Sono stati studiati attraverso modelli in vitro e in vivo (cellule FC umane e topi FC) i meccanismi alla base del meccanismo che lega l’ipossia al recettore RAGE, in particolare l’impatto che esso determina sull’infiammazione polmonare e sulla resistenza antimicrobica. Il recettore RAGE è espresso nei polmoni anche sotto forma solubile (sRAGE). L’inibizione di RAGE in vivo con la forma solubile sRAGE restaura l’omeostasi polmonare e ripristina la naturale resistenza immunologica. Nei pazienti FC il livello di sRAGE è notevolmente inferiore rispetto ai controlli sani.
In this study researchers characterized the impact of the hypoxia/RAGE pathway on pathogenic airway inflammation preventing effective pathogen clearance in CF and elucidate the potential role of this danger signal in pathogenesis and therapy of lung inflammation. They employed in vivo and in vitro models to study the impact of hypoxia on RAGE expression and activity in human and murine CF, the nature of the RAGE ligand and the impact of RAGE on lung inflammation and antimicrobial resistance in fungal pneumonia. Sustained expression of RAGE and its ligand S100B exerted a proximal role in promoting inflammation in murine and human CF, as revealed by functional studies and analysis of the genetic variability of AGER in patients with CF. Both hypoxia and infections contributed to the sustained activation of the S100B/RAGE pathway, being RAGE up-regulated by hypoxia and S100B by infection via Toll-like receptors. Inhibiting the RAGE pathway in vivo with soluble (s)RAGE restored lung immune homeostasis in experimental CF while sRAGE production was defective in CF patients. This pathway could be a useful therapeutic target and biomarker of lung inflammation in this disease.
