Invited Review Article Microparticles and Acute Lung Injury

Articles in PresS. Am J Physiol Lung Cell Mol Physiol (June 22, 2012). doi:10.1152/ajplung.00354.2011
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Invited Review Article
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Microparticles and Acute Lung Injury
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Mark McVey1,2, Arata Tabuchi1, Wolfgang M. Kuebler1,3-6
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The Keenan Research Centre at the Li Ka Shing Knowledge Institute of St. Michael´s;
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Departments of 2Anesthesia, 3Surgery and 4Physiology, University of Toronto, ON; 5Institute of
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Physiology, Charité – Universitätsmedizin Berlin and 6German Heart Institute Berlin, Germany;
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Author contributions: All three authors contributed towards the writing and editing of the paper.
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Declaration of Conflicts of Interest: None
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Running head: Microparticles and acute lung injury
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Body of the manuscript: 8616 words
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Address for Correspondence:
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Wolfgang M. Kuebler, MD Dr. med.
Email: kueblerw@smh.ca
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The Keenan Research Centre
Phone: 416 864 5924
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Li Ka Shing Knowledge Institute
Fax: 416 864 5958
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St. Michael´s Hospital
209 Victoria Street
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M5B 1W8 Toronto, Ontario
Canada
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Key words: Acute lung injury, ARDS, microparticles, permeability, coagulation, inflammation,
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endothelial function
Copyright © 2012 by the American Physiological Society.
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Abstract
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The pathophysiology of acute lung injury and its most severe form, ARDS, is characterized by
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increased vascular and epithelial permeability, hypercoagulation and hypofibrinolysis,
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inflammation and immune modulation. These detrimental changes are orchestrated by crosstalk
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between a complex network of cells, mediators and signaling pathways. A rapidly growing
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number of studies have reported the appearance of distinct populations of microparticles (MPs)
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in both the vascular and alveolar compartment in animal models of ALI/ARDS or respective
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patient populations, where they may serve as diagnostic and prognostic biomarkers. MPs are
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small cytosolic vesicles with an intact lipid bilayer that can be released by a variety of vascular,
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parenchymal or blood cells and that contain membrane and cytosolic proteins, organelles, lipids
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and RNA supplied from and characteristic for their respective parental cells. Due to this
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endowment, MPs can effectively interact with other cell types via fusion, receptor-mediated
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interaction, uptake, or mediator release, thereby acting as intrinsic stimulators, modulators or
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even attenuators in a variety of disease processes.
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This review summarizes current knowledge on the formation and potential functional role of
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different MPs in inflammatory diseases with a specific focus on ALI/ARDS. ALI has been
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associated with the formation of MPs from such diverse cellular origins as platelets, neutrophils,
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monocytes, lymphocytes, red blood cells, endothelial and epithelial cells. Due to their
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considerable heterogeneity in terms of origin and functional properties, MPs may contribute via
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both harmful and beneficial effects to the characteristic pathologic features of ALI/ARDS. A
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better understanding of the formation, function and relevance of MPs may give rise to new
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promising therapeutic strategies to modulate coagulation, inflammation, endothelial function and
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permeability either through removal or inhibition of "detrimental" MPs, or through
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administration or stimulation of "favorable" MPs.
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INTRODUCTION
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ALI/ARDS. Acute lung injury (ALI) as a result from either direct or indirect mechanical, toxic,
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infectious, or inflammatory challenges to the lung, presents initially as dyspnea and hypoxemia
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which can rapidly progress to respiratory failure. ALI and its most severe form, the acute
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respiratory distress syndrome (ARDS) are characterized by bilateral exudative chest infiltrates
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visible by roentgenograms with no evidence of left heart failure and a PaO2/FiO2 ratio < 300
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(ALI) or even < 200 (ARDS) (151, 171). Within days, ALI progresses from an initial
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inflammatory exudative phase with a leaky edematous lung to a proliferative phase involving
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fibrin deposition and a concomitant decrease in respiratory compliance that finally, if the patient
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survives, proceeds to a fibrotic phase where the lung is burdened with scarring as it remodels
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while attempting to heal. Despite the well-documented benefit of protective ventilatory strategies
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and increasing knowledge of the etiological mechanisms of ARDS, mortality rates remain
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relatively stagnant around 40% (133), with incidence estimates of up to 75 per 100 000 (171).
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A broad spectrum of different cell types contribute to the pathogenesis of ARDS, including
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alveolar epithelial and vascular endothelial cells which undergo changes in permeability leading
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to edema formation and alveolo-capillary injuries, as well as platelets and immune cells such as
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polymorphonuclear neutrophils (PMNs), alveolar macrophages and monocytes which are
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critically involved in inflammatory responses (104, 108, 170, 171). In contrast to the
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characteristic anticoagulant and profibrinolytic basal state of the lung, ALI is associated with a
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prothrombotic and antifibrinolytic shift which favours deposition of fibrin and accelerates and
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potentiates inflammation (19). Considerable research has focused on the direct interaction and
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communication between different cell types both in vivo and in vitro, and revealed important
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pathophysiological aspects of ALI. However a rapidly growing number of studies have recently
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started to recognize the critical role of microparticles (MPs) as biomarkers, communication
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shuttles between these different cells and cell types, and independent functional effectors in a
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large variety of diseases ranging from endemic pathologies such as hypertension, diabetes and
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atherosclerosis to frequently lethal syndromes such ALI (7, 16, 27, 28, 31, 36, 44, 60, 65, 79, 99,
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118, 129, 135, 138, 155, 172). Here we provide a brief overview on the main characteristics of
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MPs, review the current knowledge on their role in inflammatory disease with a particular focus
2
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on ALI, and oppose their proposed detrimental and beneficial effects in lung injury, thus
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providing a rationale for their future use as both therapeutics targets and tools.
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MICROPARTICLES. The first accounts of MPs date back to 1967 at which time they were
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considered to be nothing more than cellular dust (177). In fact, MPs are tiny cell-derived, intact
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vesicles that are formed by partitioning off from activated or apoptotic eukaryotic cells (Figure
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1). MPs are defined by their size, which ranges between 50 nm and 1 µm, and their distinctive
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lipid layer composition. MPs have intact lipid bilayers, yet their outer layer has a
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characteristically high level of negatively charged phospholipids, particularly phosphatidylserine
86
(PS). MPs may contain membrane and cytosolic proteins, transcription factors, genetic material
87
such as ribosomal RNA (rRNA), messenger RNA (mRNA), and microRNAs (miRNA) as well
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as lipids or even organelles supplied from parent cells (22, 32, 109, 116). Occasionally,
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membrane vesicles of less than 0.1 µm are sub-categorized as nanoparticles, and have been
90
proposed to originate from lipid rafts on parent cell membranes; accordingly, they may display
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distinct protein endowments and functions (reviewed in 77, 134, 155).
92
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MICROPARTICLES SUBSERVE INTERCELLULAR INFORMATION EXCHANGE. The
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distinct cellular elements retained from precursor cells allow MPs to function as transcellular
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delivery systems for the exchange of biological signals. Notably, information exchange between
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MPs and target cells can occur in a bidirectional manner, thus generating a continuous and
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dynamic exchange of antigens, cell signaling molecules and genetic material that opens an entire
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new spectrum of opportunities for tightly regulated (or dysregulated) signal propagation.
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In principle, MPs can transfer information from the MP-generating donor cell to a wide range of
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target cells by either direct cell-cell contact for delivery of genetic material, proteins and lipids or
101
alternatively by remote interaction through secretion of soluble mediators and effectors by MPs.
