Extracellular Vesicles and Alveolar Epithelial-Capillary Barrier Disruption in Acute Respiratory Distress Syndrome: Pathophysiological Role and Therapeutic Potential

Abstract

Extracellular vesicles (EVs) mediate intercellular communication by transferring genetic material, proteins and organelles between different cells types in both health and disease. Recent evidence suggests that these vesicles, more than simply diagnostic markers, are key mediators of the pathophysiology of acute respiratory distress syndrome (ARDS) and other lung diseases. In this review, we will discuss the contribution of EVs released by pulmonary structural cells (alveolar epithelial and endothelial cells) and immune cells in these diseases, with particular attention to their ability to modulate inflammation and alveolar-capillary barrier disruption, a hallmark of ARDS. EVs also offer a unique opportunity to develop new therapeutics for the treatment of ARDS. Evidences supporting the ability of stem cell-derived EVs to attenuate the lung injury and ongoing strategies to improve their therapeutic potential are also discussed.

Role of released mitochondrial DNA in acute lung injury

“…EVs, a heterogeneous group of cell-derived membranous structures comprising exosomes, microvesicles (MVs) ( 74 , 75 ), and apoptotic EVs (ApoEVs) ( 76 ), are considered a mode of intercellular communication, acting as transport cargo of different messengers, including nucleic acids (mitochondrial and genomic DNA, non-coding RNA) and proteins ( 74 , 77 )…”

Nanomedicine approaches to reduce cytokine storms in severe infections

“… [54] In models of acute lung injury (ALI) associated with severe pneumonia and sepsis, mesenchymal stem cell EVs (MSC-EVs) reduced macrophage infiltration and cytokine production drastically. [55] , [56] In an ex vivo scenario in which infused human lungs were infected with Escherichia coli , systemic treatment of human MSC-EVs decreased inflammatory influx and expression of TNFα. Exposure to E. coli causes severe bacterial pneumonia .…”

Exploring extracellular vesicles as mediators of clinical disease and vehicles for viral therapeutics: Insights from the COVID-19 pandemic

“…EVs have previously been shown to contribute to ALI and ARDS in sepsis models [ 2 , 46 ] , and they may be involved in COVID-19-associated lung injury as well. EVs recovered from bronchoalveolar lavage fluid (BALF-EVs) during ARDS exhibit a complex interplay of communication between alveolar epithelial cells (AECs) and alveolar macrophages.…”

“…EVs recovered from bronchoalveolar lavage fluid (BALF-EVs) during ARDS exhibit a complex interplay of communication between alveolar epithelial cells (AECs) and alveolar macrophages. In LPS-induced ARDS mouse models, BALF-EVs were enriched with miRNA that was shown to induce proinflammatory cytokines by AECs as well as alveolar macrophages (AMs) in cell culture experiments [ 46 – 48 ] . BALF-EVs containing increased amounts of miR-466g and miR-466m-5p were shown to activate the inflammasome and induce IL-1 in AMs [ 48 ] .…”

“…Additionally, BALF-EVs enriched with miR-155 and miR-146a induced overexpression of TNF-α and IL-6 in AECs. These miRNAs also decreased the expression of the tight-junction protein, ZO-1, thereby increasing the permeability of the alveolar epithelial-capillary barrier [ 46 , 47 ] . Therefore, EVs have been shown to contribute to the increased alveolar vascular permeability, decreased alveolar ventilation and lung compliance, and the hyperinflammatory response that occurs in the lungs during ARDS.…”