A Role for RAGE/TXNIP/Inflammasome Axis in Alveolar Macrophage Activation During ARDS (RIAMA): a Proof-of-concept Clinical Study
Condition: Acute Respiratory Distress Syndrome; Mechanical Ventilation
MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
Study type: Observational

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.
    

Intervention name(s): RAGE TXNIP Inflammasome axis
Intervention type(s): Other
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
      
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