1 Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
Am J Respir Crit Care Med. 2013 Dec 1;188(11):1338-50. doi: 10.1164/rccm.201305-0986OC.
Hypoxia regulates the inflammatory-antiinflammatory balance by the receptor for advanced glycation end products (RAGE), a versatile sensor of damage-associated molecular patterns. The multiligand nature of RAGE places this receptor in the midst of chronic inflammatory diseases.
To characterize the impact of the hypoxia-RAGE pathway on pathogenic airway inflammation preventing effective pathogen clearance in cystic fibrosis (CF) and elucidate the potential role of this danger signal in pathogenesis and therapy of lung inflammation.
We used 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 and bacterial pneumonia.
Sustained expression of RAGE and its ligand S100B was observed in murine lung and human epithelial cells and 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 by Toll-like receptors. Inhibiting the RAGE pathway in vivo with soluble (s) RAGE reduced pathogen load and inflammation in experimental CF, whereas sRAGE production was defective in patients with CF.
A causal link between hyperactivation of RAGE and inflammation in CF has been observed, such that targeting pathogenic inflammation alleviated inflammation in CF and measurement of sRAGE levels could be a useful biomarker for RAGE-dependent inflammation in patients with CF.
缺氧通过晚期糖基化终产物受体（RAGE）调节炎症-抗炎平衡，RAGE 是一种损伤相关分子模式的多功能传感器。RAGE 的多配体性质使其成为慢性炎症性疾病的中心受体。
描述缺氧-RAGE 通路对致病性气道炎症的影响，防止囊性纤维化（CF）中有效病原体清除，并阐明该危险信号在肺部炎症发病机制和治疗中的潜在作用。
我们使用体内和体外模型研究缺氧对 CF 中人和鼠 RAGE 表达和活性的影响、RAGE 配体的性质以及 RAGE 对真菌和细菌性肺炎中肺炎症和抗微生物耐药性的影响。
在鼠肺和人上皮细胞中观察到 RAGE 及其配体 S100B 的持续表达，并通过功能研究和 CF 患者中 AGER 遗传变异的分析揭示了其在促进 CF 中炎症的近端作用。缺氧和感染都导致 S100B-RAGE 通路的持续激活，RAGE 被缺氧上调，S100B 被 Toll 样受体感染上调。在体内用可溶性（s）RAGE 抑制 RAGE 通路可减少实验性 CF 中的病原体负荷和炎症，而 CF 患者的 sRAGE 产生有缺陷。
已经观察到 CF 中 RAGE 过度激活与炎症之间存在因果关系，因此靶向致病性炎症可缓解 CF 中的炎症，并且 sRAGE 水平的测量可能是 CF 患者中 RAGE 依赖性炎症的有用生物标志物。
