Receptor for advanced glycation end products expressed on alveolar epithelial cells is the main target for hyperoxia-induced lung injury

2016 ◽  
Vol 54 (2) ◽  
pp. 98-108 ◽  
Author(s):  
Chiharu Ota ◽  
Kota Ishizawa ◽  
Mitsuhiro Yamada ◽  
Yukiko Tando ◽  
Mei He ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Lung Injury ◽  
Advanced Glycation End Products ◽  
Alveolar Epithelial Cells ◽  
Advanced Glycation ◽  
Alveolar Epithelial ◽  
Glycation End Products ◽  
End Products ◽  
Main Target

scholarly journals Proteolytic release of the receptor for advanced glycation end products from in vitro and in situ alveolar epithelial cells

2011 ◽  
Vol 300 (4) ◽  
pp. L516-L525 ◽  
Author(s):  
Naoko Yamakawa ◽  
Tokujiro Uchida ◽  
Michael A. Matthay ◽  
Koshi Makita
Keyword(s):  
Epithelial Cells ◽  
Advanced Glycation End Products ◽  
Alveolar Epithelial Cells ◽  
Advanced Glycation ◽  
Alveolar Epithelial ◽  
Lps Challenge ◽  
Soluble Rage ◽  
Glycation End Products ◽  
End Products

Although the receptor for advanced glycation end products (RAGE) has been used as a biological marker of alveolar epithelial cell injury in clinical studies, the mechanism for release of soluble RAGE from lung epithelial cells has not been well studied. Therefore, these studies were designed to determine the mechanism for release of soluble RAGE after lipopolysaccharide (LPS) challenge. For these purposes, alveolar epithelial cells from rat lungs were cultured on Transwell inserts, and LPS was added to the apical side (500 μg/ml) for 16 h on day 7. On day 7, RAGE was expressed predominantly in surfactant protein D-negative cells, and LPS challenge induced release of RAGE into the medium. This response was partially blocked by matrix metalloproteinase (MMP) inhibitors. Transcripts of MMP-3 and MMP-13 were upregulated by LPS, whereas RAGE transcripts did not change. Proteolysis by MMP-3 and MMP-13 resulted in soluble RAGE expression in the bronchoalveolar lavage fluid in the in situ rat lung, and this reaction was inhibited by MMP inhibitors. In human studies, both MMP-3 and -13 antigen levels were significantly correlated with the level of RAGE in pulmonary edema fluid samples. These results support the conclusion that release of RAGE is primarily mediated by proteolytic damage in alveolar epithelial cells in the lung, caused by proteases in acute inflammatory conditions in the distal air spaces.

The Potential of Receptor for Advanced Glycation End Products (RAGE) as a Therapeutic Target for Lung Associated Diseases

2019 ◽  
Vol 20 (6) ◽  
pp. 679-689 ◽  
Author(s):  
Tejinder Pal Khaket ◽  
Sun Chul Kang ◽  
Tapan Kumar Mukherjee
Keyword(s):  
Epithelial Cells ◽  
Advanced Glycation End Products ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Chronic Obstructive ◽  
Advanced Glycation ◽  
Comprehensive Overview ◽  
Associated Diseases ◽  
Glycation End Products ◽  
End Products

The receptor for advanced glycation end products (RAGE) is a multi-ligand pattern recognition receptor that is highly expressed in lung epithelial cells. It helps alveolar epithelial cells to maintain their morphology and specific architecture. However, in various pathophysiological conditions, pulmonary tissues express a supraphysiological level of RAGE and its ligands including advanced glycation end products, high mobility group box 1 proteins, and S100 proteins. On interaction with RAGE, these ligands stimulate downstream signaling that generates inflammation and oxidative stress leading to asthma, chronic obstructive pulmonary disease, lung cancers, idiopathic pulmonary fibrosis, acute lung injury, pneumonia, bronchopulmonary dysplasia, cystic fibrosis, and sepsis. Thus, pharmacological agents that can either suppress the production of RAGE or block its biological activity would offer promising therapeutic value against pathogenesis of the aforementioned lungassociated diseases. This review presents a comprehensive overview of the recent progress made in defining the functions of RAGE in lung-associated diseases.

scholarly journals Anti-high-mobility group box-1 (HMGB1) mediates the apoptosis of alveolar epithelial cells (AEC) by receptor of advanced glycation end-products (RAGE)/c-Jun N-terminal kinase (JNK) pathway in the rats of crush injuries