102
Currently, we distinguish at least four distinct mechanisms how MPs may interact with their
103
target cells which are illustrated schematically in Figure 2. First, MPs are able to stimulate
104
outside-in-signaling in target cells via presentation of membrane-associated ligands that directly
3
105
bind to their respective surface receptors, or via release of secreted factors such as for example
106
cytokines which act on the target cell via receptor-mediated or receptor-independent mechanisms
107
(102). Second, MPs can be internalized into recipient cells, a process that has also been proposed
108
to underlie the rapid clearance of circulating MPs from the blood (41). For example,
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fluorescently tagged PMPs can be endocytosed by brain microvascular endothelial cells, and are
110
subsequently detectable in endosomes and lysosomes (50). Third, MPs may fully or partially
111
fuse with the target cell, allowing for complete or selective transfer of contents including
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membrane and cytosolic proteins, bioactive lipids (109, 139) or even whole cell organelles as
113
recently demonstrated for the microvesicular delivery of mitochondria by mesenchymal stem
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cells (73). Last, MPs may deliver genetic material in form of mRNA and miRNA. While the
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encoding mRNAs can be directly translated to alter the target cell proteome (6, 45), miRNAs are
116
small non-coding RNAs that can modulate gene expression in target cells at the post-
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transcriptional level, in that they bind to complementary sequences on target mRNAs, commonly
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resulting in translational repression and gene silencing. The export of miRNA from donor cells is
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largely regulated by ceramide (166), a notion that gains relevance in light of the parallel
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implication of ceramide in MP generation (155) which may thus facilitate miRNA egress with
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MPs in a coordinated fashion. At the level of the target cell, subsequent miRNA entry is
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facilitated by either endocytosis of MPs, or by fusion of their lipid bilayer with the plasma
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membrane (166). Lately, miRNAs have been detected in a wide variety of different MPs as
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generated from peripheral blood cells in humans (70), mesenchymal (39) or embryonic stem
125
cells (180), respectively, and miRNA transfer by MPs has been demonstrated to critically
126
modulate target cell responses such as for example angiogenesis in endothelial cells (64). As
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miRNAs have recently been recognized to contribute to injurious mechanisms in ALI (183),
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transfer of miRNA from MPs to inflammatory or lung parenchymal cells may present an exciting
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novel pathomechanisms in this disease which clearly deserves further exploration.
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ORIGIN OF MICROPARTICLES. Parent cells of MPs include but are not limited to platelets,
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megakaryocytes, monocytes, epithelial cells, lymphocytes, PMNs, endothelial cells, red blood
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cells, reticulocytes, mast cells, stem cells, astrocytes, glial cells, smooth muscle cells and cancer
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cells (16, 20, 23, 139). Similar to the wide range of parent cells, MP formation can be triggered
135
by diverse physiological, pathophysiological or experimental stimuli as discussed in greater
136
detail below.
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Unstimulated, resting cells actively maintain their membrane asymmetry via phospholipid
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transporter enzymes which localize negatively charged phospholipids on the inner leaflet, facing
139
into the cell. When cellular homeostasis is disturbed or lost such as in apoptosis, the activities of
140
these phospholipid flippases, floppases and scramblases are dysregulated leading to hastened
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changes in membrane composition of the inner and outer membrane leaflets. This process is a
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characteristic feature of MP formation, as it allows for the relocation of the PS rich layer of the
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inner leaflet to the exterior leaflet (116, 155). The resulting changes in membrane composition
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and regular asymmetry in conjunction with processes such as intracellular calcium accumulation
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and calpain activation reviewed in detail elsewhere (116, 119) cause membrane blebbing and
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ultimately the formation of MPs (Figure 3).
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Externalization of PS is a precursor step in MP formation allowing for a common shared surface
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marker for identification of many MPs which can be assayed by annexin V binding. Interestingly
149
however, it appears that there are MPs which do not stain appreciably for annexin V, which adds
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controversy to the identification and strict definition of what constitutes an MP (116, 153).
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Further it seems that some MPs can also be formed before regular membrane asymmetry is
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disrupted, such as in cultured endothelial cells (155). Specifically, Davizon and colleagues have
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linked MP formation to lipid rafts in cell membranes (42, 155), raising the possibility that lipid
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rafts may be actively involved in MP formation under some conditions, and that MPs may
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maintain part of the unique functional and signaling properties of membrane lipid rafts (Figure
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3). Currently, the cellular machinery implicated in MP formation constitutes an active area of
157
research (reviewed in 134), that is expected to yield important insights not only into the
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mechanisms of MP formation, but likewise into its regulation and function.
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In healthy humans, circulating MPs are largely derived from platelets with some contributions
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from leukocytes and minimally from endothelial cells (34, 36). Size and composition of this
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population of basal MPs depends on physiological variables including exercise, menstrual cycle,
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age, or exposure to extreme environments such as SCUBA diving, in addition to countless
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pathologic conditions some of which are discussed in later sections of this review (34, 55, 163).
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Platelet MPs have a short circulating half life of less than 10 minutes in rabbits (141), but were
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shown to circulate for approximately 30 minutes in mice (53). MP clearance from the circulation
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occurs predominantly by endothelial cell internalization (41) or splenic removal, and the half live
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of platelet MPs is markedly prolonged in splenectomized mice as compared to controls (129).
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Moreover, a recent study in thrombocytopenic humans reported a markedly longer half life for
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circulating MPs that was in the order of 5 to 6 hours (142, 143). The considerable variation in
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half lives in these studies suggests a major influence of both host and MP variables such as
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species, blood cell levels and mode of activation, as well as potential methodological variability
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with respect to isolation and assay for MPs between these different studies.
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Tracking the origin of MPs is complicated not only by the wide variety of possible parent cell
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sources and triggering stimuli, but in addition by the fact that these cell-derived vesicles can be
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and presumably are constantly phenotypically modified by contact with different cell types at
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different steps in their production. Different mechanisms of fusion between cells and MPs which
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could lead to phenotypic modulation of MPs and/or other cells have been recently reviewed in
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detail by Quesenberry and colleagues (139). A particularly striking example in this respect is the
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provocative hypothesis that endothelial progenitor cells may origin from the fusion of platelet
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microparticles (PMPs) with mononuclear cells as suggested by proteomic analyses (137).
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Repetitive fusion events with tissue factor (TF) expressing cells may also account for the
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expression of TF on various types of cells and MPs which would not otherwise express this
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marker. For example, platelets can become TF positive after contact with TF expressing MPs
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shed
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(lipopolysaacharide; LPS) or protein kinase C activation by phorbol myristate acetate (PMA),
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platelets and subsequent PMPs may obtain their TF antigens from either fusion with monocytes
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or monocyte MPs (MMPs) (28). Beyond mixing of distinct lineage markers between cells and
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MPs there are also challenging distinctions between MPs of similar parent cell origins. Subtle
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variations in parent cells can be difficult to detect due to phenotypic similarities of their
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respective MPs, as in the case of platelet versus megykaryocyte-derived MPs (54, 143). Hence, a
from
PMNs
and
monocytes
(145).
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Following
stimulation
with
endotoxin
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series of elaborate experimental techniques have been developed to allow for the exact
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identification of the origin of MPs and the functional significance of these cell-derived vesicles.
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CHARACTERIZATION OF MICROPARTICLES. In the stepwise process of experimentally
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isolating MPs there are considerable technical variables which can impact on the recovery and
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phenotype of MPs obtained. Some of these procedural differences include the actual phlebotomy,
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the use of anticoagulants, storage conditions, length and number of freeze-thaw cycles,
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centrifugation, washing, pelletting or filtration of MPs, and specific recommendations (Table 1)
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have been developed to optimize each of these steps (186). A series of review articles have
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scrutinized the impact of these variables which underline the sensitive and precarious nature of
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MP isolation and stress how caution is required to avoid undesired differences in MP isolates
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obtained from slight variations in handling and processing procedures (91, 134, 153, 155). The
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rapidly growing number of publications pertaining to MPs showcases a diverse array of
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techniques for preparation and isolation of MPs which is bound to generate considerable
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variability in terms of the final products assayed (78, 134). In recent years, this dilemma has
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stimulated workshops and meetings specifically dedicated to the attempt to limit variability and
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standardize the study of MPs, and namely the International Society on Thrombosis and
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Haemostatis has made strides to centralize methodologic approaches for MP isolation (90).
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Detection and characterization of MPs has involved strategies such as antibody capture ELISA
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assays, flow cytometry, functional coagulation assays, electron (Figure 1), atomic force or
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confocal microscopy, HPLC, capillary electrophoresis and mass spectrophotometry (11, 24, 37,
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43, 75, 77-79, 89, 91, 115, 129, 137, 153, 155, 162, 174, 181, 185). Each of these techniques
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comes with its specific advantages and limitations, as summarized in table 2. Due to its general
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availability and versatility, flow cytometry has become the most commonly used technique for
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characterization of MPs and discerning their parent cell of origin depending on the expression of
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characteristic surface markers (Table 3). Most strategies with flow cytometry involve
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identification of MPs based on forward and side scatter characteristics as well as annexin V
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staining for PS in conjunction with analysis of markers characteristic for specific parent cells to
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test for their contribution to the individual MPs being assayed. The use of flow cytometry to this
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end bears a series of strengths, but also some limitations (77, 78, 89, 147, 153) which have been
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discussed in detail in recent literature. Proteomics presents an important alternative tool for
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particularly small particles not amenable to flow cytometry (117) as it can yield comprehensive
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information on characteristic protein expression patterns which may be utilized to identify and/or
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characterize MPs. This approach has been used in a series of investigations to assay different
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aspects of the human MP proteome (75, 96).
