A Role for RAGE/TXNIP/Inflammasome Axis in Alveolar Macrophage Activation During ARDS (RIAMA): a Proof-of-concept Clinical Study
Study Details
Study Description
Brief Summary
RAGE (the receptor for advanced glycation end-products) is a marker of alveolar type I cell injury and a pivotal mediator of acute inflammation and innate immunity. RAGE pathway is highly regulated; the interaction of the transmembrane receptor with its various ligands (e.g. HMGB1, S100A12) ultimately leads to NF-kB activation and RAGE upregulation itself, but precise RAGE functions and intracellular pathways remain underexplored. During ARDS, monocyte and macrophage activation could modulate alveolar inflammation and repair.
As RAGE is also expressed at the surface of monocytes/macrophages, we hypothesize that alveolar monocyte/macrophage activation may be mediated through a RAGE-TXNIP (thioredoxin interacting protein)-NLRP3/inflammasome intracellular pathway. The purpose of this observational prospective study is to compare alveolar monocyte/macrophage activation profiles (as assessed by Fluorescence-Activated Cell Sorting (FACS)) in mechanically ventilated patients with or without ARDS.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Detailed Description
BACKGROUND:
The receptor for advanced glycation end products (RAGE) was recently identified as a promising new marker of alveolar type I cell injury. RAGE is a member of the immunoglobulin superfamily that acts as a multiligand receptor and is involved in propagating inflammatory responses in various cell populations. While the precise function of RAGE remains unclear, the elevated levels of RAGE, and its soluble isoform sRAGE, correlate with severity of acute respiratory distress syndrome (ARDS) in human and animal studies.
RAGE pathway is highly regulated; the interaction of the transmembrane receptor with its various ligands (e.g. HMGB1, S100A12) ultimately leads to NF-kB activation and RAGE upregulation itself. During ARDS, monocyte and macrophage activation could modulate alveolar inflammation and repair. As RAGE is also expressed at the surface of monocytes/macrophages, we hypothesize that alveolar monocyte/macrophage activation may be mediated through a RAGE-TXNIP (thioredoxin interacting protein)-NLRP3/inflammasome intracellular pathway.
DESIGN NARRATIVE:
The purpose of this monocentric observational prospective pathophysiology study is to compare alveolar monocyte/macrophage activation profiles between patients with or without ARDS.
Using Fluorescence-Activated Cell Sorting (FACS) analysis, monocyte/macrophage activation profiles will be characterized in patients within the first 24 hours after onset of ARDS and in matched mechanically ventilated controls. Markers of M1 ("pro-inflammatory") or M2 ("anti-inflammatory") activation, along with RAGE, TXNIP, NLRP3 FACS labeling in alveolar monocytes/macrophages will be analyzed along with protein measurements (IL-1β, TXNIP, NLRP3, sRAGE, HMGB1, S100A12) in the bronchoalveolar lavage fluid.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| ARDS Group (acute respiratory distress syndrome) The purpose of this monocentric observational prospective pathophysiology study is to compare alveolar monocyte/macrophage activation profiles between patients with or without ARDS |
Other: RAGE TXNIP Inflammasome axis
|
| control group The purpose of this monocentric observational prospective pathophysiology study is to compare alveolar monocyte/macrophage activation profiles between patients with or without ARDS |
Other: RAGE TXNIP Inflammasome axis
|
Outcome Measures
Primary Outcome Measures
- FACS analysis of RAGE-TXNIP-NLRP3 pathway in alveolar monocytes/macrophages [at day1]
FACS analysis of RAGE-TXNIP-NLRP3 pathway in alveolar monocytes/macrophages from patients within the first 24 hours after onset of ARDS (ARDS group) and from sex- and age-matched mechanically ventilated controls (control group)
Secondary Outcome Measures
- - FACS analysis of M1 ("pro-inflammatory") and M2 ("anti-inflammatory") markers [at baseline]
- FACS analysis of M1 ("pro-inflammatory") and M2 ("anti-inflammatory") markers (e.g., CD45, CD16, CD14, CD163, CD206, ICAM-1) in alveolar monocytes/macrophages from patients from both groups at baseline
- IL-1β, TXNIP, NLRP3, sRAGE, HMGB1, S100A12 measurements [at baseline]
- IL-1β, TXNIP, NLRP3, sRAGE, HMGB1, S100A12 measurements (duplicate ELISA) in the bronchoalveolar lavage fluid from patients from both groups at baseline
Eligibility Criteria
Criteria
Inclusion Criteria:
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ICU patients without ARDS and under mechanical ventilation for less than 24 hours
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Patients within the first 24 hours after onset of moderate to severe ARDS according to the 2012 Berlin definition (ARDS group)
Exclusion Criteria:
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- Pregnancy
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Acute exacerbation of diabetes (ketoacidosis, hyperosmolar hyperglycemic state)
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Patient under mechanical ventilation for > 7 days
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Dialysis-dependent chronic renal failure
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Alzheimer's disease
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Amyloidosis
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Evolutive neoplastic lesion
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Chronic pulmonary disease requiring long-term oxygen therapy or mechanical ventilation
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Chemotherapy treatment in the last 30 days
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Severe neutropenia (<0.5 G/l)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | CHU Clermont-Ferrand | Clermont-Ferrand | France | 63003 |
Sponsors and Collaborators
- University Hospital, Clermont-Ferrand
Investigators
- Principal Investigator: Mathieu JABAUDON, University Hospital, Clermont-Ferrand
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CHU-0243