2022 ◽  
Vol 17 (1) ◽  
Author(s):  
Bin-Fei Zhang ◽  
Wei Song ◽  
Jun Wang ◽  
Peng-Fei Wen ◽  
Yu-Min Zhang
Keyword(s):  
Lung Injury ◽  
Western Blot ◽  
High Mobility ◽  
Alveolar Epithelial Cells ◽  
Advanced Glycation ◽  
Jnk Pathway ◽  
Alveolar Epithelial ◽  
Glycation End Products ◽  
End Products ◽  
Crush Injuries

Abstract Objectives The lung injury is often secondary to severe trauma. In the model of crush syndrome, there may be secondary lung injury. We hypothesize that high-mobility group box 1 (HMGB1), released from muscle tissue, mediates the apoptosis of alveolar epithelial cells (AEC) via HMGB1/Receptor of advanced glycation end-products (RAGE)/c-Jun N-terminal kinase (JNK) pathway. The study aimed to investigate how HMGB1 mediated the apoptosis of AEC in the rat model. Methods Seventy-five SD male rats were randomly divided into five groups: CS, CS + vehicle, CS + Ethyl pyruvate (EP), CS + FPS-ZM1 group, and CS + SP600125 groups. When the rats CS model were completed after 24 h, the rats were sacrificed. We collected the serum and the whole lung tissues. Inflammatory cytokines were measured in serum samples. Western blot and RT-qPCR were used to quantify the protein and mRNA. Lastly, apoptotic cells were detected by TUNEL. We used SPSS 25.0 for statistical analyses. Results Nine rats died during the experiments. Dead rats were excluded from further analysis. Compared to the CS group, levels of HMGB1 and inflammatory cytokines in serum were downregulated in CS + EP, CS + FPS-ZM1, and CS + SP600125 groups. Western blot and RT-qPCR analysis revealed a significant downregulation of HMGB1, RAGE, and phosphorylated-JNK in CS + EP, CS + FPS-ZM1, and CS + SP600125 groups, compared with the CS groups, excluding total-JNK mRNA. Apoptosis of AEC was used TUNEL to assess. We found the TUNEL-positive cells were downregulated in CS + EP, CS + FPS-ZM1, and CS + SP600125 groups. Conclusion The remote lung injury begins early after crush injuries. The HMGB1/RAGE/JNK signaling axis is an attractive target to abrogate the apoptosis of AEC after crush injuries.

scholarly journals Reduced receptor for advanced glycation end products is associated with α-SMA expression in patients with idiopathic pulmonary fibrosis and mice

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Hyosin Baek ◽  
Soojin Jang ◽  
Jaehyun Park ◽  
Jimin Jang ◽  
Jooyeon Lee ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Western Blot ◽  
Advanced Glycation End Products ◽  
Alveolar Epithelial Cells ◽  
Advanced Glycation ◽  
Alveolar Epithelial ◽  
Glycation End Products ◽  
End Products ◽  
Rage Expression

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease. Despite alveolar epithelial cells is crucial role in lung, its contribution and the associated biomarker remain unknown in the pathogenesis of IPF. Recently, environmental factors including stone dust, silica and cigarette smoking were found as risk factors involved in IPF. Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin super family of cell surface receptors. It has been shown that interaction between RAGE and its ligands on immune cells mediates cellular migration and regulation of pro-inflammation. RAGE is highly expressed in the lung, in particular, alveolar epithelial cells. Therefore, we determined whether RAGE expression is associated with fibrosis-associated genes in patients with IPF and mice. Results When bleomycin (BLM) was intratracheally administered to C57BL/6 mice for 1, 2 weeks, macrophage and neutrophils were significantly increased. The fibrotic nodule formed and accumulation of collagen was determined after BLM injection in H&E- and Masson’s trichrome staining. Levels of elastin, Col1a1 and fibronectin were increased in quantitative real-time PCR and protein levels of α-SMA was increased in western blot analysis. In the lung tissues of 1 mg/kg BLM-induced mice, RAGE expression was gradually decreased in 1- and 2 weeks in immunohistochemistry and western blot analysis, and 3 mg/kg of BLM-induced mice exhibited decreased RAGE levels while α-SMA expression was increased. We next determined RAGE expression in the lungs of IPF patients using immunohistochemistry. As a result, RAGE expression was decreased, while α-SMA expression was increased compared with non-IPF subjects. Conclusions Our findings suggest that reduced RAGE was associated with increased fibrotic genes in BLM-induced mice and patients with IPF. Therefore, RAGE could be applied with a biomarker for prognosis and diagnosis in the pathogenesis of IPF.

scholarly journals Receptor for advanced glycation end-products (RAGE) is an indicator of direct lung injury in models of experimental lung injury

