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The RAGE axis in systemic inflammation, acute lung injury and myocardial dysfunction: an important therapeutic
Benedict C Creagh-Brown1,2, Gregory J Quinlan1,2, Timothy W Evans1,2
1Unit of Critical Care, Respiratory Science, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College, London, UK.
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.
Insights
The receptor for advanced glycation end-products (RAGE) axis plays a key role in sepsis-induced inflammation and organ damage. Inhibiting RAGE shows promise for treating critical illness, offering a wider therapeutic window.
Area of Science:
- Critical care medicine
- Immunology
- Pathophysiology
Background:
- Sepsis syndromes cause significant mortality, often involving pulmonary and cardiac dysfunction.
- Previous targeted therapies for sepsis-induced inflammation have shown limited success.
- The receptor for advanced glycation end-products (RAGE) axis is explored for its potential therapeutic window in sepsis.
Purpose of the Study:
- To review evidence on the RAGE axis in systemic inflammation, acute lung injury (ALI), and myocardial dysfunction.
- To examine challenges and conflicts within RAGE-related studies.
- To propose strategies for resolving these issues.
Main Methods:
- A comprehensive literature search of MEDLINE from 1990 to 2010 was conducted.
- Relevant studies were collected and critically reviewed.
- Evidence for RAGE's role in sepsis pathogenesis was synthesized.
Main Results:
- RAGE acts as an inflammation-perpetuating receptor with multiple ligands.
- Animal studies demonstrate beneficial effects of RAGE axis inhibition in systemic inflammation, ALI, and myocardial dysfunction.
- Compelling evidence supports the RAGE axis's role in sepsis pathogenesis.
Conclusions:
- The RAGE axis is implicated in the development of systemic inflammation, ALI, and myocardial dysfunction.
- Inhibiting RAGE-mediated inflammation presents a potential therapeutic strategy for human sepsis.
- Further research is needed to address outstanding questions regarding RAGE inhibition.
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