Role of Soluble Receptor for Advanced Glycation End Products on Endotoxin-induced Lung Injury

Zhang, Haiying; Tasaka, Sadatomo; Shiraishi, Yuichi; Fukunaga, Koichi; Yamada, Wakako; Seki, Hiroyuki; Ogawa, Yuko; Miyamoto, Keisuke; Nakano, Yukiko; Hasegawa, Naoki; Miyasho, Taku; Maruyama, Ikuro; Ishizaka, Akitoshi

doi:10.1164/rccm.200707-1069oc

Cited by 122 publications

(108 citation statements)

References 41 publications

(46 reference statements)

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“…Similar findings of the effect of RAGE blockade have been observed in hepatic ischemia reperfusion models (33,34). Furthermore, administration of sRAGE attenuated lung injury in a murine model of LPS-induced lung injury suggesting a role for RAGE ligands in the augmentation of lung injury that is blocked by sRAGE (35). These data suggest a role for RAGE ligands in the augmentation of lung injury and should provide an impetus for further research into the relationship between RAGE, RAGE ligands, and the initiation and perpetuation of transplant-associated lung injury.…”

Section: Discussionsupporting

confidence: 78%

Plasma Levels of Receptor for Advanced Glycation End Products, Blood Transfusion, and Risk of Primary Graft Dysfunction

Christie¹,

Shah²,

Kawut³

et al. 2009

Am J Respir Crit Care Med

121

106

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Rationale:The receptor for advanced glycation end products (RAGE) is an important marker of lung epithelial injury and may be associated with impaired alveolar fluid clearance. We hypothesized that patients with primary graft dysfunction (PGD) after lung transplantation would have higher RAGE levels in plasma than patients without PGD. Objectives: To test the association of soluble RAGE (sRAGE) levels with PGD in a prospective, multicenter cohort study. Methods: We measured plasma levels of sRAGE at 6 and 24 hours after allograft reperfusion in 317 lung transplant recipients at seven centers. The primary outcome was grade 3 PGD (Pa O 2 /FI O 2 , 200 with alveolar infiltrates) within the first 72 hours after transplantation. Measurements and Main Results: Patients who developed PGD had higher levels of sRAGE than patients without PGD at both 6 hours (median 9.3 ng/ml vs. 7.5 ng/ml, respectively; P 5 0.028) and at 24 hours post-transplantation (median 4.3 ng/ml vs. 1.9 ng/ml, respectively; P , 0.001). Multivariable logistic regression analyses indicated that the relationship between levels of sRAGE and PGD was attenuated by elevated right heart pressures and by the use of cardiopulmonary bypass. Median sRAGE levels were higher in subjects with cardiopulmonary bypass at both 6 hours (P 5 0.003) and 24 hours (P , 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearman's r 5 0.39, P 5 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P 5 0.02). Conclusions: Elevated plasma levels of sRAGE are associated with PGD after lung transplantation. Furthermore, plasma sRAGE levels are associated with blood product transfusion and use of cardiopulmonary bypass.

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Section: Discussionsupporting

confidence: 78%

Plasma Levels of Receptor for Advanced Glycation End Products, Blood Transfusion, and Risk of Primary Graft Dysfunction

Christie¹,

Shah²,

Kawut³

et al. 2009

Am J Respir Crit Care Med

121

106

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“…This study has also shown that sRAGE, a truncated soluble form carrying extracellular ligand-binding domain of RAGE, has protective effects against LPS-induced septic shock in mice. Previous studies using sRAGE demonstrated its beneficial effects on RAGEassociated diseases such as atherosclerosis and inflammation (20,40,41). The treatment with sRAGE reduced the LPS induction of TNF-a and IL-6 and of liver and lung damages and significantly improved survival rate (Fig.…”

Section: Discussionmentioning

confidence: 75%

Septic Shock Is Associated with Receptor for Advanced Glycation End Products Ligation of LPS