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HETEROGENEITY OF MICROPARTICLES. Our current understanding of the conditions
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under which MPs are formed, and their individual actions is still incomplete. Little is known
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about exact parameters which dictate when, how, from where, why, which and how many MPs
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are formed. What is becoming evident is the vast variation in terms of genetic material and
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antigens MPs can express from their parent cells of origin or other cells or MPs they contact
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during formation or during circulation, which can be incorporated or eventually redistributed to
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other MPs or cells. The literature has likely not captured the full extent of variations possible as
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the characterization of MPs under different conditions is incomplete and we currently lack the
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tools to accurately assay antigens present at very low abundances on the surface of MPs. MPs
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come in a variety of sizes ranging from smaller nanoparticles such as those often produced by
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red blood cells up to microparticles large enough to rival platelets (134). Similar parent cells are
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able to produce a spectrum of different sized MPs depending upon whether MP formation occurs
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spontaneously at baseline or following stimulation (25, 74). Even cell lines such as Jurkat T cells
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yield a spectrum of different sized MPs (164). Notably, this heterogeneity in size can directly
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impact on MP surface marker expression and function as shown for platelet MPs which contain
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different antigens such as growth factors, chemokines and receptors depending on their size (74).
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Similar to their heterogeneity in terms of origin, size, and endowment with antigens, MPs also
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differ widely with regard to their functional effects. MPs can shuttle information from remote
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cells to similar or phenotypically different cells which might never be in direct proximity.
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Different MPs can affect certain cells in different ways as for example diabetics’ T cell-derived
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MPs can decrease endothelial NO synthase (eNOS) and increase caveolin-1 expression causing
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endothelial dysfunction as opposed to MPs formed by in vitro activation of human T cells which
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express sonic hedge hog on their membranes and can stimulate NO production as evidenced by
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the improved endothelial function in a cardiac ischemia reperfusion injury model (106, 114).
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Alternatively, a single MP subtype such as PMPs can interact with and recruit numerous target
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cells such as monocytes, NK cell, B and T cells (114).
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MP generation is triggered by a spectrum of stimuli ranging from physiological to experimental
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stimuli (Table 4). MPs can be formed constitutively by various parent cells under physiological
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conditions but in differing amounts, resulting in a higher abundance of circulating PMPs as
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compared to red blood cell or lymphocyte derived MPs (RMP and LMP, respectively) in healthy
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patients (116). Additional physiological triggers for MP formation involve stresses such as heavy
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exercise or cyclic changes such as menstruation. MP formation in response to pathophysiological
259
stimuli adds another level of complexity, as different triggers will stimulate MP formation from
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different parent cell types. Multiple simultaneous or sequential triggers can further enhance MP
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diversity and therefore potentially expand their range of function. For example, platelet storage
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conditions including platelet rich plasma, apheresis blood bank derived human platelets, or cold
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storage of platelets with and without contact with propyl gallate will produce distinct PMP
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variants (33, 144, 168, 178). Addition of platelet activation inhibitors such as prostaglandin E1
265
(PGE1), theophylline and aprotinin during storage reduce the number of large but not small
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PMPs formed, and modify their function in terms of platelet factor 3 activity (25). Under
267
experimental conditions, a diverse array of potent cell stimulants such as calcium ionophores,
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phytohemagglutinins, LPS, fMLP and PMA can be utilized to induce MP formation with a high
269
efficiency and reproducibility (Table 4).
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MICROPARTICLES IN INFLAMMATORY DISEASE
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Some of the MPs characterized to date have been identified as biomarkers for a wide variety of
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inflammatory conditions. Elevated levels of circulating PMP, LMP, MMP and endothelial MPs
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(EMPs) have been shown to accompany pathologic conditions such as atherosclerosis, type 2
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diabetes, vasculitis, pulmonary hypertension, coronary disease, cardiopulmonary resuscitation,
276
lupus, Crohn´s disease and rheumatoid arthritis (7, 27, 28, 36, 52, 118, 129, 135, 138, 155).
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Likewise, systemic inflammatory states in pregnancy such as preeclampsia are associated with
278
elevated plasma levels of MPs (146). Infectious diseases are either directly associated with
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increased levels of MPs as seen in malaria (61), or can give rise to disproportionate inflammatory
280
responses such as the systemic inflammatory response syndrome (SIRS), sepsis or the multi-
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organ dysfunction syndrome (MODS), which are again associated with elevated levels of MPs
282
(129, 155). MPs have also been implicated mechanistically on several levels in the
283
pathophysiology of sepsis, including proinflammatory signaling pathways such as target cell
284
activation through reactive oxygen species production and coagulopathy in terms of MP
285
mediated TF presentation (113).
286
A survey comparing 36 patients with sepsis with 18 healthier patients without sepsis showed
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elevated blood levels of total MPs, specifically PMPs and EMPs, whereas CD45+ LMPs were
288
lower in patients with sepsis as compared to controls (122). Interestingly, MPs from septic
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patients enhanced aortic contraction when transfused intravenously to mice. This effect was
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independent of NO modulation or COX enzyme expression but blocked by the specific
291
thromboxane A2 (TXA2) antagonist SQ-29548, indicating that circulating MPs may prevent
292
vascular hyporeactivity accounting for systemic hypotension in septic shock through a TXA2-
293
mediated mechanism (122). Furthermore, patients with SIRS have elevated levels of circulating
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EMPs, increased binding of MPs to PMNs, higher procoagulant activity and higher circulating
295
levels of triggers for MP formation such as plasminogen activator inhibitor 1 (PAI-1) compared
296
with healthy controls (126). As we discuss later in greater detail, the effects of MPs are
297
frequently considered to aggravate the pathology in inflammatory and cardiovascular diseases,
298
and increased formation of MPs as seen in systemic inflammatory disorders is therefore
299
generally considered to constitute not only a biomarker, but an important pathophysiological
300
mechanism driving the disease. However, inflammation and the associated increase in circulating
301
MPs may also have protective effects, as pointed out by Soriano and coworkers who
302
demonstrated that increased inflammation and the presence of EMPs, PMPs and platelet
303
leukocyte conjugates are significantly associated with survival in septic patients (158). Hence,
304
more detailed and comprehensive experimental and clinical investigations are in dire need to
10
305
discern which MPs under what conditions exert beneficial or detrimental effects in inflammatory
306
diseases.
307
Over the past decade, it has become evident that inflammatory diseases are closely associated
308
with impaired coagulation and fibrinolysis, processes that can be regulated through MPs. Many
309
but not all MPs express tissue factor (TF) which interacts with factor VIIa facilitating activation
310
of factors IX and X, thus leading to generation of thrombin (103). TF MPs are characteristically
311
found in diseases where thrombosis is common such as cancer, sepsis, unstable angina, ALI,
312
sickle cell disease and thromboembolism (128, 129, 138, 165), giving rise to the speculation that
313
they may contribute critically to the disease process. TF is a key player in the activation of the
314
coagulation pathway, yet its action is not only determined by its expression levels, but also by its
315
accessibility in terms of conformational state which is controversial for different cells types or
316
conditions (128). Much of the circulating TF is in fact in an encrypted and therefore, inactive
317
state, while MPs represent a source of decrypted, active TF (127). LPS stimulates monocytes and
318
endothelial cells to produce TF which can lead to a coagulopathy that can escalate into DIC
319
(103). Co-incubation of platelets with monocytes and PMNs which produce high amounts of TF
320
following stimulation with pro-inflammatory agents such as LPS leads to enhanced presentation
321
of decrypted TF in the form of MPs, thus generating a prothrombotic milieu (127). Even MPs not
322
expressing TF can still possess considerable procoagulant properties as they contain anionic
323
phospholipids, including PS which acts as a surface to facilitate assembly of the clotting factor
324
machinery (103, 129, 138). Hence, MPs can be involved in coagulopathies associated with
325
inflammatory diseases such as sepsis as they possess prothrombotic characteristics with exposed
326
TF and PS, but conversely may also activate fibrinolysis via changes in plasminogen and
327
metalloproteases (113), or exert anticoagulant properties mediated through protein C and tissue
328
factor pathway inhibitor (TFPI) (117). In line with the notion that MPs may have both pro- and
329
anticoagulant effects, thrombus weight was shown to correlate with plasma levels of PMPs and
330
older MPs in a murine thrombus model, while LMPs showed an inverse correlation (140).
