Abstract
BackgroundAcute respiratory distress syndrome (ARDS) is a life-threatening disease; however, its treatment has not yet been fully established. The progression of ARDS is considered to be mediated by altered intercellular communication between immune and structural cells in the lung. One of several factors involved in intercellular communication is the extracellular vesicle (EV). They act as carriers of functional content such as RNA molecules, proteins, and lipids and deliver cargo from donor to recipient cells. EVs have been reported to regulate the nucleotide-binding oligomerization like receptor 3 (NLRP3) inflammasome. This has been identified as the cellular machinery responsible for activating inflammatory processes, a key component responsible for the pathogenesis of ARDS.MethodsHere, we provide comprehensive genetic analysis of microRNAs (miRNAs) in EVs, demonstrating increased expression of the miRNA-466 family in the bronchoalveolar lavage fluid of a mouse ARDS model.ResultsTransfection of bone marrow-derived macrophages (BMDMs) with miRNA-466 g and 466 m-5p resulted in increased interleukin-1 beta (IL-1β) release after LPS and ATP treatment, which is an established in vitro model of NLRP3 inflammasome activation. Moreover, LPS-induced pro-IL-1β expression was accelerated by miRNA-466 g and 466 m-5p in BMDMs.ConclusionsThese findings imply that miRNA-466 family molecules are secreted via EVs into the airways in an ARDS model, and this exacerbates inflammation through the NLRP3 inflammasome. Our results suggest that the NLRP3 inflammasome pathway, regulated by extracellular vesicle miRNA, could act as a therapeutic target for ARDS.
Highlights
Acute respiratory distress syndrome (ARDS) is a life-threatening disease; its treatment has not yet been fully established
The pathophysiology associated with ARDS, involves 1) activated macrophages overproducing inflammatory cytokines such as interleukin-1 beta (IL-1β) and interleukin-8 (IL-8), which activate neutrophils that have difficulty in Shikano et al BMC Pulmonary Medicine (2019) 19:110 passing through microvessels in the lung; 2) vascular endothelia in the lung overproduce adhesion molecules, and these phenomena result in neutrophil accumulation in the lung vessels; and 3) under the influence of chemoattractants released by macrophages, neutrophils migrate into the lung interstitium or pulmonary alveoli where they produce neutrophil elastase and reactive oxygen species, resulting in alveolar epithelial cell injuries [7]
Our study suggested that extracellular vesicle (EV) miRN A-466, which is secreted into the airways, can exacerbate inflammation in a mouse ARDS model via the nucleotide-binding oligomerization like receptor 3 (NLRP3) inflammasome, and this pathway might represent a therapeutic target for ARDS
Summary
Acute respiratory distress syndrome (ARDS) is a life-threatening disease; its treatment has not yet been fully established. One of several factors involved in intercellular communication is the extracellular vesicle (EV) They act as carriers of functional content such as RNA molecules, proteins, and lipids and deliver cargo from donor to recipient cells. EVs have been reported to regulate the nucleotide-binding oligomerization like receptor 3 (NLRP3) inflammasome This has been identified as the cellular machinery responsible for activating inflammatory processes, a key component responsible for the pathogenesis of ARDS. Acute respiratory distress syndrome (ARDS) is an acute, diffuse, inflammatory form of lung injury [1]. SIRS induces the overproduction of inflammatory cytokines and causes multiple organ dysfunction syndrome (MODS); ARDS is considered a component of MODS [3]. The development of new therapies for the treatment of ARDS is urgently needed
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