Receptor for Advanced Glycation End-Products Is a Marker of Type I Cell Injury in Acute Lung Injury

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.

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Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury

Thorax ◽

10.1136/thx.2008.095588 ◽

2008 ◽

Vol 63 (12) ◽

pp. 1083-1089 ◽

Cited By ~ 190

Author(s):

C S Calfee ◽

L B Ware ◽

M D Eisner ◽

P E Parsons ◽

B T Thompson ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Clinical Outcomes ◽

Advanced Glycation End Products ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products

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Upregulation of Matrix Metalloproteinase-9 Protects against Sepsis-Induced Acute Lung Injury via Promoting the Release of Soluble Receptor for Advanced Glycation End Products

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/8889313 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Hui Zhang ◽

Yan-Fei Mao ◽

Ying Zhao ◽

Dun-Feng Xu ◽

Yan Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Lung Injury ◽

Lung Injury ◽

Matrix Metalloproteinase ◽

Signaling Pathway ◽

Advanced Glycation End Products ◽

Advanced Glycation ◽

Decoy Receptor ◽

Glycation End Products ◽

End Products

Dysregulation of matrix metalloproteinase- (MMP-) 9 is implicated in the pathogenesis of acute lung injury (ALI). However, it remains controversial whether MMP-9 improves or deteriorates acute lung injury of different etiologies. The receptor for advanced glycation end products (RAGE) plays a critical role in the pathogenesis of acute lung injury. MMPs are known to mediate RAGE shedding and release of soluble RAGE (sRAGE), which can act as a decoy receptor by competitively inhibiting the binding of RAGE ligands to RAGE. Therefore, this study is aimed at clarifying whether and how pulmonary knockdown of MMP-9 affected sepsis-induced acute lung injury as well as the release of sRAGE in a murine cecal ligation and puncture (CLP) model. The analysis of GEO mouse sepsis datasets GSE15379, GSE52474, and GSE60088 revealed that the mRNA expression of MMP-9 was significantly upregulated in septic mouse lung tissues. Elevation of pulmonary MMP-9 mRNA and protein expressions was confirmed in CLP-induced mouse sepsis model. Intratracheal injection of MMP-9 siRNA resulted in an approximately 60% decrease in pulmonary MMP-9 expression. It was found that pulmonary knockdown of MMP-9 significantly increased mortality of sepsis and exacerbated sepsis-associated acute lung injury. Pulmonary MMP-9 knockdown also decreased sRAGE release and enhanced sepsis-induced activation of the RAGE/nuclear factor-κB (NF-κB) signaling pathway, meanwhile aggravating sepsis-induced oxidative stress and inflammation in lung tissues. In addition, administration of recombinant sRAGE protein suppressed the activation of the RAGE/NF-κB signaling pathway and ameliorated pulmonary oxidative stress, inflammation, and lung injury in CLP-induced septic mice. In conclusion, our data indicate that MMP-9-mediated RAGE shedding limits the severity of sepsis-associated pulmonary edema, inflammation, oxidative stress, and lung injury by suppressing the RAGE/NF-κB signaling pathway via the decoy receptor activities of sRAGE. MMP-9-mediated sRAGE production may serve as a self-limiting mechanism to control and resolve excessive inflammation and oxidative stress in the lung during sepsis.

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