Paradoxical function for the receptor for advanced glycation end products in mouse models of pulmonary fibrosis

Our plain-English summary of Paradoxical function for the receptor for advanced glycation end products in mouse models of pulmonary fibrosis, by J.M. Englert, C.R. Kliment, L. Ramsgaard, et al (International Journal of Clinical and Experimental Pathology, 2011).

The study

• Authors: J.M. Englert, C.R. Kliment, L. Ramsgaard, P.S. Milutinovic, L. Crum, J.M. Tobolewski, T.D. Oury
• Journal: International Journal of Clinical and Experimental Pathology
• Published: 2011;4(3):241-54
• Cited by: 45 articles, as counted by NIH iCite
• Read it: PubMed · Free full text

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor survival. The identification of therapeutic targets is essential to improving outcomes. Previous studies found that expression of the receptor for advanced glycation end products (RAGE) in the lung is significantly decreased in human IPF lungs and in two animal models of pulmonary fibrosis. In addition, RAGE-null mice spontaneously develop pulmonary fibrosis with age and more severe fibrosis when challenged with asbestos. In contrast to the findings that the lack of RAGE enhanced pulmonary fibrosis, He et al. found that RAGE null mice were protected from bleomycin-induced fibrosis and suggested the effect was due to a lack of HMGB1 induced RAGE signaling. The current study further tests this hypothesis by blocking RAGE signaling via administration of soluble RAGE, a decoy receptor, to determine if this will also protect against pulmonary fibrosis. Wild-type, RAGE(+/-), and RAGE(-/-) mice were treated with bleomycin and assessed for fibrosis. Wild-type mice were also treated with exogenous soluble RAGE or vehicle control. In addition, in vitro studies with primary alveolar epithelial cells from wild-type and RAGE null mice were used to investigate the effect of RAGE on cell viability and migration in response to injury. A lack of RAGE was found to be protective against bleomycin injury in both in vivo and in vitro studies. However, soluble RAGE administration was unable to ameliorate fibrosis. This study confirms paradoxical responses to two different models of pulmonary fibrosis and suggests a further role for RAGE in cellular migration.

In plain English

This was a laboratory study, in mice and mouse lung cells, of a lung protein called RAGE. The authors noted that earlier studies had reported that mice lacking RAGE developed more lung scarring (fibrosis) after asbestos but were protected after the drug bleomycin. In this study, normal mice and mice lacking all or half of their RAGE were given bleomycin into the windpipe. Both groups lacking RAGE had significantly less fibrosis than normal mice. Normal mice were also given 0.04 units of bleomycin or 100 µg of crocidolite asbestos, plus daily injections of soluble RAGE (a decoy form of the protein) or a control protein, starting three days before injury. Asbestos significantly increased fibrosis, but soluble RAGE made no difference in either model. In cell experiments, cells with and without RAGE died equally from asbestos or bleomycin. Cells lacking RAGE healed a scratch wound better after bleomycin. After asbestos, healing was equally impaired in both cell types. The authors concluded that soluble RAGE may not be an effective treatment approach. They noted that knockout animals can have unintended changes in other genes.

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 (mice) with in vitro experiments on primary mouse alveolar epithelial cells
• Who was studied: Eight-week-old male C57BL/6 (wild-type), RAGE heterozygote and RAGE null mice, studied at the University of Pittsburgh. Groups were generally 3 to 7 mice; the asbestos experiment used 6 mice per group. Primary alveolar epithelial cells came from 6 to 7 week old female C57BL/6 and RAGE null mice. Study dates were not stated.
• Exposure: In the mouse experiments, a single dose was placed into the windpipe: either 0.04 units of bleomycin (saline as control) or 100 µg of crocidolite asbestos (titanium dioxide as inert particle control). Some mice also received daily abdominal injections of 50 µg of bovine soluble RAGE or bovine serum albumin. These injections started 3 days before the injury and continued every 24 hours until the end of the experiment. In the cell experiments, bleomycin, crocidolite asbestos (20 µg/mL in the wound assay, 0 to 100 µg/mL in the viability assay) and soluble RAGE at 25 µg/mL were used.
• Main results:
  • In RAGE null mice given bleomycin, fibrosis was significantly less than in wild-type mice, at both 14 and 21 days.
  • In RAGE heterozygote mice given bleomycin, fibrosis was significantly less than in wild-type mice at 14 days. Lavage fluid protein and cell counts did not differ between the two groups.
  • In wild-type mice given bleomycin, lung hydroxyproline (a measure of fibrosis) did not differ between the soluble RAGE and control-protein groups.
  • In wild-type mice, crocidolite asbestos significantly increased fibrosis, but there was no difference between the soluble RAGE and control-protein groups.
  • Alveolar epithelial cells from wild-type and RAGE null mice were equally susceptible to being killed by bleomycin or asbestos in culture.
  • In the scratch wound assay, RAGE null cells healed significantly better than wild-type cells after bleomycin.
  • In the scratch wound assay with asbestos, healing was equally impaired in wild-type and RAGE null cells.
  • Levels of bleomycin hydrolase, an enzyme that breaks down bleomycin, did not differ between the lungs of wild-type and RAGE null mice.
• The authors' conclusion: The authors concluded that soluble RAGE treatment had no effect on the harmful effects of bleomycin or asbestos, in mice or in cells, and may not be an effective therapeutic approach. They also concluded that lacking membrane RAGE appears to improve the ability of alveolar epithelial cells to migrate and repair after bleomycin injury, but not after asbestos injury.
• Limitations the authors state:
  • The authors stated that studies in knockout animals can be confounded, because deleting a gene before birth can cause unintended changes in other genes or compensatory changes in the animals.

Topics

Medical terms in this study, explained in our Lexicon: Pulmonary Fibrosis, Idiopathic, Fibrosis, High Mobility Group Box 1 (HMGB1).

Related studies

• A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis — J.M. Englert, L.E. Hanford, et al. (2008)
• The role of the receptor for advanced glycation end-products in a murine model of silicosis — L. Ramsgaard, J.M. Englert, et al. (2010)
• Oxidative stress alters syndecan-1 distribution in lungs with pulmonary fibrosis — C.R. Kliment, J.M. Englert, et al. (2009)
• Mitochondrial biogenesis in the pulmonary vasculature during inhalational lung injury and fibrosis — M.S. Carraway, H.B. Suliman, et al. (2008)
• A novel method for accurate collagen and biochemical assessment of pulmonary tissue utilizing one animal — C.R. Kliment, J.M. Englert, et al. (2011)
• Alternative activation of macrophages and pulmonary fibrosis are modulated by scavenger receptor, macrophage receptor with collagenous structure — S. Murthy, J.L. Larson-Casey, et al. (2015)

Browse return to medical research.