331
332
MICROPARTICLES AND ACUTE LUNG INJURY. Several studies have shown associations
333
of MPs with key structures and cells in ALI, giving rise to the notion that similar to systemic
11
334
inflammatory diseases, MPs may be a biomarker of the disease and play important roles by either
335
aggravating or counteracting (or potentially both) the ongoing disease process. For example,
336
interactions between cells such as platelets, PMNs and endothelial cells are central to the
337
pathology of ALI/ARDS, and MPs have been demonstrated to critically regulate these
338
interactions, and/or modify the phenotypes of the contributing cells by fusion and subsequent
339
transfer of cellular components. In the following, we will summarize recent data in support of an
340
association and possible functional role of MPs in ALI/ARDS and discuss potential novel
341
interactions between MPs and lung parenchyma or circulating blood cells that are likely pertinent
342
to lung injury.
343
344
POTENTIAL DETRIMENTAL EFFECTS OF MICROPARTICLES IN ALI
345
Excessive inflammation, changes in coagulation and fibrin deposition and increased permeability
346
of the alveolocapillary barrier with resulting protein extravasation and lung edema formation are
347
characteristic hallmarks of ALI (Figure 4). In the following, we highlight how MPs may impact
348
either directly or indirectly on the pathophysiology underlying these symptoms.
349
350
INFLAMMATION. Inflammatory changes in ALI/ARDS involve an abundance of
351
proinflammatory intra- and intercellular signaling pathways which include, but are in no way
352
confined to signaling via arachadonic acid (AA), TXA2, plasminogen activator inhibitor-1 (PAI-
353
1), nitric oxide (NO), reactive oxygen species (ROS), cytokines and protease activated receptors
354
(PARs). In this section, we highlight data demonstrating that MPs can modulate and/or replicate
355
these pathways (114, 120), and thus act as proinflammatory agents promoting ALI/ARDS.
356
Over past years, the tight interplay between platelets and PMNs has emerged as important aspect
357
in the pathogenesis of ALI (100, 160, 182). Similar to platelets, circulating PMPs can interact
358
with PMNs via linkages including glycoprotein Ib/Mac-1, β2-integins (CD11b)/Mac-1, or P-
359
selectin/PSGL-1 on PMPs/PMNs, thus causing PMN activation involving secretion of
360
interleukin (IL)-8 secretion, oxidative burst, degranulation, and enhanced leukocyte rolling (79,
12
361
99). Likewise, PMPs generated from LPS-stimulated platelets promote endothelial activation as
362
exemplified by the finding that they further increase the IL-1β induced expression of vascular
363
cell adhesion molecule (VCAM)-1 (30). Hence, circulating PMPs are not only a biomarker, but
364
more importantly, an active promoter of inflammatory disease processes in that they stimulate
365
endothelial cells, PMNs and notably also platelets. The latter was demonstrated in experiments
366
where PMPs were stimulated by soluble phospholipase A2; the newly formed AA is then rapidly
367
converted by PMPs to TXA2, a classic activator of platelets (14). In line with this view, ExoU, a
368
Pseudomonas aeruginosa cytotoxin with phospholipase A2 activity, increases both, PMP release
369
and TXA2 formation, and accordingly, resulted in lung thrombus formation and increased
370
vascular permeability in a murine model of pneumosepsis (101). Overall, a series of
371
proinflammatory effects of PMPs has emerged that is based on the activation of platelets,
372
monocytes, and vascular endothelial cells either directly by MP-derived AA, or by its
373
metabolism to bioactive prostanoids (12, 13, 15). This recognition substantiates a critical role of
374
PMPs in ALI, as TXA2 contributes pivotally to lung vascular leakage and inflammation in
375
experimental models of the disease (72).
376
Platelet-PMN and endothelial-PMN co-stimulation may not only be promoted by PMPs, but
377
likewise by PMN microparticles (NMPs), as endotoxin (LPS) can stimulate adherent PMNs to
378
release NMPs that generate platelet-activating factor (PAF), thus causing activation of platelets
379
(172), endothelium (149) and other inflammatory cells. In the airspaces, NMPs may also trigger
380
inflammatory responses and epithelial cell damage, as suggested from their abundance in sputum
381
from patients with cystic fibrosis (136). NMPs can furthermore directly activate endothelial cells
382
to generate proinflammatory cytokines such as interleukin-6, thereby further promoting vascular
383
inflammation (8, 111, 112). Endothelial cells may in turn likewise release MPs (EMPs) which
384
modulate inflammation and coagulation, and most prominently vascular barrier function, for
385
which reason they are discussed in greater detail in the section Permeability.
386
Lastly, inflammatory diseases such as ALI and ARDS are often associated with immune
387
modulation and its complex functional consequences including inflammatory damage to
388
bystander cells (123, 158, 173). Such immune modulation also involves platelets which can
389
actively alter innate and adaptive immune function (94, 152). For example, PMPs can stimulate
13
390
endothelial cells to generate a range of proinflammatory cytokines including IL-1, IL-6, IL-8 and
391
monocyte chemoattractant protein-1 (MCP-1) as well as monocyte derived interleukin (IL)-1,
392
tumor necrosis factor alpha (TNFα) and IL-8 (reviewed in 20, 120). MPs have also been directly
393
associated with immunomodulatory effector molecules such as RMP and PMP derived CD40L,
394
IgG and complement found in stored blood products (80). Immunomodulatory and
395
proinflammatory effects of MPs may be particularly relevant in the context of transfusion-related
396
ALI (TRALI), as storage of blood products will propel formation of MPs (25, 33, 144) that will
397
subsequently activate PMNs (80). Taken together, MPs of diverse cellular origins including
398
LMPs, PMPs, RMPs, NMPs and EMPs directly or indirectly promote inflammatory responses
399
and may thus propel ALI, in that they stimulate cytokine release and promote PMN activation,
400
migration and PMN-platelet interaction.
401
402
COAGULATION. Severe infections lead to activation of the coagulation cascade and altered
403
fibrinolysis, with the lung being a key recipient of fibrin and clots during ALI and sepsis (165).
404
The hypercoagulable and hypofibrinolytic changes seen in ALI/ARDS contribute pivotally to the
405
pathology of the disease (170, 171) and involve characteristic changes in mediators of
406
coagulation and fibrinolysis, including TF, thrombomodulin, TFPI, plasminogen activator
407
inhibitor 1 (PAI-1), PS, and von Willebrand factor (vWF).
