Microparticles and acute lung injury

Abstract

<jats:p>The pathophysiology of acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), is characterized by increased vascular and epithelial permeability, hypercoagulation and hypofibrinolysis, inflammation, and immune modulation. These detrimental changes are orchestrated by cross talk between a complex network of cells, mediators, and signaling pathways. A rapidly growing number of studies have reported the appearance of distinct populations of microparticles (MPs) in both the vascular and alveolar compartments in animal models of ALI/ARDS or respective patient populations, where they may serve as diagnostic and prognostic biomarkers. MPs are small cytosolic vesicles with an intact lipid bilayer that can be released by a variety of vascular, parenchymal, or blood cells and that contain membrane and cytosolic proteins, organelles, lipids, and RNA supplied from and characteristic for their respective parental cells. Owing to this endowment, MPs can effectively interact with other cell types via fusion, receptor-mediated interaction, uptake, or mediator release, thereby acting as intrinsic stimulators, modulators, or even attenuators in a variety of disease processes. This review summarizes current knowledge on the formation and potential functional role of different MPs in inflammatory diseases with a specific focus on ALI/ARDS. ALI has been associated with the formation of MPs from such diverse cellular origins as platelets, neutrophils, monocytes, lymphocytes, red blood cells, and endothelial and epithelial cells. Because of their considerable heterogeneity in terms of origin and functional properties, MPs may contribute via both harmful and beneficial effects to the characteristic pathological features of ALI/ARDS. A better understanding of the formation, function, and relevance of MPs may give rise to new promising therapeutic strategies to modulate coagulation, inflammation, endothelial function, and permeability either through removal or inhibition of “detrimental” MPs or through administration or stimulation of “favorable” MPs.</jats:p>

Role of Claudin-5 in the Attenuation of Murine Acute Lung Injury by Simvastatin

“…This is an important area of future investigation, although we speculate that these effects are relevant to the complex pathobiology of ALI, perhaps, for example, via increased paracellular flux of microparticles that contribute to injury (35). Accordingly, it is certainly possible that strategies aimed at augmenting either claudin-5 expression directly or upstream signaling pathways may lead to novel and effective therapies for patients with ALI.…”

Novel regulators of endothelial barrier function

“…Not only inflammatory cells, but also microparticles released from neutrophils, platelets, or lymphocytes, can increase endothelial permeability and trigger lung vascular barrier failure. Such microparticles are extracellular vesicles of 50 nm up to 1 m in size with a lipid bilayer that can act as intercellular carriers for multiple membrane and cytosolic proteins, organelles, lipids, and RNA from their respective parental cells to various target cells (86). As such, microparticles can shuttle, e.g., short-lived barrier-disruptive lipid mediators such as thromboxane A 2 or platelet-activating factor to endothelial cells and, thus, promote barrier failure (86).…”

“…The glycocalyx, an extracellular covering on the apical side of endothelium, along with the monolayer adhesive property provided by the intercellular endothelial junctions, integrin receptors, and their protein partners, maintains the albumin-impermeable nature of the vessel wall under basal conditions. Barrier disruption often stems from compromised interendothelial junctions, resulting in the formation of gaps between normally contiguous cells, while barrier reinforcement arises from stabilization of junctional complexes (86). Canonically, barrier disruptive substances have included thrombin, platelet activating factor, tumor necrosis factor-␣ (TNF-␣), vascular endothelial growth factor (VEGF), histamine and bradykinin, while sphingosine-1-phosphate (S1P) and angiopoietin-1 are regarded as barrier stabilizing (87).…”

Improved resolution in extracellular vesicle populations using 405 instead of 488 nm side scatter

“…Beyond their association with specific disease states, EVs may in fact directly mediate and disseminate disease processes as they are capable of releasing or transferring internal or membrane-bound cargo to other cells or become incorporated directly into target cells [4]. …”