Yamamoto

Harashima

Saito

et al. 2011

The Journal of Immunology

173

153

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Septic shock is a severe systemic response to bacterial infection. Receptor for advanced glycation end products (RAGE) plays a role in immune reactions to recognize specific molecular patterns as pathogen recognition receptors. However, the interaction between LPS, the bioactive component of bacterial cell walls, and RAGE is unclear. In this study, we found direct LPS binding to RAGE by a surface plasmon resonance assay, a plate competition assay, and flow cytometry. LPS increased TNF-α secretion from peritoneal macrophages and an NF-κB promoter-driven luciferase activity through RAGE. Blood neutrophils and monocytes expressed RAGE, and TLR2 was counterregulated in RAGE−/− mice. After LPS injection, RAGE+/+ mice showed a higher mortality, higher serum levels of IL-6, TNF-α, high mobility group box 1, and endothelin-1, and severe lung and liver pathologies compared with RAGE−/− mice without significant differences in plasma LPS level. Administration of soluble RAGE significantly reduced the LPS-induced cytokine release and tissue damage and improved the LPS-induced lethality even in RAGE−/− as well as RAGE+/+ mice. The results thus suggest that RAGE can associate with LPS and that RAGE system can regulate inflammatory responses. Soluble RAGE would be a therapeutic tool for LPS-induced septic shock.

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“…RAGE expressed on bone marrow-derived cells (e.g., monocyte/macrophages) specifically contributes to atherosclerosis, as transplantation of Ager null/Apoe null bone marrow into Apoe null mice results in markedly reduced atherosclerosis compared with those receiving bone marrow from Ager-positive Apoe null mice (47). Administration of sRAGE markedly decreases atherosclerosis and oxidative injury in animal models (11,41,68,71,72). Thus, activation of RAGE by IsoLG-PE could plausibly contribute to the development of atherosclerosis and liver disease associated with hypercholesterolemia or obesity.…”

Section: Discussionmentioning

confidence: 99%

Isolevuglandin-Type Lipid Aldehydes Induce the Inflammatory Response of Macrophages by Modifying Phosphatidylethanolamines and Activating the Receptor for Advanced Glycation Endproducts

Guo

Chen

Amarnath

et al. 2015

Antioxidants & Redox Signaling

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Aims: Increased lipid peroxidation occurs in many conditions associated with inflammation. Because lipid peroxidation produces lipid aldehydes that can induce inflammatory responses through unknown mechanisms, elucidating these mechanisms may lead to development of better treatments for inflammatory diseases. We recently demonstrated that exposure of cultured cells to lipid aldehydes such as isolevuglandins (IsoLG) results in the modification of phosphatidylethanolamine (PE). We therefore sought to determine (i) whether PE modification by isolevuglandins (IsoLG-PE) occurred in vivo, (ii) whether IsoLG-PE stimulated the inflammatory responses of macrophages, and (iii) the identity of receptors mediating the inflammatory effects of IsoLG-PE. Results: IsoLG-PE levels were elevated in plasma of patients with familial hypercholesterolemia and in the livers of mice fed a high-fat diet to induce obesity and hepatosteatosis. IsoLG-PE potently stimulated nuclear factor kappa B (NFjB) activation and expression of inflammatory cytokines in macrophages. The effects of IsoLG-PE were blocked by the soluble form of the receptor for advanced glycation endproducts (sRAGE) and by RAGE antagonists. Furthermore, macrophages derived from the bone marrow of Ager null mice failed to express inflammatory cytokines in response to IsoLG-PE to the same extent as macrophages from wild-type mice. Innovation: These studies are the first to identify IsoLG-PE as a mediator of macrophage activation and a specific receptor, RAGE, which mediates its biological effects. Conclusion: PE modification by IsoLG forms RAGE ligands that activate macrophages, so that the increased IsoLG-PE generated by high circulating cholesterol levels or high-fat diet may play a role in the inflammation associated with these conditions. Antioxid. Redox Signal. 22, 1633-1645.

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Role of Soluble Receptor for Advanced Glycation End Products on Endotoxin-induced Lung Injury

Abstract: RAGE plays an important role in the pathogenesis of LPS-induced lung injury in mice. It was suggested that sRAGE should be tested as a treatment modality in other models of acute lung injury.

Cited by 122 publications

References 41 publications

Plasma Levels of Receptor for Advanced Glycation End Products, Blood Transfusion, and Risk of Primary Graft Dysfunction

Plasma Levels of Receptor for Advanced Glycation End Products, Blood Transfusion, and Risk of Primary Graft Dysfunction

Septic Shock Is Associated with Receptor for Advanced Glycation End Products Ligation of LPS

Isolevuglandin-Type Lipid Aldehydes Induce the Inflammatory Response of Macrophages by Modifying Phosphatidylethanolamines and Activating the Receptor for Advanced Glycation Endproducts

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