408
TF is considered to play an important role in the pathophysiology of lung injury, as it can
409
activate PAR1 and PAR2 which are involved in inflammatory and procoagulatory responses
410
causing fibrin deposition in the lung (82, 165). Importantly, TF is not only expressed on
411
activated mononuclear cells, endothelial cells, alveolar epithelium, or respiratory macrophages,
412
but likewise on many MPs (11, 165). The procoagulant activity of PMP membranes exceeds that
413
of their parent platelet membranes by up to 100-fold (116, 156). In vascular homeostasis, the
414
effects of TF are counteracted by TFPI which blocks the TF-induced stimulation of the
415
coagulation cascade by reversibly inhibiting factor Xa and thrombin. Severe infections such as
416
sepsis which constitute typical predispositions for ALI are characterized by an imbalance
417
between elevated TF and lowered TFPI levels causing enhanced coagulation and inflammation
418
(165). The relevance of this imbalance is highlighted by observations from humans (56) and
14
419
experimental models of ALI in which blockade of TF by antibodies (175) or TFPI (48) reduced
420
lung damage and improved pulmonary function. Monocytic MPs (MMPs) can attenuate the
421
expression of TFPI and thrombomodulin, an endothelium-derived anti-coagulant factor, thus
422
increasing thrombogenicity in vitro (4), whereas TF is abundantly expressed on MPs under
423
inflammatory conditions (91). In healthy human volunteers, MP-borne TF procoagulant activity
424
increased 8-fold within 4 hours after infusion of LPS (11). Hence, infectious or inflammatory
425
stressors may contribute to and/or aggravate ALI in part by the formation and release of TF
426
studded MPs which in the presence of an attenuated anticoagulatory response will generate the
427
characteristic prothrombotic milieu associated with ALI, especially in consideration of the
428
previously discussed fact that TF on MPs is often decrypted and active. Notably, TF activity on
429
MPs in ALI/ARDS is not necessarily confined to the vascular compartment (16), but – in line
430
with the clinical presentation of fibrin clots in the distal airspaces – may similarly apply to the
431
alveolar compartment where increased TF production by alveolar epithelial cells has been
432
documented (18, 165). In pulmonary edema fluid from mechanically ventilated (<7 ml/kg tidal
433
volume) patients with ARDS, Bastarache and colleagues detected higher concentrations of
434
epithelial cell marker receptor for advanced glycation end products (RAGE) and TF enriched
435
MPs in BALF as compared to patients with hydrostatic lung edema whose MPs also expressed
436
less TF and RAGE (16). It is possible that ARDS leads to either larger MPs that express more
437
RAGE receptors or perhaps a numeric increase in RAGE positive MPs compared with ARDS-
438
negative hydrostatic edema controls. Patients who died had a trend towards a higher MP
439
concentration in lung edema fluid compared with those who survived (p=0.073), attesting to a
440
detrimental effect of MPs in ALI/ARDS. Similar MPs could be generated in vitro by stimulation
441
of cultured alveolar epithelial cells with a mix of the proinflammatory mediators TNF-α, IL-1β,
442
and interferon-γ (16, 17). While both ARDS and non-ARDS controls in Bastarache’s study were
443
severely sick, BALF analyses from healthy pigs with volume controlled ventilation set to
444
maintain normocapnia (37.5-41 mmHg PaCO2) with 5 cmH2O PEEP revealed PMPs that were
445
positive for fibrinogen, vWF and P-selectin (124). This finding gains relevance in light of the
446
fact that mechanical ventilation, in particular at tidal volumes > 6 mL/kg body weight, will
447
exacerbate ALI and promote ventilator induced lung injury (VILI). PMPs in BALF were evident
15
448
after only 1 h of mechanical ventilation, yet unfortunately, actual tidal volumes applied were not
449
reported in this study so that it is unclear whether this effect was attributable to overventilation or
450
occurs even under conditions of protective ventilation. Notably, presence of PMPs was likewise
451
detected in human tracheal mucus obtained from five humans at extubation after surgery,
452
suggesting that this finding may reflect a more general effect of mechanical ventilation and/or
453
surgical trauma.
454
Similar to TF expressing MPs, a pro-coagulant environment in ALI may be likewise promoted
455
by PMPs. However, the degree to which circulating PMPs are actually elevated in patients with
456
ALI or ARDS remains to be elucidated. Earlier work by George and coworkers did not detect an
457
increase in blood PMPs in patients with ARDS from various causes, while post cardiac bypass
458
patients exhibited an increased plasma concentration of PMPs (60). Yet, it is conceivable that the
459
radiolabelled GPIIb antibody technique used to assay PMPs in this study did not screen for the
460
entire population of PMPs in the ARDS cohort. Beyond TF expression, MPs expose large
461
amounts of PS on their outer membranes thus creating an ideal surface for activation of the
462
coagulation pathway (148). In addition, MPs generate and release other prothrombotic factors
463
including thrombin (80) or vWF multimers which can promote and stabilize platelet aggregation
464
(20). In summary, there is ample evidence from in vitro, animal and human studies
465
demonstrating the formation of MPs with procoagulant activity under inflammatory conditions
466
and in ALI in both the vascular and alveolar compartment, where they are likely to contribute
467
pivotally to the hypercoagulable and hypofibrinolytic state characteristic for ALI/ARDS.
468
469
PERMEABILITY. The increased permeability of capillary and alveolar barriers in ALI leads to
470
the extravasation of high molecular weight protein and inflammatory cells into the airspaces of
471
the lung, thus impairing respiratory mechanics, attenuating gas exchange, causing increased
472
shunting and ventilation perfusion mismatch and contributing to the consolidation of lung tissue
473
during the subsequent fibroproliferative phase of ALI/ARDS. Several biolipid mediators such as
474
TXA2, phospho- and sphingolipids have been implicated in the pathogenesis of permeability-
475
type lung edema, and are notably also linked directly or indirectly to the formation and function
476
of MPs (62, 104).
16
477
As discussed before, PMPs can promote the formation of TXA2 from AA (14). This finding
478
gains relevance in the context of permeability-type edema as TXA2 inhibitors can reduce lung
479
vascular permeability in animal models of ALI (72, 182). In line with this view, increased levels
480
of circulating PMPs were associated with elevated TXA2 plasma concentrations and lung
481
vascular permeability in a mouse model of bacterial pneumosepsis with histological evidence of
482
thrombus formation in the lungs (101). In sepsis, the increased MP associated formation of TXA2
483
may serve to maintain a basal vasopressor effect (120, 122), yet this beneficial effect does not
484
translate to the low pressure system of the lung where increased TXA2 formation will primarily
485
promote lung edema.
486
In addition to eicosanoids, phospho- and sphingolipid mediators such as PAF and ceramide have
487
been proposed to contribute critically to vascular hyperpermeability in ALI (62). PAF can be
488
expressed on the surface of NMPs and promote platelet aggregation and association with PMNs
489
(172) while ceramide has been implicated in MP formation due to its involvement in lipid rafts
490
(155). Acid sphingomyelinase (ASM), which catalyzes the conversion of sphingomyelin to
491
ceramide, triggers the release of brain glial MPs, an effect that is blocked by ASM inhibitors or
492
in astrocytes obtained from ASM deficient (Smpd1-/-) mice (23). While it remains to be shown
493
whether a similar ASM-mediated mechanism contributes to MP formation in other non-glial cell
494
types, this finding raises the intriguing notion that the demonstrated detrimental effects of
495
ASM/ceramide signaling in ALI (87) relate to the increased formation of MPs.
496
497
ENDOTHELIAL FUNCTION. Apart from biolipid mediators, various MPs may directly impact
498
on endothelial function, thereby critically regulating vascular barrier properties as well as
499
promoting the hyper-inflammatory and hyper-coagulatory responses discussed in previous
500
sections. EMPs can attenuate NO release from cultured endothelial cells, and induce a
501
corresponding decrease in eNOS phosphorylation at Ser1179 and a decrease in hsp90 association
502
consistent with the notion of EMP-induced endothelial dysfunction (44). In line with this view,
503
EMP treatment impaired endothelium-mediated vasodilation in both mouse and human ex vivo
504
vessel preparations (44). Likewise, EMPs attenuate vasorelaxation in rat aortas in a dose
505
dependent fashion involving impaired NO signaling and endothelial function (29). These finding
17
506
gain relevance in the context of ALI in view of the frequently barrier-protective (85, 179), anti-
507
inflammatory and anti-coagulatory effects of basal endothelial NO production in the lung.
508
Endothelial dysfunction and impaired aortic vasorelaxation was likewise inducible in mice by
509
LMPs which caused overexpression of caveolin-1 and concomitant inhibition of endothelial
510
nitric oxide synthase (eNOS) (106). Endothelial NO production is also inhibited by smooth
511
muscle cell MPs via a β3 integrin mediated mechanism (49). The relevance of impaired
512
endothelial NO formation in the context of ALI and inflammation is highlighted by the fact that
513
IL-8 dependent PMN migration and endothelial transmigration in vitro are enhanced by the NO
514
synthase inhibitor L-NAME, and likewise by NMPs generated by L-NAME treatment, but not by
515
D-NAME or untreated PMNs (125). Conversely, NO may also regulate MP formation although
516
in different ways depending on cell type and/or experimental conditions, as highlighted by the
517
finding that L-NAME induced NMP formation from PMNs (125), while macrophage MP
518
formation in response to toll-like receptor agonists such as LPS is reduced by inhibition of
519
inducible nitric oxide synthase (iNOS) (59). Taken together, MP formation can be modulated by
520
the bioavailability of NO, and once formed MPs can attenuate local NO production, in particular
521
with respect to endothelial cells (20), which in turn may promote ALI and barrier permeability.
