Emphysema Requires the Receptor for Advanced Glycation End-Products Triggering on Structural Cells

Waseda, Koichi; Miyahara, Nobuaki; Taniguchi, Akihiko; Kurimoto, Etsuko; Ikeda, Genyo; Koga, Hikari; Fujii, Utako; Yamamoto, Yasuhiko; Gelfand, Erwin W.; Yamamoto, Hiroshi; Tanimoto, Mitsune; Kanehiro, Arihiko

doi:10.1165/rcmb.2014-0027oc

Cited by 32 publications

(25 citation statements)

References 52 publications

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“…This may be because R was lower at baseline for the Ager -/- mice, thus requiring less methacholine to double the resistance. Inherent phenotypic variations between WT and Ager-/- mice have been observed elsewhere [ 34 , 112 ]. We observed baseline differences in MLI between WT-PBS and Ager -/— PBS.…”

Section: Discussionmentioning

confidence: 97%

Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: A case-cohort study and murine model of acute particulate exposure

Caraher¹,

Kwon²,

Haider³

et al. 2017

PLoS ONE

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World Trade Center-particulate matter(WTC-PM) exposure and metabolic-risk are associated with WTC-Lung Injury(WTC-LI). The receptor for advanced glycation end-products (RAGE) is most highly expressed in the lung, mediates metabolic risk, and single-nucleotide polymorphisms at the AGER-locus predict forced expiratory volume(FEV). Our objectives were to test the hypotheses that RAGE is a biomarker of WTC-LI in the FDNY-cohort and that loss of RAGE in a murine model would protect against acute PM-induced lung disease. We know from previous work that early intense exposure at the time of the WTC collapse was most predictive of WTC-LI therefore we utilized a murine model of intense acute PM-exposure to determine if loss of RAGE is protective and to identify signaling/cytokine intermediates. This study builds on a continuing effort to identify serum biomarkers that predict the development of WTC-LI. A case-cohort design was used to analyze a focused cohort of male never-smokers with normal pre-9/11 lung function. Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with soluble RAGE (sRAGE)≥97pg/mL, CRP≥2.4mg/L, and MMP-9≤397ng/mL, respectively, assessed in a multivariate logistic regression model (ROCAUC of 0.72). Wild type(WT) and RAGE-deficient(Ager-/-) mice were exposed to PM or PBS-control by oropharyngeal aspiration. Lung function, airway hyperreactivity, bronchoalveolar lavage, histology, transcription factors and plasma/BAL cytokines were quantified. WT-PM mice had decreased FEV and compliance, and increased airway resistance and methacholine reactivity after 24-hours. Decreased IFN-γ and increased LPA were observed in WT-PM mice; similar findings have been reported for firefighters who eventually develop WTC-LI. In the murine model, lack of RAGE was protective from loss of lung function and airway hyperreactivity and was associated with modulation of MAP kinases. We conclude that in a multivariate adjusted model increased sRAGE is associated with WTC-LI. In our murine model, absence of RAGE mitigated acute deleterious effects of PM and may be a biologically plausible mediator of PM-related lung disease.

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Section: Discussionmentioning

confidence: 97%

Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: A case-cohort study and murine model of acute particulate exposure

Caraher¹,

Kwon²,

Haider³

et al. 2017

PLoS ONE

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show abstract

“…Alternatively, it is possible that the same functional variant (potentially rs2060700) influences sRAGE protein levels and disease susceptibility by different mechanisms. Nonetheless, as noted above, murine studies with conditional over-expressed RAGE result in increased emphysema, suggesting increased RAGE signaling is detrimental, not protective, while administration of sRAGE is generally protective, and RAGE (-/-) mice are protected from emphysema (52). In addition, a second genetic variant -429T/C (rs1800625) (53) that is associated with increased lung disease severity in cystic fibrosis has also been studied in vitro, and the minor allele is associated with increased RAGE expression and promoter activity.…”

