All the “RAGE” in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses

Abstract

SUMMARY The receptor for advanced glycation endproducts (RAGE) is a pro-inflammatory pattern recognition receptor (PRR) that has been implicated in the pathogenesis of numerous inflammatory diseases. It was discovered in 1992 on endothelial cells and was named for its ability to bind advanced glycation endproducts and promote vascular inflammation in the vessels of patients with diabetes. Further studies revealed that RAGE is most highly expressed in lung tissue and spurred numerous explorations into RAGE’s role in the lung. These studies have found that RAGE is an important mediator in allergic airway inflammation (AAI) and asthma, pulmonary fibrosis, lung cancer, chronic obstructive pulmonary disease (COPD), acute lung injury, pneumonia, cystic fibrosis, and bronchopulmonary dysplasia. RAGE has not yet been targeted in the lungs of paediatric or adult clinical populations, but the development of new ways to inhibit RAGE is setting the stage for the emergence of novel therapeutic agents for patients suffering from these pulmonary conditions.

TAZ is required for lung alveolar epithelial cell differentiation after injury

“…Taken together, these observations suggest that while steady-state blood sRAGE levels may reflect overall AEC1 health, acute injury and massive AEC1 death may result in the release of significant quantities of sRAGE into the systemic circulation. On the other hand, the decreased levels of serum sRAGE in IPF are likely to reflect chronic low-level injury and inability to repair alveolar epithelium, hence the levels of this biomarker must be interpreted in specific disease contexts (48). Taken together, our observations of decreased sRAGE in IPF associated with disease progression are consistent with IPF representing a condition of a chronically inadequate capacity to regenerate alveolar epithelium, which predisposes to an excessive interstitial fibrotic response.…”

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

“…The receptor for advanced glycation endproducts (RAGE) is constitutively highly expressed on alveolar epithelial cells in the lungs, while other tissues show little to no RAGE expression during basic conditions (Brett et al 1993;Bierhaus et al 2005;Oczypok et al 2017). Subsequent studies have localized RAGE expression to the basal membrane of type 1 alveolar epithelial cells, and RAGE has been defined as a specific marker of these cells (Shirasawa et al 2004;Fehrenbach et al 1998;Ota et al 2016).…”

“…Conflicting results have been reported regarding RAGE expression on type 2 alveolar epithelial cells (Shirasawa et al 2004;Katsuoka et al 1997). RAGE will be expressed on vascular endothelial cells and macrophages during inflammatory responses (Brett et al 1993) (Bierhaus et al 2005;Oczypok et al 2017). RAGE was originally identified in diabetes research as a cell surface receptor generating a cascade of intracellular signaling, including nuclear NF-kB translocation and proinflammatory cytokine release (Schmidt et al 1996).…”

Structural and Social Determinants of Health in Asthma in Developed Economies: a Scoping Review of Literature Published Between 2014 and 2019

“…This finding was limited to beverages with a high fructose to glucose ratio (e.g., sodas high in fructose corn syrup and apple juice), but not for beverages without excess free fructose (e.g., diet soda and orange juice) [102••]. This difference may relate to intestinal formation of advanced glycation end products which may trigger pulmonary inflammation via RAGE receptors [109,110]. These findings, if confirmed in further prospective studies and trials, would be particularly amenable to policy interventions for dietary guidelines, school lunch nutritional requirements, and food assistance programs.…”