522
Accordingly, EMPs derived from PAI-1 stimulated endothelial cells can induce direct ALI in
523
mice and stimulate the release of IL-1β and tumor necrosis factor (TNF)-α leading to increased
524
PMN recruitment to the lung (31). In brown Norway rats, intravenous infusion of EMPs at
525
pathophysiologically relevant concentrations induced characteristic signs of pulmonary edema,
526
lung PMN infiltration and increased lung vascular permeability (44). Increased lung capillary
527
permeability was likewise evident in C57BL/6 mice when EMPs were infused as either primary
528
or secondary hit (44). EMPs infusion into C57BL/6 mice likewise led to increased inflammatory
529
cytokine release and lung PMN recruitment (31) and exacerbated LPS-induced lung injury.
530
Notably, the aggravation of LPS-induced lung injury was particularly prominent when EMPs
531
were infused prior to rather than simultaneous with LPS (31), indicating that EMPs can both
532
prime the lung for subsequent injurious stimuli or exacerbate lung damage in previously
533
challenged lung tissue.
534
18
535
CLINICAL IMPLICATIONS. The recognition of a potential detrimental effect of MPs in the
536
pathophysiology of ALI/ARDS opens up new therapeutic perspectives, in that removal of MPs
537
and/or inhibition of MP functions may present promising strategies for future treatment
538
interventions (32, 184). Based on a similar rationale, removal of PMPs by a membrane plasma
539
separator was recently tested in 8 patients undergoing apheresis, yet while considerable amounts
540
of PMPs were removed by filtration total numbers of circulating PMPs could not be diminished
541
by this intervention, potentially due to a stimulation of PMP formation by the plasmapheresis
542
procedure per se (66). As compared with mechanical removal, pharmacological attenuation of
543
circulating MP levels may not only be feasible, but may have inadvertently already been
544
introduced into the treatment of inflammatory diseases, as glucocorticoid treatment has been
545
shown to significantly reduce circulating PMP levels in patients with polymyositis and
546
dermatomyositis (154). Yet at the current stage, the significance of immunosuppression or
547
immunomodulation by glucocorticoids in the treatment of ALI/ARDS remains unclear due to
548
mixed clinical results (173), and a thorough analysis of the effects of steroid administration on
549
circulating MP levels and subpopulations is yet lacking.
550
Notably, agonists of peroxisome proliferator activated receptor (PPAR)-γ such as rosiglitazone,
551
which have been introduced as anti-diabetic drugs but also show efficiency in lung diseases such
552
as pulmonary hypertension (67, 68) may present an alternative approach to target deleterious MP
553
functions in inflammatory diseases. MMPs increase macrophage and monocyte superoxide anion
554
production, cytokine release and nuclear factor kappa-light-chain-enhancer of activated B cells
555
(NF-κB) activation via a PPAR-γ regulated mechanism that can be inhibited by PPAR-γ agonists
556
(5). PPAR-γ agonists have also been demonstrated to inhibit LMP mediated vascular dysfunction
557
and increased release of proinflammatory proteins from isolated murine aortae, (120), and the
558
upregulation of proinflammatory cytokines including IL-8 and monocyte chemotactic protein-1
559
by monocyte MPs in cultured human lung epithelial cells (83). PPAR-γ expression has been
560
shown to be reduced in ALI (97) while agonists of PPAR-α or -γ can attenuate experimental ALI
561
(9, 98, 150). While PPAR agonists may thus have therapeutic potential in the context of
562
ALI/ARDS, their effects on circulating MP levels and MP function in this disease remain to be
563
determined.
19
564
Several reviews of MPs have highlighted the interesting strategy to modulate PMP formation by
565
statin or polyunsaturated fatty acid (PUFA) therapy (42, 91). While PUFAs have been pursued as
566
therapeutic interventions in ARDS with reported benefits in terms of decreased permeability and
567
PMN recruitment (157), statin treatment remains controversial yet is actively pursued as
568
potential therapy for ALI/ARDS (26, 86). As randomized clinical trials are currently underway,
569
it will be of interest to see whether potential benefits of statin therapy in ARDS are likewise
570
associated with reduced levels or altered profiles of circulating MPs.
571
Importantly, attenuation of MP formation may also provide an attractive strategy to reduce
572
complications associated with the administration of stored blood products, including TRALI.
573
RMPs typically form after 10 days of storage, while PMPs accumulate earlier within days, and
574
levels of both can be significantly reduced if packed cells are leukoreduced or in the presence of
575
storage additives such as glucose, pyruvate, inosine, adenine and phosphate (80). Storage of
576
platelets with PGE1, theophylline or aprotinin as well as pharmacological inhibition of αIIbβ3
577
integrin signaling have been proposed to reduce ex vivo PMP production (25, 33) and may thus
578
help to reduce PMN activation and sequestration in the lungs subsequent to transfusion of stored
579
blood products. Compounds such as cyclospoin A and Orai 1 inhibitors have been proposed as a
580
means of decreasing levels of EMPs and PMPs respectively (5, 10, 21, 32). Further work is
581
required to examine the effects of eliminating or altering selected MP populations generated in
582
stored blood products to test whether such interventions may positively impact on the mortality
583
and morbidity of transfused experimental animals and ultimately patients.
584
585
POTENTIAL BENEFICIAL EFFECTS OF MICROPARTICLES IN ALI
586
MPs are not necessarily always associated with progressive organ dysfunction and disease
587
outcome. As recently discussed in seminal reviews by Morel and coworkers (120) and Dignat-
588
George and Boulanger (46), MPs are by no way always detrimental, but may frequently exert
589
beneficial effects, in that they exhibit anti-inflammatory and anti-coagulant potential and can
590
improve endothelial and vascular function under pathologic conditions (Figure 5). Experimental
591
evidence for the beneficial effects of MPs comprise the promotion of myocardial tissue repair
592
post infarction by PMPs, the stimulation of matrix degradation and new blood vessel formation
20
593
by EMPs through activation of matrix metalloproteases, or the triggering of angiogenic
594
endothelial responses and the reconstitution of endothelial function and NO generation
595
associated with reduced ROS production by LMPs carrying the developmental morphogen sonic
596
hedgehog (3, 20, 114). These findings exemplify the seemingly paradoxical beneficial effects
597
which have been documented for a variety of MPs under different pathologic conditions, a
598
notion that gains particular relevance in the context of ALI by the clinical observation that higher
599
levels of circulating LMPs or EMPs, respectively, are associated with increased survival in both
600
sepsis and ARDS (65, 158). The potential role of beneficial MPs gains additional momentum in
601
light of the fact that considerable numbers of MPs can also be released by mesenchymal stem
602
cells (MSCs) and may thus – at least in part – account for the paracrine effects by which MSCs
603
have emerged as a promising new therapeutic strategy in ALI (63, 92, 93, 107). MSCs secrete
604
MPs that are enriched in pre-miRNAs (35) and – in a rat renal injury model - could inhibit
605
apoptosis and promote proliferation of kidney epithelial cells by paracrine effects that are in part
606
mediated via intercellular transfer of mRNA and miRNA (58). MSCs have also recently been
607
shown to donate mitochondria to lung parenchymal cells in ALI by a microvesicular mechanism
608
that could imply microparticles (73); yet, the relevance of mitochondrial transfer for the effects
609
of MSCs has been challenged by others (38). Further investigations are needed to characterize
610
the contributions of MSC derived MPs in the benefits these cells appear to offer in the setting of
611
lung injury. In the following, we will discuss mechanisms which may potentially contribute to
612
the beneficial effects of non-stem cell derived MPs in ALI focusing on the same
613
pathophysiological characteristics of the disease as previously done for the detrimental role of
614
MPs.
615
616
INFLAMMATION. While we previously emphasized the role of TXA2 in the context of the
617
delivery and release of AA and AA metabolites by MPs, it must be taken into consideration that
618
not all eicosanoids are proinflammatory and increase barrier permeability. Notably, PMPs
619
contain lipoxygenase 12 which, when transferred to mast cells promotes production of the anti-
620
inflammatory leukotriene lipoxin 4A (LXA4) (161). In a murine model of experimental colitis,
621
injection of PMPs and LXA4 attenuated inflammatory responses, whereas lipoxygenase 12
21
622
protein deficient MPs or mast cell depletion reversed this beneficial effect (161). As LXA4
623
analogs have been shown to attenuate ALI in animal models (47, 76), MP mediated generation of
624
LXA4 might prove beneficial in ALI.
