Understanding acute respiratory distress syndrome

TAURA is a research project that aims to fill in knowledge gaps in acute respiratory distress syndrome. Associate Professor Matthieu Jabaudon explains

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterised by widespread inflammation of the lung. It usually develops in critically ill patients, as a complication of an existing condition and occurs when the lungs become severely inflamed due to infection or injury, for example, after pneumonia, extra pulmonary sepsis, blood poisoning or severe chest trauma. As a result, gas exchange in the lungs is impaired, thus resulting in low arterial oxygenation and acute respiratory failure. There is no specific test to diagnose the syndrome; instead, an in-depth assessment is performed with a view to diagnosing the underlying cause. In spite of therapeutic advances in ventilation strategy and fluid management, morbidity and mortality remain high, with hospital mortality rates ranging from 35 to 45%. Unfortunately, no disease modifying pharmacologic therapies for the syndrome have been identified to date. Therefore, a better understanding of the disease, particularly its pathogeny, is required.

Translational Approach

Our research teams at Clermont-Ferrand University Hospital and Université Clermont Auvergne, France, have recently embraced a highly translational and collaborative project that seeks to fill a part of this knowledge gap. TAURA (Translational Approach to Understanding RAGE pathway in acute respiratory distress syndrome) is a four-year project funded by the French National Research Agency (ANR), with additional support from the Auvergne Regional Council, French Ministry of Health (DGOS) and Clermont-Ferrand University Hospital. Therefore, we have set out to contribute to the assembly of many pieces of a puzzle designed to explore the pathophysiologic, diagnostic and therapeutic implications of the receptor for advanced glycation end-products (RAGE) in ARDS. The reason our teams have chosen to focus on RAGE is that the receptor was recently identified as a promising marker of alveolar type I cell injury. The receptor is hypothesised to have a causative effect in a number of inflammatory diseases and, based on recent data, we believe targeting RAGE may attenuate lung injury. We are therefore working on gaining and enhancing knowledge about the ligands and basic mechanisms of RAGE in lung injury and repair, in an effort to pave the way for identifying new biomarkers and therapeutic options.

In order to characterise the roles of the RAGE pathway during ARDS, a translational approach that comprises preclinical and clinical studies has been developed. Firstly, observational and interventional clinical studies have been designed to test plasma soluble RAGE (sRAGE) as a biomarker of alveolar epithelial injury in ARDS. Its diagnostic, prognostic and predictive values, its correlation with lung injury severity, and its value as a tool to tailor therapy were therefore evaluated. Our teams then used cultures of epithelial cells, macrophages, and a translational mouse model of acid-induced lung injury to describe the effects of the RAGE pathway on alveolar fluid clearance and inflammation, two major pathophysiological features that are associated with worse prognosis in ARDS. Subsequently, acid-injured mice were treated with an anti-RAGE monoclonal antibody or recombinant sRAGE, with the goal to test in vivo the impact of RAGE inhibition on alveolar fluid clearance and features of experimental ARDS. An additional motivation behind investigating the RAGE pathway is to propose new markers of epithelial injury and alveolar inflammation, including soluble proteins, membrane or intracytoplasmic proteins, gene regulatory mechanisms or polymorphisms. Similarly to the processes being undertaken with sRAGE, the methodology is also aimed at validating each specific feature of a biomarker, with new biomarkers being tested alone or in combination with others.

The multidisciplinary consortium on which relies the TAURA project comprises clinical researchers, clinicians, and biologists from Clermont-Ferrand University Hospital and scientists, as well as academics from the Université Clermont Auvergne who are specialists in medicine, molecular biology, physiology, pathology, animal models, and/or in vitro studies. The project is coordinated by Matthieu Jabaudon, MD, PhD, who is an associate professor of medicine, anaesthesiology, and critical care. The presence of an international expert team leading the field in RAGE research (Pr Ann Marie Schmidt, New York University, USA) further strengthens the consortium, and allows, among others, studies involving knockout animals in addition to providing additional, highly valuable expertise into project design and analyses.

The design of our project is based on a translational approach. First, sRAGE is assessed as a reliable biomarker in clinical ARDS. Then, roles of the RAGE pathway in lung epithelial integrity and alveolar fluid clearance (AFC) are investigated using in vivo and in vitro experiments. The aim of this approach is to better understand the endotypes associated with phenotypes of patients with ARDS, the degree of AFC impairment, and inflammatory profiles, in order to further enhance ARDS recognition, assess response to therapy, and ultimately improve patient care. Clinical validations are performed within the project through mono-centre and multi-centre investigations involving regional, national and international networks.

Although we believe there is still much work to be done, particularly to better understand the implications of our results to date, we have already accomplished a significant number of achievements. Among these findings are: 1) that sRAGE is a biomarker of ARDS; 2) the pathophysiologic implications of the RAGE pathway in ARDS, with special emphasis on alveolar fluid clearance and alveolar inflammation.; 3) that the RAGE pathway is a promising therapeutic target in ARDS.

Future objectives for the team include the development of a bedside sRAGE measurement tool and a therapeutic agent to improve epithelial function in ARDS. However, these ultimate goals extend beyond the remit of TAURA. Although the results from the TAURA project (including collected data and specimens) are valuable sources for such a development, patent projects are out of the scope of TAURA itself, and other sources of funding are under study. We are doing our best to move from strength to strength, with bigger plans to ultimately improve patient management and impact clinical outcomes. Hopefully, the future for those affected by ARDS might be significantly brighter, may we succeed in our aims.

Matthieu Jabaudon

Associate Professor of Medicine,

Anesthesiology, and Critical Care

CHU Clermont-Ferrand, Université Clermont Auvergne, CNRS UMR 6293, INSERM U1103, GReD

mjabaudon@chu-clermontferrand.fr

www.taura-project.com

www.gred-clermont.fr

@TAURA_project

@mj0b

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