Benedict C Creagh-Brown1,2, Gregory J Quinlan1,2, Timothy W Evans1,2, Anne Burke-Gaffney3,4. 1. Unit of Critical Care, Respiratory Science, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College, London, UK. 2. NIHR Respiratory Disease Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust, London, UK. 3. Unit of Critical Care, Respiratory Science, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College, London, UK. a.burke-gaffney@imperial.ac.uk. 4. NIHR Respiratory Disease Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust, London, UK. a.burke-gaffney@imperial.ac.uk.
Abstract
BACKGROUND: The sepsis syndromes, frequently complicated by pulmonary and cardiac dysfunction, remain a major cause of death amongst the critically ill. Targeted therapies aimed at ameliorating the systemic inflammation that characterises the sepsis syndromes have largely yielded disappointing results in clinical trials. Whilst there are many potential reasons for lack of success of clinical trials, one possibility is that the pathways targeted, to date, are only modifiable very early in the course of the illness. More recent approaches have therefore attempted to identify pathways that could offer a wider therapeutic window, such as the receptor for advanced glycation end-products (RAGE) and its ligands. PURPOSE: The objectives of this study were to review the evidence supporting the role of the RAGE axis in systemic inflammation and associated acute lung injury and myocardial dysfunction, to explore some of the problems and conflicts that these RAGE studies have raised and to consider strategies by which they might be resolved. METHODS: MEDLINE was searched (1990-2010) and relevant literature collected and reviewed. RESULTS AND CONCLUSION: RAGE is an inflammation-perpetuating receptor with a diverse range of ligands. Evidence supporting a role of the RAGE axis in the pathogenesis of systemic inflammation, ALI and myocardial dysfunction is compelling with numerous animal experiments showing the beneficial effects of inhibiting the RAGE axis. Despite a number of unanswered questions that need to be further addressed, the potential for inhibiting RAGE-mediated inflammation in humans undoubtedly exists.
BACKGROUND: The sepsis syndromes, frequently complicated by pulmonary and cardiac dysfunction, remain a major cause of death amongst the critically ill. Targeted therapies aimed at ameliorating the systemic inflammation that characterises the sepsis syndromes have largely yielded disappointing results in clinical trials. Whilst there are many potential reasons for lack of success of clinical trials, one possibility is that the pathways targeted, to date, are only modifiable very early in the course of the illness. More recent approaches have therefore attempted to identify pathways that could offer a wider therapeutic window, such as the receptor for advanced glycation end-products (RAGE) and its ligands. PURPOSE: The objectives of this study were to review the evidence supporting the role of the RAGE axis in systemic inflammation and associated acute lung injury and myocardial dysfunction, to explore some of the problems and conflicts that these RAGE studies have raised and to consider strategies by which they might be resolved. METHODS: MEDLINE was searched (1990-2010) and relevant literature collected and reviewed. RESULTS AND CONCLUSION: RAGE is an inflammation-perpetuating receptor with a diverse range of ligands. Evidence supporting a role of the RAGE axis in the pathogenesis of systemic inflammation, ALI and myocardial dysfunction is compelling with numerous animal experiments showing the beneficial effects of inhibiting the RAGE axis. Despite a number of unanswered questions that need to be further addressed, the potential for inhibiting RAGE-mediated inflammation in humans undoubtedly exists.
Authors: Jean-Louis Vincent; Yasser Sakr; Charles L Sprung; V Marco Ranieri; Konrad Reinhart; Herwig Gerlach; Rui Moreno; Jean Carlet; Jean-Roger Le Gall; Didier Payen Journal: Crit Care Med Date: 2006-02 Impact factor: 7.598
Authors: Christoph Engel; Frank M Brunkhorst; Hans-Georg Bone; Reinhard Brunkhorst; Herwig Gerlach; Stefan Grond; Matthias Gruendling; Guenter Huhle; Ulrich Jaschinski; Stefan John; Konstantin Mayer; Michael Oppert; Derk Olthoff; Michael Quintel; Max Ragaller; Rolf Rossaint; Frank Stuber; Norbert Weiler; Tobias Welte; Holger Bogatsch; Christiane Hartog; Markus Loeffler; Konrad Reinhart Journal: Intensive Care Med Date: 2007-02-24 Impact factor: 17.440
Authors: Antoine Vieillard-Baron; Vincent Caille; Cyril Charron; Guillaume Belliard; Bernard Page; François Jardin Journal: Crit Care Med Date: 2008-06 Impact factor: 7.598
Authors: Teresa A Williams; Geoffrey J Dobb; Judith Claire Finn; Matthew William Knuiman; Elizabeth Geelhoed; K Y Lee; Steven A R Webb Journal: Crit Care Med Date: 2008-05 Impact factor: 7.598
Authors: Juciano Gasparotto; Carolina S Girardi; Nauana Somensi; Camila T Ribeiro; José C F Moreira; Monique Michels; Beatriz Sonai; Mariane Rocha; Amanda V Steckert; Tatiana Barichello; João Quevedo; Felipe Dal-Pizzol; Daniel P Gelain Journal: J Biol Chem Date: 2017-11-10 Impact factor: 5.157
Authors: Alice Kunzler; Eduardo Antônio Kolling; Jeferson Delgado da Silva; Juciano Gasparotto; Matheus Augusto de Bittencourt Pasquali; José Cláudio Fonseca Moreira; Daniel Pens Gelain Journal: Neurochem Res Date: 2017-05-11 Impact factor: 3.996
Authors: John P Reilly; Scarlett Bellamy; Michael G S Shashaty; Robert Gallop; Nuala J Meyer; Paul N Lanken; Sandra Kaplan; Daniel N Holena; Addison K May; Lorraine B Ware; Jason D Christie Journal: Ann Am Thorac Soc Date: 2014-06
Authors: Peter J Smit; Weidun A Guo; Bruce A Davidson; Barbara A Mullan; Jadwiga D Helinski; Paul R Knight Journal: J Surg Res Date: 2014-04-08 Impact factor: 2.192