Lack of the Receptor for Advanced Glycation End-Products Attenuates E. coli Pneumonia in Mice

Abstract

BackgroundThe receptor for advanced glycation end-products (RAGE) has been suggested to modulate lung injury in models of acute pulmonary inflammation. To study this further, model systems utilizing wild type and RAGE knockout (KO) mice were used to determine the role of RAGE signaling in lipopolysaccharide (LPS) and E. coli induced acute pulmonary inflammation. The effect of intraperitoneal (i.p.) and intratracheal (i.t.) administration of mouse soluble RAGE on E. coli injury was also investigated.Methodology/Principal FindingsC57BL/6 wild type and RAGE KO mice received an i.t. instillation of LPS, E. coli, or vehicle control. Some groups also received i.p. or i.t. administration of mouse soluble RAGE. After 24 hours, the role of RAGE expression on inflammation was assessed by comparing responses in wild type and RAGE KO. RAGE protein levels decreased in wild type lung homogenates after treatment with either LPS or bacteria. In addition, soluble RAGE and HMGB1 increased in the BALF after E. coli instillation. RAGE KO mice challenged with LPS had the same degree of inflammation as wild type mice. However, when challenged with E. coli, RAGE KO mice had significantly less inflammation when compared to wild type mice. Most cytokine levels were lower in the BALF of RAGE KO mice compared to wild type mice after E. coli injury, while only monocyte chemotactic protein-1, MCP-1, was lower after LPS challenge. Neither i.p. nor i.t. administration of mouse soluble RAGE attenuated the severity of E. coli injury in wild type mice.Conclusions/SignificanceLack of RAGE in the lung does not protect against LPS induced acute pulmonary inflammation, but attenuates injury following live E. coli challenge. These findings suggest that RAGE mediates responses to E. coli-associated pathogen-associated molecular pattern molecules other than LPS or other bacterial specific signaling responses. Soluble RAGE treatment had no effect on inflammation.

Limited Role of the Receptor for Advanced Glycation End Products during <b><i>Streptococcus pneumoniae</i></b> Bacteremia

“…The pattern of RAGE staining, however, remained unchanged. Similarly to our finding, the level of pulmonary RAGE expression was found to decrease in other lung injury and pulmonary fibrosis models [26,27]. In addition, RAGE was hardly detected in naïve or infected spleens and livers.…”

RAGE processing in chronic airway conditions: Involvement of Staphylococcus aureus and ECP

“…In the inflamed lung, decreased RAGE protein concentrations in tissue homogenates 9,16,29 are indeed often accompanied by increased sRAGE levels in the bronchoalveolar lavage fluid of experimental animals. [29][30][31] Enhanced proteolytic cleavage per se can thus explain the clear-cut increased levels of sRAGE in tissue homogenates from CRSsNP patients in this study. cRAGE constitutes together with esRAGE the sRAGE pool.…”

Combined effects of maternal inflammation and neonatal hyperoxia on lung fibrosis and RAGE expression in newborn rats

“…Studies of the responses of RAGE to intratracheal LPS exposure have been inconsistent in adult animal models (37)(38)(39) reported decreased levels of RAGE expression in lung tissues in LPS-induced lung injury. However, the effect of maternal LPS exposure on the expression of RAGE in the lungs of offspring had not been previously characterized.…”