Protease Activated Receptors: A Pathway to Boosting Mesenchymal Stromal Cell Therapeutic Efficacy in Acute Respiratory Distress Syndrome?

Naveen Gupta

doi:10.3390/ijms23031277

Abstract

Acute Respiratory Distress Syndrome is the most common cause of respiratory failure among critically ill patients, and its importance has been heightened during the COVID-19 pandemic. Even with the best supportive care, the mortality rate in the most severe cases is 40–50%, and the only pharmacological agent shown to be of possible benefit has been steroids. Mesenchymal stromal cells (MSCs) have been tested in several pre-clinical models of lung injury and been found to have significant therapeutic benefit related to: (a) potent immunomodulation; (b) secretion of epithelial and endothelial growth factors; and (c) augmentation of host defense to infection. Initial translational efforts have shown signs of promise, but the results have not yielded the anticipated outcomes. One potential reason is the relatively low survival of MSCs in inflammatory conditions as shown in several studies. Therefore, strategies to boost the survival of MSCs are needed to enhance their therapeutic effect. Protease-activated receptors (PARs) may represent one such possibility as they are G-protein coupled receptors expressed by MSCs and control several facets of cell behavior. This review summarizes some of the existing literature about PARs and MSCs and presents possible future areas of investigation in order to develop potential, PAR-modified MSCs with enhanced therapeutic efficiency.

Highlights

Acute Respiratory Distress Syndrome (ARDS) is the most common cause of acute respiratory failure among critically ill patients
There are several peptides available that can act as pharmacological agonists or antagonists of the Protease-activated receptors (PARs), and their activation state can be modified on cells, such as Mesenchymal stromal cells (MSCs), prior to administration to patients afflicted with severe lung injury
PAR1 and PAR2 significantly attenuated fibronectin secretion as did inhibition of ERK1/2. These results suggest that thrombin cleavage of PAR1 and activation of ERK1/2 are involved in fibronectin secretion by MSCs under in vitro conditions

Summary

Introduction

Acute Respiratory Distress Syndrome (ARDS) is the most common cause of acute respiratory failure among critically ill patients. This is important in conditions such as ARDS since patients are critically ill and there is not sufficient time to isolate and purify new MSCs from culture Given these pleiotropic effects and promising experimental results, MSCs have been studied in several clinical trials targeting patients with ARDS and severe sepsis [21,22,23,24,25]. There are several peptides available that can act as pharmacological agonists or antagonists of the PARs, and their activation state can be modified on cells, such as MSCs, prior to administration to patients afflicted with severe lung injury This represents a unique opportunity to optimize the biological properties of MSCs ex-vivo in order to achieve a more robust clinical effect

MSCs—Preclinical Studies in Acute Lung Injury

MSCs—Clinical Studies in ARDS

Protease-Activated Receptors

PARs and MSCs

Findings

Conclusions and Future