625
Though certain MPs formed in ALI may have the ability to cause detrimental immune
626
modulation as described in previous sections, others may confer beneficial immune functions
627
capable of enhancing survival or reducing morbidity. NMPs can stimulate secretion of
628
transforming growth factor (TGF)-β which blocks macrophage activity, and can express annexin
629
A1 which acts as an anti-inflammatory protein blocking adhesion of PMNs to endothelial cells
630
(40, 57). In addition, MPs generated from KATO-III human gastric cancer cells can interact with
631
monocytes and change their cytokine release profile from proinflammatory mediators such as
632
TNF-α to anti-inflammatory cytokines such as IL-10 (83). While the relevance of such effects in
633
the context of ALI/ARDS remains to be elucidated, these findings underscore the anti-
634
inflammatory potential harbored by many MPs. A recent analysis of ARDS patients
635
demonstrated elevations in both LMPs and NMPs within BAL samples of ARDS patients
636
compared to spontaneously breathing controls (65), while levels of PMPs did not differ amongst
637
ARDS patients compared with simplified acute physiology score (SAPS II) and sequential organ
638
failure assessment (SOFA) score matched ventilated intensive care patient controls without
639
ARDS and spontaneously breathing patients being bronchoscopically investigated for suspected
640
chronic lung diseases. Notably, survivors of ARDS had statistically elevated levels of LMPs
641
compared to the ventilated and spontaneously breathing control groups. This unexpected finding
642
raises the possibility that LMPs may not only be a biomarker of ARDS and/or potentially
643
promote inflammatory signaling and parenchymal damage, but may at times also be protective
644
and reflect a "healthy" level of immune function. This physiological effect may be absent in
645
severe inflammatory diseases such as ARDS, causing "immune paralysis" or a relative anergy of
646
immune function which may have ramifications on the host that directly impact mortality (123).
647
648
COAGULATION. While the high expression levels of TF in MPs are generally considered to be
649
procoagulant and barrier disruptive, they may also have anti-coagulant and barrier protective
650
properties through PAR1-mediated transactivation of PAR2 signaling pathways (82). In addition,
22
651
MPs can express a variety of anti-coagulant factors including thrombomodulin, TFPI, EPCR and
652
protein S (120). Thus, the potential involvement of MPs in anticoagulant pathways may present
653
both an intrinsic protective mechanism and a possible future therapeutic target in lung injury.
654
Notably, LMPs from hepatitis C patients have been shown to cause increased fibrinolysis after
655
fusion with hepatic stellate cells, thus decreasing fibrin deposition (84).
656
Activated protein C (APC) proteolytically inactivates key coagulation factors including Factor
657
Va and Factor VIIIa. Recombinant activated protein C has been shown to reduce acute lung
658
injury and increase alveolar ventilation in experimental animal models (71, 110, 167) and
659
individual clinical case reports (81). In sepsis patients, treatment with activated protein C (APC)
660
has been reported to show a trend towards increased survival that is notably associated with MP
661
formation and concomitant anti-inflammatory effects (132). However, a recent Cochrane review
662
did not recommend its use due to a failure to improve survival and an increased bleeding risk,
663
which has led to a decrease in its use as a therapy for severe sepsis (105). Interestingly
664
nevertheless in the context of this review, APC induces the release of MP-associated endothelial
665
protein C receptor (EPCR) that can bind APC and exert anti-coagulatory (131) and potentially
666
also anti-inflammatory and barrier protective effects (120). EPCR (131) is a member of the
667
major histocompatibility complex/CD1 superfamily that promotes protein C activation at the cell
668
surface (159), yet upon metalloprotease-mediated cleavage circulates in a soluble form (sEPCR)
669
(88) which neutralizes APC so that it can no longer inactivate Factor Va (95). Importantly, APC
670
bound to EPCR in microparticulate form retains anti-coagulant activity (131), and has been
671
shown to exert both anti-apoptotic and barrier-protective effects (130).
672
673
PERMEABILITY. APC may also exert important barrier protective effects, in that EPCR
674
ligation promotes transactivation of sphingosine 1-phosphate receptor 1 (S1P1) via PI3K-
675
dependent phosphorylation (51). Hence, APC-bearing MPs may limit vascular permeability via
676
the well-documented barrier enhancing signaling cascade downstream of S1P1 (169). This notion
677
is supported by experimental data demonstrating that EPCR/APC-bearing EMPs reduce
678
endothelial permeability in vitro via a mechanism that involves PAR-1, PI3K and notably also
679
the vascular endothelial growth factor receptor 2 (130).
23
680
681
ENDOTHELIAL FUNCTION. While MPs are frequently associated with endothelial and
682
vascular dysfunction (vide supra), several studies by the group of Ramarosin Andriantsitohaina
683
and Maria Carmen Martinez have demonstrated that the endothelium may also receive beneficial
684
signals from MPs carrying sonic hedgehog resulting in correction of endothelial injury,
685
reconstitution of NO release and reduced ROS production (3, 114, 121). The role of NO in this
686
context however is complex as it can exert both attenuating and aggravating effects on
687
inflammatory, coagulatory or permeability changes depending on its location, concentrations and
688
local microenvironment (85). While a recent meta-analysis did not support the rationale for
689
inhaled NO as an effective treatment strategy in ALI/ARDS (2), reconstitution of endogenous
690
NO production and an intact endothelial and vascular function may nonetheless provide
691
important benefits which could positively impact on clinical outcome in ALI/ARDS.
692
693
CLINICAL IMPLICATIONS. Taken together, MPs possess a variety of mechanisms by which
694
they may exert anti-inflammatory, anti-coagulatory and barrier-enhancing effects under healthy
695
or diseased conditions. While our understanding of these properties of MPs in general, and in the
696
context of ALI/ARDS in particular, is still in its infancy, the potential to exploit this intrinsic
697
property for therapeutic purposes poses a challenging, yet promising path to pursue.
698
699
SYNOPSIS AND IMPLICATIONS
700
There has been little in the way of effective innovations and interventions in the treatment of
701
ALI/ARDS beyond the introduction of protective ventilation (1) and restrictive fluid
702
management strategies (176). ALI/ARDS is commonly associated with increased formation of
703
MPs from various cellular origins found in both the distal airspaces and circulating blood. These
704
MPs are small vesicles with an intact lipid bilayer that may contain membrane and cytosolic
705
proteins, lipids, organelles, and genetic material from their parent cells that can function
706
autonomously or transfer their contents to other cells. While most studies have looked at MPs as
707
potential biomarkers for disease and progression of illness, MPs bear the potential to convey
24
708
both detrimental as well as beneficial effects with respect to the excessive inflammatory,
709
coagulatory and permeability responses characteristic for ALI/ARDS (Figure 4). Further
710
investigations into MPs actions are required to better understand their role in the
711
pathophysiology of acute lung disease, and to utilize their potential for therapeutic interventions.
712
Such concepts may include strategies to prevent the formation of MPs by altering flip flop
713
scramblase enzyme activities (116) or therapeutic manipulation of MP populations by
714
pharmacological interventions (138). Even more attractive is the potential perspective to use
715
specifically engineered "designer" MPs as vectors to move genes, proteins or specific cellular
716
functions between cells (20). Clearly, MPs add another layer of complexity to the already
717
multifaceted mechanisms involved in ALI/ARDS, but in parallel they may offer hope of
718
obtainable and specific sites for future pharmacologic manipulation.
719
720
ACKNOWLEDGEMENTS
721
Illustrations in tables 3 and 4, and figure 1 are courtesy of Stefania Spano.
722
25
723
LEGENDS
724
Table 1: Technical variables and recommendations for microparticle isolation.
725
Flow chart of variables and current recommendations for the isolation, storage and purification
726
of microparticles as proposed for platelet microparticles by Zwicker and colleagues (186).
727
CTAD, citrate theophylline adenosine and diphyridamole; MP, microparticle; PFP, platelet free
728
plasma; PMP, platelet microparticle.
729
730
Table 2: Advantages and limitations of techniques commonly applied in microparticle analysis.
731
Shown are commonly applied techniques for the analysis of microparticles and their relative
732
strengths and weaknesses in terms of microparticle enumeration, microparticle sizing,
733
determining the parent cell of origin, throughput, cost and availability. AFM, atomic force
734
microscopy; CLM, confocal laser microscopy; ELISA, enzyme-linked immune sorbent assay;
735
EM, electron microscopy; FCM, flow cytometry; HPLC, high performance liquid
736
chromatography; MS, mass spectrometry.
