A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis

Our plain-English summary of A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis, by J.M. Englert, L.E. Hanford, N. Kaminski, et al (The American Journal of Pathology, 2008).

The study

• Authors: J.M. Englert, L.E. Hanford, N. Kaminski, J.M. Tobolewski, R.J. Tan, C.L. Fattman, L. Ramsgaard, T.J. Richards, I. Loutaev, P.P. Nawroth, M. Kasper, A. Bierhaus, T.D. Oury
• Journal: The American Journal of Pathology
• Published: 2008;172(3):583-91
• Cited by: 178 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Idiopathic pulmonary fibrosis (IPF) is a severely debilitating disease associated with a dismal prognosis. There are currently no effective therapies for IPF, thus the identification of novel therapeutic targets is greatly needed. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptors whose activation has been linked to various pathologies. In healthy adult animals, RAGE is expressed at the highest levels in the lung compared to other tissues. To investigate the hypothesis that RAGE is involved in IPF pathogenesis, we have examined its expression in two mouse models of pulmonary fibrosis and in human tissue from IPF patients. In each instance we observed a depletion of membrane RAGE and its soluble (decoy) isoform, sRAGE, in fibrotic lungs. In contrast to other diseases in which RAGE signaling promotes pathology, immunohistochemical and hydroxyproline quantification studies on aged RAGE-null mice indicate that these mice spontaneously develop pulmonary fibrosis-like alterations. Furthermore, when subjected to a model of pulmonary fibrosis, RAGE-null mice developed more severe fibrosis, as measured by hydroxyproline assay and histological scoring, than wild-type controls. Combined with data from other studies on mouse models of pulmonary fibrosis and human IPF tissues indicate that loss of RAGE contributes to IPF pathogenesis.

In plain English

This laboratory study tested whether RAGE (the receptor for advanced glycation end products), a protein abundant in the lung, is involved in idiopathic pulmonary fibrosis (IPF). The authors used mice given crocidolite asbestos or bleomycin to cause lung fibrosis, mice bred to lack RAGE, and human lung tissue. In untreated mice, membrane RAGE was highest in the lung among the tissues tested. After asbestos, both forms of RAGE fell significantly by 24 hours and stayed low through 14 days. Bleomycin had a similar effect. In 13 human IPF lung samples compared with 11 control samples, RAGE was the most reduced gene transcript, with a 4.65-fold reduction. Aged, uninjured mice lacking RAGE showed increased collagen staining in 18 of 28 animals, versus 2 of 20 normal mice. They also had more lung hydroxyproline, a measure of collagen. After asbestos, mice lacking RAGE developed more severe fibrosis than normal mice, and injecting the soluble form of RAGE did not change this. The authors concluded that decreased RAGE expression contributes to pulmonary fibrosis. They noted that the loss might instead reflect loss of the lung cells that carry RAGE.

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: Laboratory study combining animal experiments (asbestos and bleomycin mouse models of pulmonary fibrosis, RAGE knockout mice) with analysis of archived human lung tissue (microarray and Western blot)
• Who was studied: C57BL/6 wild-type mice and RAGE knockout (RAGE-null) mice. Archived human lung tissue from the University of Pittsburgh: 13 IPF samples and 11 control samples (histologically normal lung resected from lung cancer patients) for microarray, plus a separate, unnumbered set of IPF and control samples for protein analysis.
• Exposure: Mice received a single dose of 0.1 mg crocidolite asbestos into the windpipe (intratracheally), or titanium dioxide as an inert particle control. Bleomycin was used as a second fibrosis model. Other exposures studied were genetic absence of RAGE, and daily intraperitoneal injections of bovine soluble RAGE (sRAGE) versus bovine serum albumin in asbestos-treated knockout mice.
• Main results:
  • In untreated wild-type mice, membrane RAGE protein was found at the highest levels in the lung compared with other tissues tested.
  • In wild-type mice given asbestos, lung membrane RAGE and soluble RAGE decreased significantly by 24 hours and remained depressed through 14 days.
  • In asbestos-treated mice, RAGE gene mRNA showed a 1.5-fold decrease after 14 days compared with mice given titanium dioxide for 24 hours.
  • In the bleomycin mouse model, membrane and soluble RAGE were also significantly depleted and remained significantly lower up to 7 days after injury.
  • In human lung samples, RAGE was the most down-regulated gene transcript in IPF lungs compared with control lungs, with a 4.65-fold reduction in IPF lungs.
  • In a separate set of human samples, membrane and soluble RAGE protein levels were reduced in fibrotic areas of IPF lungs compared with control lungs.
  • Aged RAGE knockout mice with no injury showed increased collagen type I staining in the lung in 64% (18 of 28), compared with 10% (2 of 20) of wild-type mice.
  • Right-lung hydroxyproline, a collagen measure, was significantly higher in 48-week-old RAGE knockout mice (n = 4) than in age-matched wild-type mice (n = 3).
  • No hydroxyproline differences were seen between 8- and 12-week-old knockout and wild-type mice. The authors interpreted this as suggesting the increase in fibrosis is age-related.
  • In 6-month-old mice (5 per group), average total-lung hydroxyproline was 260 per total lung in wild-type mice versus 367 per total lung in RAGE knockouts. The unit symbol is garbled in the text. The P value is printed as 0.0001, with the comparison sign lost.
  • Fourteen days after asbestos, RAGE-null mice developed more severe pulmonary fibrosis than wild-type controls. This was measured by blinded histological scoring and supported by total lung hydroxyproline.
  • In asbestos-treated RAGE knockout mice, daily soluble RAGE injections made no difference in the degree of fibrosis by hydroxyproline compared with bovine serum albumin control injections (5 per group).
• The authors' conclusion: The authors concluded that the normally high expression of membrane RAGE in the lungs plays a protective/homeostatic role, and that decreased RAGE expression contributes to the pathogenesis of pulmonary fibrosis.
• Limitations the authors state:
  • The authors noted that the loss of RAGE might reflect a loss of type I alveolar epithelial cells rather than reduced expression within those cells.
  • The authors noted that the genetic manipulation used to create knockout mice may have effects independent of losing the gene itself.

Topics

Medical terms in this study, explained in our Lexicon: Idiopathic, Pulmonary Fibrosis, Prognosis, Pathology, Fibrosis.

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)
• The role of the receptor for advanced glycation end-products in a murine model of silicosis — L. Ramsgaard, J.M. Englert, et al. (2010)
• 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)
• Relative release of interleukin-1 beta and interleukin-1 receptor antagonist by alveolar macrophages. A study in asbestos-induced lung disease, sarcoidosis, and idiopathic pulmonary fibrosis — J.N. Kline, D.A. Schwartz, et al. (1993)
• Oxidative stress alters syndecan-1 distribution in lungs with pulmonary fibrosis — C.R. Kliment, J.M. Englert, et al. (2009)
• Idiopathic pulmonary fibrosis in asbestos-exposed workers — E.A. Gaensler, P.J. Jederlinic, et al. (1991)

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