Hypoxia promotes danger -mediated inflammation via RAGE in Cystic Fibrosis

Ref ID: 19529

Author:

RG Iannitti1*, A Casagrande2, A De Luca1, C Cunha1, G Sorci1, F Riuzzi1, M Borghi1, C Galosi1,
CM Benedetti1, TD Oury3, C Colombo4, F Majo5, E Fiscarelli6, C Lass-Flörl7, FM De Benedictis8,
A Carvalho1, L Romani1

Author address:

1Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy
2Istituto Superiore di Sanití , Rome, Italy
3Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, USA
4Fondazione IRCCS Ca’ Granda,

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Purpose:
Hypoxia regulates the inflammatory/anti-inflammatory balance via the receptor for advanced
glycation end products (RAGE), a versatile sensor of damage-associated molecular patterns. The
multi-ligand nature of RAGE places this receptor in the midst of chronic inflammatory disease.
Our objective is 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.
Methods:
We 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 and bacterial pneumonia.
Results:
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 via Toll-like receptors. Inhibiting
the RAGE pathway in vivo with soluble (s)RAGE reduced pathogen load and inflammation in
experimental CF while sRAGE production was defective in CF patients.
Conclusions:
A causal link between hyper-activation 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 CF patients.

Abstract Number: 56

Conference Year: 2014

Link to conference website: http://www.AAA2014.org

New link: NULL

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