B.T. Mossman
• Journal: The American Journal of Pathology
• Published: 2011;178(5):1975-85
• Cited by: 52 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Inflammation and lung remodeling are hallmarks of asbestos-induced fibrosis, but the molecular mechanisms that control these events are unclear. Using laser capture microdissection (LCM) of distal bronchioles in a murine asbestos inhalation model, we show that osteopontin (OPN) is up-regulated by bronchiolar epithelial cells after chrysotile asbestos exposures. In contrast to OPN wild-type mice (OPN(+/+)) inhaling asbestos, OPN null mice (OPN(-/-)) exposed to asbestos showed less eosinophilia in bronchoalveolar lavage fluids, diminished lung inflammation, and decreased mucin production. Bronchoalveolar lavage fluid concentrations of inflammatory cytokines (IL-1β, IL-4, IL-6, IL-12 subunit p40, MIP1α, MIP1β, and eotaxin) also were significantly less in asbestos-exposed OPN(-/-) mice. Microarrays performed on lung tissues from asbestos-exposed OPN(+/+) and OPN(-/-) mice showed that OPN modulated the expression of a number of genes (Col1a2, Timp1, Tnc, Eln, and Col3a1) linked to fibrosis via initiation and cross talk between IL-1β and epidermal growth factor receptor-related signaling pathways. Novel targets of OPN identified include genes involved in cell signaling, immune system/defense, extracellular matrix remodeling, and cell cycle regulation. Although it is unclear whether the present findings are specific to chrysotile asbestos or would be observed after inhalation of other fibers in general, these results highlight new potential mechanisms and therapeutic targets for asbestosis and other diseases (asthma, smoking-related interstitial lung diseases) linked to OPN overexpression.

Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

In plain English

This animal experiment exposed male mice to chrysotile asbestos (8.5 mg/m3, 6 hours a day, 5 days a week) or clean air for 3, 9 or 40 days, with four to five mice per group. It studied osteopontin (OPN), a protein involved in immune responses and tissue remodeling. OPN gene activity in lung tissue rose over time after asbestos inhalation. In cells collected from the lining of small airways, OPN was one of 9 out of 113 genes tested that increased at 3 and/or 9 days. In a second experiment, normal mice and mice lacking the OPN gene inhaled asbestos or clean air for 9 days. Compared with normal asbestos-exposed mice, asbestos-exposed mice lacking OPN had less injury in lung wash fluid, fewer eosinophils (a type of white blood cell), less lung inflammation, less airway mucin and lower levels of several inflammatory signaling proteins. Fifty-two lung genes differed between these two groups. The authors concluded that OPN plays a multifactorial role after asbestos exposure. They said it is unclear whether the findings are specific to chrysotile.

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: mouse inhalation model comparing asbestos-exposed and clean-air mice, plus a comparison of normal (OPN wild-type) mice with mice lacking the OPN gene (OPN null)
• Who was studied: Male C57BL/6 mice, 8 to 12 weeks old, housed at the University of Vermont animal inhalation facility. There were four to five animals per group per time point (three lungs per group for microarrays). A separate experiment used age-matched male OPN wild-type and OPN null mice.
• Exposure: Inhaled chrysotile asbestos (National Institute of Environmental Health Sciences reference sample) at 8.5 mg/m3 air (figure legends state 8 mg/m3 per day), 6 hours a day, 5 days a week, for 3, 9 or 40 days. The comparison of OPN wild-type and OPN null mice used 9 days of exposure. Control mice breathed clean air.
• Main results:
  • In lung tissue of C57BL/6 mice, OPN gene activity (mRNA) increased significantly over time at 3, 9 and 40 days after chrysotile inhalation.
  • In epithelial cells microdissected from distal bronchioles (small airways), 9 out of 113 genes analyzed, including OPN and its receptor Cd44, were up-regulated at 3 days and/or 9 days after asbestos inhalation. The OPN increase was significant at 9 days and the Cd44 increase at 3 days.
  • After 9 days of asbestos, OPN null mice had less overall injury (measured by lactate dehydrogenase in lung wash fluid) than asbestos-exposed wild-type mice. They also had lower total cell numbers in lung wash fluid and significantly fewer eosinophils.
  • Asbestos-exposed OPN null mice had less severe lung inflammation on tissue scoring than asbestos-exposed wild-type mice. They also had significantly fewer distal bronchioles with mucin-positive epithelial cells.
  • Of 23 cytokines measured, 8 were significantly raised in asbestos-exposed wild-type mice compared with air-exposed controls. IL-1β, IL-4, IL-6, IL-12 subunit p40, MIP1α and MIP1β were significantly lower in asbestos-exposed OPN null mice than in asbestos-exposed wild-type mice, and eotaxin was undetectable in asbestos-exposed OPN null mice.
  • IL-5 and MCP-1 showed trends toward lower levels in asbestos-exposed OPN null mice compared with wild-type mice, but these differences were not significant.
  • Expression of 52 genes differed significantly between lungs of asbestos-exposed OPN null mice and asbestos-exposed wild-type mice. Several asbestos-induced genes the authors link to fibrosis or matrix remodeling, including Col1a2, Col3a1, Eln, Timp1 and Tnc, showed significantly less expression in OPN null mice.
• The authors' conclusion: The authors concluded that the lung epithelial cell is a major source of OPN up-regulation at the transcriptional level, and that OPN plays a multifactorial role in immune cell recruitment and remodeling after exposure to asbestos fibers.
• Limitations the authors state:
  • The authors state it is unclear whether the findings are specific to chrysotile asbestos or would occur after inhalation of other fibers. Other asbestos types and non-asbestos fibers were not examined.
  • The authors state that the role of mucin in asbestos-induced fibrogenesis remains unclear and requires further study.

Topics

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

Medical terms in this study, explained in our Lexicon: Osteopontin, Inflammation, Fibrosis, Chrysotile, Asbestos Exposure, Bronchoalveolar Lavage (BAL), Cytokine, Interstitial Lung Disease.

Related studies

• Gene expression profiles reveal increased mClca3 (Gob5) expression and mucin production in a murine model of asbestos-induced fibrogenesis — T. Sabo-Attwood, M. Ramos-Nino, et al. (2005)
• Airway epithelial NF-kappaB activation modulates asbestos-induced inflammation and mucin production in vivo — A. Haegens, T.F. Barrett, et al. (2007)
• A dual role for the immune response in a mouse model of inflammation-associated lung cancer — M. Dougan, D. Li, et al. (2011)
• 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)
• Similar tumor suppressor gene alteration profiles in asbestos-induced murine and human mesothelioma — C. Lecomte, P. Andujar, et al. (2005)
• Important functional role of the protein osteopontin in the progression of malignant pleural mesothelioma — E. Digifico, M. Erreni, et al. (2023)

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