The role of the receptor for advanced glycation end-products in a murine model of silicosis

Our plain-English summary of The role of the receptor for advanced glycation end-products in a murine model of silicosis, by L. Ramsgaard, J.M. Englert, J. Tobolewski, et al (PloS One, 2010).

The study

• Authors: L. Ramsgaard, J.M. Englert, J. Tobolewski, L. Tomai, C.L. Fattman, A.S. Leme, A.M. Kaynar, S.D. Shapiro, J.J. Enghild, T.D. Oury
• Journal: PloS One
• Published: 2010;5(3):e9604
• Cited by: 37 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The role of the receptor for advanced glycation end-products (RAGE) has been shown to differ in two different mouse models of asbestos and bleomycin induced pulmonary fibrosis. RAGE knockout (KO) mice get worse fibrosis when challenged with asbestos, whereas in the bleomycin model they are largely protected against fibrosis. In the current study the role of RAGE in a mouse model of silica induced pulmonary fibrosis was investigated.

Methodology/principal Findings: Wild type (WT) and RAGE KO mice received a single intratracheal (i.t.) instillation of silica in saline or saline alone as vehicle control. Fourteen days after treatment mice were subjected to a lung mechanistic study and the lungs were lavaged and inflammatory cells, protein and TGF-beta levels in lavage fluid determined. Lungs were subsequently either fixed for histology or excised for biochemical assessment of fibrosis and determination of RAGE protein- and mRNA levels. There was no difference in the inflammatory response or degree of fibrosis (hydroxyproline levels) in the lungs between WT and RAGE KO mice after silica injury. However, histologically the fibrotic lesions in the RAGE KO mice had a more diffuse alveolar septal fibrosis compared to the nodular fibrosis in WT mice. Furthermore, RAGE KO mice had a significantly higher histologic score, a measure of affected areas of the lung, compared to WT silica treated mice. A lung mechanistic study revealed a significant decrease in lung function after silica compared to control, but no difference between WT and RAGE KO. While a dose response study showed similar degrees of fibrosis after silica treatment in the two strains, the RAGE KO mice had some differences in the inflammatory response compared to WT mice.

Conclusions/significance: Aside from the difference in the fibrotic pattern, these studies showed no indicators of RAGE having an effect on the severity of pulmonary fibrosis following silica injury.

In plain English

This mouse study concerned silica; its asbestos findings describe earlier studies. The authors compared ordinary (wild type) mice with mice lacking a protein called RAGE. Mice received one dose of silica, or salt water as a control, into the windpipe. In a separate dose study, female mice received 0.2, 1 or 5 mg of silica. Silica lowered lung RAGE protein and RAGE mRNA in wild type mice. Lung collagen (hydroxyproline), a measure of scarring (fibrosis), rose in both strains, with no significant difference between them at any dose. Under the microscope, wild type mice formed scar nodules. RAGE-lacking mice had more diffuse scarring that spread into the air-sac walls, and a significantly higher scarring score at 14 days but not at 28 days. Lung function fell in both strains, with no significant difference between them. Silica-treated RAGE-lacking mice differed somewhat from silica-treated wild type mice in inflammatory cells. At 14 days they had more protein and significantly less total TGF-beta in lung-lavage fluid. The authors concluded that, apart from the scarring pattern, nothing suggested RAGE alters the degree of fibrosis after silica.

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 comparing wild type and RAGE knockout mice given silica or saline
• Who was studied: Wild type and RAGE knockout mice (C57BL/6 background), 8 to 10 weeks old. Males were used for all experiments except the dose response study, which used females. Groups were mostly 3 to 9 mice depending on the experiment. The work was done at the University of Pittsburgh.
• Exposure: A single instillation of silica into the trachea (0.2, 1 or 5 mg per mouse in the dose study) or saline as a vehicle control. No asbestos was given in this study.
• Main results:
  • In wild type mice 14 days after silica, total RAGE protein in lung tissue fell significantly.
  • In silica-injured lungs, RAGE mRNA levels were also significantly lower.
  • Hydroxyproline (collagen) was significantly higher in silica-treated than control lungs of both strains at 14 and 21 days, with no significant difference between wild type and RAGE knockout mice.
  • Wild type mice developed nodular fibrosis. RAGE knockout mice developed nodules with more diffuse fibrosis extending into the alveolar septa.
  • The histologic score (affected lung area) was significantly higher in silica-treated RAGE knockout mice than in silica-treated wild type mice at 14 days, but not at 28 days.
  • At 14 days after silica, wild type mice had a larger increase in neutrophils, and RAGE knockout mice had more lymphocytes, in lavage fluid.
  • At 14 days after silica, RAGE knockout mice had significantly higher protein in lavage fluid than wild type mice; at 21 days there was only a trend.
  • Total TGF-beta in lavage fluid was measured 14 days after treatment. Silica-treated RAGE knockout mice had a significantly lower concentration than silica-treated wild type mice.
  • Lung function decreased after silica compared with controls, with no statistically significant difference between wild type and RAGE knockout mice.
  • In the female dose study, hydroxyproline did not differ between strains at any of the three silica doses.
• The authors' conclusion: The authors concluded that, except for the altered histologic pattern, there are no data suggesting RAGE expression alters the degree of fibrosis in this silica model.
• Limitations the authors state:
  • The knockout mice lacked RAGE throughout life, so they may have adaptive changes in other proteins.

Topics

Medical terms in this study, explained in our Lexicon: Silicosis, Pulmonary Fibrosis, Fibrosis, Histology.

Related studies

• Paradoxical function for the receptor for advanced glycation end products in mouse models of pulmonary fibrosis — J.M. Englert, C.R. Kliment, et al. (2011)
• A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis — J.M. Englert, L.E. Hanford, et al. (2008)
• The Nalp3 inflammasome is essential for the development of silicosis — S.L. Cassel, S.C. Eisenbarth, et al. (2008)
• Osteopontin modulates inflammation, mucin production, and gene expression signatures after inhalation of asbestos in a murine model of fibrosis — T. Sabo-Attwood, M.E. Ramos-Nino, et al. (2011)
• 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)
• Increased sensitivity to asbestos-induced lung injury in mice lacking extracellular superoxide dismutase — C.L. Fattman, R.J. Tan, et al. (2006)

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