2009 ◽  
Vol 297 (1) ◽  
pp. L1-L5 ◽  
Author(s):  
Xiao Su ◽  
Mark R. Looney ◽  
Naveen Gupta ◽  
Michael A. Matthay
Keyword(s):  
Lung Injury ◽  
Advanced Glycation End Products ◽  
Cell Injury ◽  
Alveolar Epithelial Cell ◽  
Experimental Models ◽  
Alveolar Type ◽  
Type I ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

Receptor for advanced glycation end-products (RAGE) is a marker of alveolar type I cells and is elevated in the pulmonary edema fluid of patients with acute lung injury (ALI). We tested the hypothesis that RAGE in the bronchoalveolar lavage (BAL) would be elevated in experimental models of direct ALI characterized by alveolar epithelial cell injury. We developed ELISA measurements for RAGE and studied ALI (direct and indirect) mouse models and collected BAL at specified endpoints to measure RAGE. We also tested whether levels of BAL RAGE correlated 1) with the severity of lung injury in acid and hyperoxia-induced ALI and 2) with the beneficial effect of a novel treatment, mesenchymal stem cells (MSC), in LPS-induced ALI. In ALI models of direct lung injury induced by intratracheal instillation of acid, LPS, or Escherichia coli, the BAL RAGE was 58-, 22-, and 13-fold elevated, respectively. In contrast, BAL RAGE was not detectable in indirect models of ALI induced by an intraperitoneal injection of thiourea or by an intravenous injection of MHC I monoclonal antibody that produces a mouse model of transfusion-related ALI. BAL RAGE did correlate with the severity of lung injury in acid and hyperoxia-induced ALI. In addition, with LPS-induced ALI, BAL RAGE was markedly reduced with MSC treatment. In summary, BAL RAGE is an indicator of ALI, and it may be useful in distinguishing direct from indirect models of ALI as well as assessing the response to specific therapies.

scholarly journals Consumption of Dietary Advanced Glycation End Products Promotes Prostate Tumor Growth by Creating a Tumor Enhancing Stromal Microenvironment

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 359-359
Author(s):  
David Turner ◽  
Bradley Krisanits ◽  
Callan Frye ◽  
Lourdes Nogueira ◽  
Ried Schuster ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tumor Growth ◽  
Advanced Glycation End Products ◽  
Prostate Tumor ◽  
Migration And Invasion ◽  
Advanced Glycation ◽  
Neoplastic Growth ◽  
Incidence And Mortality ◽  
Glycation End Products ◽  
End Products

Abstract Objectives The literature regarding the role of advanced glycation end products (AGEs) on tumor biology has shown only moderate promise reflected by increases in cell growth, migration and invasion in vitro which is not supported by increased tumor growth in vivo14-16– A caveat to these studies is that they are centered upon a single AGE peptide and a subsequent assessment of their molecular effects on tumor epithelial cells. The objective is to show that by feeding mice a high AGE diet we can recapitulate a microenvironment comprising of a wide spectrum of AGEs which can influence neoplastic growth. Methods We recapitulated a dietary-AGE induced microenvironment in syngeneic xenograft and spontaneous breast and prostate mouse cancer models and the effects on tumor growth assessed. The mechanistic consequences of dietary-AGEs on the tumor microenvironment were further defined using mouse and human primary and immortalized two-compartment co-culture ex vivo culture models. Results Dietary-AGE consumption in breast and prostate tumor models significantly accelerated tumor growth by functioning as ligand to the transmembrane receptor for AGE (RAGE). Our studies demonstrate that AGEs promote neoplastic growth by functioning as ligand to RAGE expressed in the tumor stroma not the tumor epithelial cells. Dietary-AGE activation of RAGE in both breast and prostate tumors caused a regulatory program of ‘activated fibroblasts’ defined by increased expression of cancer associated fibroblast markers, NFkB and MYC upregulation, and pro-tumorigenic paracrine secretion. Complementary to this, our published studies show that high intake of dietary AGE after BCa diagnosis increases risk of mortality in postmenopausal women. Conclusions These data demonstrate, for the first time, the oncogenic potential of dietary-AGEs in promoting neoplastic growth. This lays the foundation for strategic changes aimed at reducing cancer incidence and mortality as pharmacological, educational and/or interventional strategies aimed at reducing the dietary-AGE accumulation pool may one day be viewed as universal cancer preventative and/or therapeutic initiatives especially when combined with existing therapies. Funding Sources David P. Turner was supported by grants from the NIH/NCI, R21 CA194469 and U54 CA21096..

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