Section: Genetics Of Ager In Pulmonary Function Copd and Emphysemamentioning

confidence: 89%

Circulating Soluble Receptor for Advanced Glycation End Products (sRAGE) as a Biomarker of Emphysema and the RAGE Axis in the Lung

Yonchuk

Silverman

Bowler

et al. 2015

Am J Respir Crit Care Med

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Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous disease that has been traditionally characterized by incompletely reversible airflow limitation. Yet, the latter is poorly correlated with many other clinically relevant characteristics of the disease. Thus, the identification of biomarkers to more accurately assess this heterogeneity and disease severity may facilitate the discovery and development of new treatments and better management of patients with COPD. One molecule that has attracted attention as a potentially useful biomarker specifically for the emphysema subpopulation is the soluble receptor for advanced glycation end products (sRAGE). As the soluble isoform of a key proinflammatory signaling receptor, sRAGE acts as a "decoy" for RAGE ligands and prevents their interaction with the receptor. Multiple reports have now linked sRAGE to COPD, and more specifically to emphysema, and evidence is accumulating that this link is likely mechanistic in nature. Here we review the current state of knowledge about sRAGE biology, the mechanistic links to COPD, and the evidence for using it as a biomarker for emphysema. We also discuss sRAGE as a potential target for therapeutic intervention in COPD.

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“…This has also been found by Waseda et al, who analyzed RAGE-dependent lung damage in a murine COPD elastase model. Intratracheal instillation of elastase resulted in a significantly increase of static lung compliance in WT mice, whereas no effect could be observed in RAGE -/- mice [22]. In another CS-exposure study, structural changes of lung parenchyma were only detected in WT mice.…”

Section: Discussionmentioning

confidence: 99%

“…These studies also demonstrated a stronger staining intensity for RAGE in pulmonary tissue [20, 21], which was associated with a decline of FEV 1 [20]. In an elastase-induced emphysema-model, RAGE knockout mice were partly protected from structural lung changes and this effect was mainly attributed to the absence of RAGE in lung structural cells [22]. Mice exposed to acute secondhand smoke showed an increase in pulmonary RAGE protein expression [23].…”

Section: Introductionmentioning

confidence: 99%

Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke

et al. 2017

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The receptor for advanced glycation endproducts (RAGE) is highly expressed in the lung but its physiological functions in this organ is still not completely understood. To determine the contribution of RAGE to physiological functions of the lung, we analyzed pulmonary mechanics and structure of wildtype and RAGE deficient (RAGE-/-) mice. RAGE deficiency spontaneously resulted in a loss of lung structure shown by an increased mean chord length, increased respiratory system compliance, decreased respiratory system elastance and increased concentrations of serum protein albumin in bronchoalveolar lavage fluids. Pulmonary expression of RAGE was mainly localized on alveolar epithelial cells and alveolar macrophages. Primary murine alveolar epithelial cells isolated from RAGE-/- mice revealed an altered differentiation and defective barrier formation under in vitro conditions. Stimulation of interferone-y (IFNy)-activated alveolar macrophages deficient for RAGE with Toll-like receptor (TLR) ligands resulted in significantly decreased release of proinflammatory cytokines and chemokines. Exposure to chronic cigarette smoke did not affect emphysema-like changes in lung parenchyma in RAGE-/- mice. Acute cigarette smoke exposure revealed a modified inflammatory response in RAGE-/- mice that was characterized by an influx of macrophages and a decreased keratinocyte-derived chemokine (KC) release. Our data suggest that RAGE regulates the differentiation of alveolar epithelial cells and impacts on the development and maintenance of pulmonary structure. In cigarette smoke-induced lung pathology, RAGE mediates inflammation that contributes to lung damage.

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Emphysema Requires the Receptor for Advanced Glycation End-Products Triggering on Structural Cells

Cited by 32 publications

References 52 publications

Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: A case-cohort study and murine model of acute particulate exposure

Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: A case-cohort study and murine model of acute particulate exposure

Circulating Soluble Receptor for Advanced Glycation End Products (sRAGE) as a Biomarker of Emphysema and the RAGE Axis in the Lung

Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke

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