737
738
Table 3: Characteristic surface markers indicative of microparticle origin.
739
Given are characteristic surface markers used to detect microparticle populations (RIGHT)
740
which originate from specific parent cells (LEFT). CD, cluster of differentiation; EMP,
741
endothelial microparticle; IgG, immunoglobin; LMP, lymphocyte microparticle; MegMP,
742
megakaryocyte microparticle; MP, microparticle; MMP, monocyte microparticle; NMP,
743
neutrophil microparticle; PMP, platelet microparticle; RMP, red blood cell microparticle; vWF,
744
von Willebrand factor.
745
746
Table 4: Triggers for microparticle formation from different parent cells of origin.
747
Depicted are physiological, pathophysiological and experimental triggers of microparticle
748
formation (RIGHT) from platelets, megakaryocytes, lymphocytes, monocytes, red blood cells,
26
749
polymorphonuclear neutrophils and endothelial cells (LEFT). APC, activated protein C; ATII,
750
angiotensin II; autoAb, autoantibodies; C5a, complement factor C5a; C5B-9, complement factor
751
C5B-9; CD40L, CD40 ligand; CHX, cyclohexamide; EC, endothelial cell; fMLP, N-
752
formylmethionyl-leucyl-phenylalanine; IL-1, interleukin-1; L-NAME, L-NG-nitroarginine
753
methyl
754
phytohemagglutinin; PAI-I, plasminogen activator inhibitor 1; PMA, phorbol myristate acetate;
755
PtdIns(4,5)P2, phosphatidylinositol-4,5-bisphosphate; ROS, reactive oxygen species; STS,
756
staurosporine; TNF-α, tumor necrosis factor-α; TRAP, thrombin receptor agonist peptide
757
SFLLRN.
ester;
LPS,
lipopolysaccharide;
PAF,
platelet
activating
factor;
PHA,
758
759
Figure 1: Release of microparticles from the surface of a polymorphonuclear neutrophil (PMN).
760
Electron micrographs of PMN and PMN derived microparticles (MPs). Scanning electron
761
micrographs show a) a fixed resting PMN (scale bar: 1.5 µm) and b) a fixed PMN stimulated
762
with 0.1 µM N-formylmethionine leucyl-phenylalanine for 5 minutes (scale bar: 1.5 µm)
763
displaying large pseudopodia and in addition, budding of small vesicles of 70-300 nm in size
764
from the PMN cell membrane (inset, arrowhead; scale bar: 400 nm). c) Transmission electron
765
micrographs following immunogold labelling show expression of cell surface antigens such as
766
complement receptor 1 on isolated MPs (scale bar – 150 nm); d) Thin sections of MPs
767
precipitated with Dynabeads prove vesicles to be bilamellar structures. Reproduced from Hess et
768
al. (69); Copyright 1999. The American Association of Immunologists, Inc.
769
770
Figure 2: Mechanisms of interactions between microparticles and target cells.
771
Interaction between microparticles (MPs) and their target cells via essentially four different
772
mechanisms: Depicted clockwise from top right to top left are a) outside-in-signaling via ligand-
773
receptor interaction or secreted factors, b) internalization and lysosomal processing of MPs
774
facilitates for example subsequent presentation of MP antigens on the surface of target cells, c)
775
fusion-mediated transfer of surface receptors, proteins and lipids, and d) delivery of genetic
776
material such as mRNA or miRNA. MPs may fuse either completely (c) or temporarily (d) with
27
777
target cells resulting in either complete or selective transfer of MP contents. Redrawn and
778
modified from a figure originally published in Beyer et al. (22).
779
780
Figure 3: Pathways of microparticle release from parent cells.
781
Cell activation and/or stimulation of pro-apoptotic signaling cascades cause a rapid loss in lipid
782
membrane asymmetry due to dysregulation of flippases, floppases, and scramblases via sudden
783
increases in intracellular calcium, resulting in externalization of phosphatidylserine (PS).
784
Concurrent cytoskeletal reorganization and contraction cause blebbing and subsequent shedding
785
of microparticles (MPs) into the extracellular space. MP formation from membrane lipid rafts
786
may lead to release of MPs that maintain part of the unique signaling characteristics of these
787
platforms. Redrawn and modified from a figure originally published in Chironi et al. (36).
788
789
Figure 4: Schematic representation of the proposed role of microparticles in acute lung injury.
790
(I) Depiction of normal healthy lung, interstitium and vasculature with associated basal
791
microparticle populations (color-coded). Acute lung injury (II) involves characteristic
792
pathologies including (IIa) increased permeability, (IIb) coagulation leading to thrombosis and
793
fibrin deposition, and (IIc) inflammation and immunomodulation. Each of these pathologies is
794
affected in distinct ways by specific microparticle populations that are in turn activated by
795
specific stimuli. AA, arachadonic acid; APC, activated protein C; EMP, endothelial MP (blue),
796
EpMP, epithelial MP (light purple); IL-1β, inteleukin 1β; INFγ, interferon-γ; LMP, lymphocyte
797
MP (red); LPS, lipopolysaccharide; LXA2, lipoxin A2; MacMP, macrophage MP (pink); MMP,
798
monocyte MP (purple); MP, microparticle; NMP, , polymorphonuclear neutrophil MP (orange);
799
PAI-1, plasminogen activator inhibitor 1; PHA, phytohemagglutinin; PMN, polymorphonuclear
800
neutrophil; PMP, platelet MP (light green); RMP red blood cell MP (dark green); ROS, reactive
801
oxygen species; TFMP, tissue factor expressing microparticle (dark purple); TNF-α, tumor
802
necrosis factor-α; TXA2, thromboxane A2.
803
28
804
Figure 5: Beneficial and detrimental potential of microparticle as highlighted by their effects on
805
endothelial cells.
806
Microparticles (MPs) influence endothelial cells in different ways (both beneficial and
807
detrimental) depending on their cell origin and the specific stimulating trigger leading to their
808
formation. Highlighted are examples of divergent MP effects on nitric oxide (NO) release, pro-
809
reactive oxidative species (ROS) production, expression of inflammatory enzymes such as
810
cyclooxygenase-2 (COX-2) or pro-coagulant factors such as tissue factor (TF), or angiogenic
811
responses including proliferation and migration. Reproduced from Benameur et al. (20) with
812
kind permission from Pharmacological Reports.
813
814
29
815
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41
analysis
(further purification of MPs)
(storage)
PFP preparation
blood collection
venipuncture
Table 1
citrate, CTAD (as EDTA can activate platelets)
avoid agitation, < 2h to centrifuge (as PMPs increase over time)
wide variety of speeds and times
platelets may persist in PFP after a single centrifugation step
-80rC, single freeze & thaw cycle
(multiple cycles reduce number of MPs)
wide variety of speeds and times
further purification can reduce background signal from plasma
at the risk of losing MPs
transportation & time
to centrifuge
speed & time of
centrifuge
number of
freeze & thaw cycles
speed & time of
centrifuge
>21G needle, light or no tourniquet to avoid platelet activation
current recommendation
anti-coagulant
needle & tourniquet
variables
i bl
(181)
(162)
(11,37)
++
++
+
MS
(43,75,115,
137)
-
(24 43 174)
HPLC (24,43,174)
-
AFM
CLM
EM
-
+*
+++
+
++
-
+
Functional
assays (78,129,
153,155)
+++
-
(78,153,155)
(79,89,155,
185)
-
ELISA
FCM
Table 2
++
+
+
++
++
+
+
+++
-
-
-
-
-
+++
+++
++
-
-
-
-
-
+
+
-
-
+
-
++
-
+++
+++
++
can perform proteome and lipidome analyses
can analyze phospholipid composition
* size fractionation
high sensitivity
can investigate cell-microparticle interactions
(e.g. internalization)
can visualize organelles
no direct enumeration but able to assay functional
parameters (e.g. coagulation)
high sensitivity
limited sensitivity for small sized particles (<500 nm)
new technologies (e.g. impedance FCM) are being
proposed to address this limitation
Table 3
Table 4
Figure 1
MP
translation
miRNA
mRNA
MP
Receptor/protein/lipid transfer
MP
MP
mRNA
miRNA
MP
Nucleic acid transfer
lysosome
MP
MP
MP
MP
MP internalization/processing
outside-in-signaling
MP
Receptor and soluble factor signaling
Figure 3
Figure 4
Figure 5