ABSTRACT
Introduction
Extracellular vesicles (EV) released constitutively or following external stimuli from structural and immune cells are now recognized as important mediators of cell-to-cell communication. They are involved in the pathogenesis of pneumonia and sepsis, leading causes of acute respiratory distress syndrome (ARDS) where mortality rates remain up to 40%. Multiple investigators have demonstrated that one of the underlying mechanisms of the effects of EVs is through the transfer of EV content to host cells, resulting in apoptosis, inflammation, and permeability in target organs.
Areas covered
The current review focuses on preclinical research examining the role of EVs released into the plasma and injured alveolus during pneumonia and sepsis.
Expert opinion
Inflammation is associated with elevated levels of circulating EVs that are released by activated structural and immune cells and can have significant proinflammatory, procoagulant, and pro-permeability effects in critically ill patients with pneumonia and/or sepsis. However, clinical translation of the use of EVs as biomarkers or potential therapeutic targets may be limited by current methodologies used to identify and quantify EVs accurately (whether from host cells or infecting organisms) and lack of understanding of the role of EVs in the reparative phase during recovery from pneumonia and/or sepsis.
Article highlights
Multiple preclinical studies of acute lung injury (ALI) or sepsis have demonstrated that circulating EVs, whether from endothelial, epithelial, or immune cells have significant proinflammatory, procoagulant, and pro-permeability effects in target cells which can result in end organ damage.
Given the critical role of EVs in the pathogenesis of diseases or syndromes, EVs are now studied as potential biomarkers and therapeutic targets to suppress the inflammatory properties of these EVs.
For example, investigators have demonstrated that instillation of high molecular weight hyaluronic acid can bind plasma EVs and suppress the injurious properties of these EVs in perfused human lungs injured with severe bacterial pneumonia.
In addition, EVs derived from stem or progenitors cells such as mesenchymal stem or stromal cells represent an attractive area of research for treating inflammatory lung diseases, including ALI or sepsis, in part due to the mechanisms underlying their therapeutic effects: the transfer of mRNAs, microRNAs, proteins, receptors, and possibly organelles from the EVs to the injured tissue.
However, current methodologies such as flow cytometry to identify and quantify EVs may not be sensitive or specific enough given that a significant portion of EVs are derived from intracellular vesicles where cell-specific markers are not present.
In addition, the phenotype of EVs derived from immune cells may change during the progression of the disease or syndrome. For example, EVs released from macrophages or regulatory T cells during the proliferative phase of ARDS may have significant immunomodulatory properties.
Thus, further research is required to better understand the role of EVs in the pathogenesis of diseases or syndromes prior to any clinical translation. A better understanding may prevent applying a therapeutic where the phenotype of the target (i.e. EVs) changes dramatically during the progression of the disease or syndrome. This may prevent the largely equivocal or negative results from previous clinical trials using anti-inflammatory drugs (i.e. corticosteroids) in ARDS and anti-TNF inhibitors in sepsis shock.
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Abbreviations
AA Arachidonic acid
AB Apoptotic bodies
ALI Acute lung injury
ARDS Acute respiratory distress syndrome
BALF Bronchoalveolar lavage fluid
CD Cluster of differentiation
COX-2Cyclooxygenase-2
DIC Disseminated intravascular coagulation
DMSO Dimethyl sulfoxide
EEV Endothelial cell derived EVs
EV Extracellular vesicles
HMW HA High molecular weight hyaluronic acid
LEV Leukocyte derived EVs
IL Interleukin
LPS Lipopolysaccharide
MEV Monocyte/macrophage derived EVs
mRNA Messenger RNA
miRNA Micro RNA
MV Microvesicles
MVB Multi-vesicular bodies
NEV Neutrophil derived EVs
NFκβNuclear Factor kappa-light-chain-enhancer of activated B cells
NO Nitric Oxide
NTA Nanoparticle tracking analysis
OMV Outer member vesicles
PEV Platelet derived EVs
RNA Ribonucleotide
TNF Tumor necrosis factor
TLR Toll like receptor
Treg Regulatory T cells
Declaration of interest
The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.