Clinical trial NCT02545621: A Role for RAGE/TXNIP/Inflammasome Axis in Alveolar Macrophage Activation During ARDS (RIAMA): a Proof-of-concept Clinical Study
Official title: A Role for RAGE/TXNIP/Inflammasome Axis in Alveolar Macrophage Activation During ARDS (RIAMA): a Proof-of-concept Clinical Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Acute Respiratory Distress Syndrome
Mechanical Ventilation
Keywords: Receptor for advanced glycation end products (RAGE)
Acute respiratory distress syndrome (ARDS)
Monocyte/Macrophage activation
Fluorescence-Activated Cell Sorting (FACS) analysis
Thioredoxin interacting protein (TXNIP)
NOD-like receptor family, pyrin domain containing 3 (NLRP3)
Inflammasome
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
First posted: 2015-09-10
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: ICU patients without ARDS and under mechanical ventilation for less than 24 hours

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.

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.

Eligibility criteria: Inclusion Criteria:

* ICU patients without ARDS and under mechanical ventilation for less than 24 hours
* Patients within the first 24 hours after onset of moderate to severe ARDS according to the 2012 Berlin definition (ARDS group)

Exclusion Criteria:

* - Pregnancy
* Acute exacerbation of diabetes (ketoacidosis, hyperosmolar hyperglycemic state)
* Patient under mechanical ventilation for \> 7 days
* Dialysis-dependent chronic renal failure
* Alzheimer's disease
* Amyloidosis
* Evolutive neoplastic lesion
* Chronic pulmonary disease requiring long-term oxygen therapy or mechanical ventilation
* Chemotherapy treatment in the last 30 days
* Severe neutropenia (\<0.5 G/l)

Primary outcomes:
measure: FACS analysis of RAGE-TXNIP-NLRP3 pathway in alveolar monocytes/macrophages
timeFrame: at day1
Secondary outcomes:
measure: - FACS analysis of M1 ("pro-inflammatory") and M2 ("anti-inflammatory") markers
timeFrame: at baseline
measure: IL-1β, TXNIP, NLRP3, sRAGE, HMGB1, S100A12 measurements
timeFrame: at baseline
Other outcomes:
Locations:
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
Study officials:
affiliation: University Hospital, Clermont-Ferrand
name: Mathieu JABAUDON
role: PRINCIPAL_INVESTIGATOR
References: