FG-4497: a new target for acute respiratory distress syndrome?

Abstract

The morbidity and mortality rates associated with acute respiratory distress syndrome (ARDS) remain high and the development of new therapeutic strategies is urgently required. Some pharmacological treatments, proposed or under evaluation for ARDS, seek to protect the endothelium and consequently mitigate fluid extravasation into the alveolar space. FG-4497 is a new compound which acts as a prolyl hydroxylase domain 2 inhibitor and mimics hypoxia in the activation of hypoxia-inducible factor-2α signaling, decreasing VE-cadherin phosphorylation and thus promoting integrity of adherens junctions. In this special report, we discuss the pharmacological characteristics of FG-4497, its effect on lung parenchyma and other organs and future perspectives in ARDS. In short, FG-4497 may be considered a novel pharmacological option targeting endothelial cell repair in lung diseases such as ARDS. Further experimental and clinical studies are warranted to better understand the mechanisms of action of FG-4497 in different types of lung injury.

Keywords:

• acute respiratory distress syndrome
• adherens junctions
• endothelium
• hypoxia
• VE-cadherin

Acknowledgements

The authors would like to express their gratitude to ME Schöttler and F Vasconcellos for their assistance in editing the manuscript.

Financial & competing interests

This work was funded by the European Community’s Seventh Framework Programme under grant agreement no. HEALTH-F4-2011–282095 (TARKINAID project), the Brazilian Council for Scientific and Technological Development (CNPq) and the Rio de Janeiro State Research Foundation (FAPERJ). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Editorial assistance funded by the CNPq grant was provided by ME Schöttler and F Vasconcellos in the production of this manuscript.

Key issues

• Despite reductions in mortality rates with the advent of protective mechanical ventilation, so far, no pharmacological interventions have been found to be efficient in treatment of the acute respiratory distress syndrome (ARDS). This is likely due to limited focus on the pathophysiology of different ARDS etiologies.

• The maintenance of endothelial barrier function is essential for adequate compartmentalization of the vascular and interstitial spaces and better transit of macromolecules and immune cells.

• New pharmacological agents that mimic the signaling pathway triggered by hypoxia can act through hypoxia response elements to stabilize the adherens junctions between endothelial cells.

• Several experimental models have shown the beneficial effects of FG-4497 in mitigating fluid leakage in specific settings.

• FG-4497 may be considered a novel pharmacological option targeting endothelial cell repair for management of lung diseases such as ARDS.

Notes