A Role for RAGE/TXNIP/Inflammasome Axis in Alveolar Macrophage Activation During ARDS (RIAMA): a Proof-of-concept Clinical Study

Acute Respiratory Distress Syndrome Clinical Trial

Official title:

A Role for RAGE/TXNIP/Inflammasome Axis in Alveolar Macrophage Activation During ARDS (RIAMA): a Proof-of-concept Clinical Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02545621
• Other study ID #: CHU-0243
• Status: Completed
• Start date: September 2015
• Est. completion date: October 2016

Study information

• Verified date: July 2016
• Source: University Hospital, Clermont-Ferrand
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: October 2016
• Est. primary completion date: September 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 95 Years

Eligibility

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)

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• Mechanical Ventilation
• Respiratory Distress Syndrome, Adult
• Respiratory Distress Syndrome, Newborn

Intervention

Other:
• RAGE TXNIP Inflammasome axis

Locations

Country	Name	City	State
France	CHU Clermont-Ferrand	Clermont-Ferrand

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Clermont-Ferrand

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	FACS analysis of RAGE-TXNIP-NLRP3 pathway in alveolar monocytes/macrophages	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)	at day1
Secondary	- FACS analysis of M1 ("pro-inflammatory") and M2 ("anti-inflammatory") markers	- 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	at baseline
Secondary	IL-1ß, TXNIP, NLRP3, sRAGE, HMGB1, S100A12 measurements	- IL-1ß, TXNIP, NLRP3, sRAGE, HMGB1, S100A12 measurements (duplicate ELISA) in the bronchoalveolar lavage fluid from patients from both groups at baseline	at baseline