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doi:10.1093/bja/aes321
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BJA Reid and Webster
Table 1 Surface antigen expression of microparticles and microparticle function. *In association with CD4212
The deleterious effect of microparticles on derived microparticles is donated to endothelial cells and sub-
vascular function sequently metabolized to thromboxane A2.25 Platelet-derived
microparticles exposed to endothelial cells and monocytes
Proinflammatory microparticles in vitro can also induce de novo expression of cycloxygenase-2
Microparticles play an important role in vascular haemosta- (COX-2) and prostacyclin (PGI2) production.24 25 Through con-
sis. A growing body of evidence, however, suggests that centrated delivery of bioactive lipids including arachidonic
they induce deleterious effects on vascular function acid, these microparticles induce cell–cell interaction of
through increased synthesis of inflammatory cytokines and monocytes to endothelial cells by an intracellular cell
chemokines, and increased expression of endothelial adhe- adhesion molecule-1 (ICAM-1)-dependent process and
sion molecules25 – 27 (Fig. 2). increased chemotaxis of monocytoid cells.26
Platelet-derived microparticles induce platelet aggrega- Microparticles derived from leucocytes also circulate at
tion through changes in transcellular lipid metabolism in low levels in the bloodstream of healthy individuals and are
endothelial cells.25 Arachidonic acid borne on platelet- up-regulated in inflammation.28 Such microparticles activate
504
Role of microparticles in sepsis BJA
endothelial cells in vitro, stimulating gene expression and contribute to the pathogenesis of inflammatory airway
release of inflammatory cytokines such as interleukin-6 disease through the up-regulation of IL-8, monocyte chemo-
(IL-6) and interleukin-8 (IL-8), and up-regulation of tactic protein-1 (MCP-1), and ICAM-1.31 More recently,
leucocyte-endothelial cell adhesion molecules ICAM-1, vas- monocyte-derived microparticles have been shown to
cular adhesion molecule-1 (VCAM-1), and E-selectin.27 In induce superoxide anion production, cytokine release, and
addition, microparticles produced after platelet activation nuclear factor kappa B (NF-kB) activation in monocytes.32
may enhance leucocyte aggregation and accumulation Taken together, these findings suggest that in certain patho-
through expression of P-selectin, a functional adhesion re- logical states, elevated levels of microparticles may amplify
ceptor for P-selectin glycoprotein ligand-1 (PSGL-1) inflammation and vascular injury.
expressed on the surface of leucocytes.29 Platelet-derived
microparticle binding to neutrophils can also increase neu- Prothrombotic microparticles
trophil aggregation and phagocytic activity.30 In human In healthy individuals, low numbers of circulating microparti-
airway epithelial cells, monocyte-derived microparticles cles, predominantly platelet and endothelial cell in origin,
trigger low levels of thrombin generation in vitro.33 Platelet-
derived microparticles exhibit an important role in primary
Aggregation and
Chemotaxis phagocytosis Endothelial
Platelet aggregation
activation
s
Monocytes VCAM-1
Leucocytes ICAM-1 IL-6
AA
A
ICAM-1 E-selectin IL-8
EC TXA2 TXA2
Subendothelial matrix
Fig 2 Proinflammatory potential of microparticles. Platelet-derived microparticles (PMPs) trigger a proinflammatory response through trans-
cellular delivery of arachidonic acid (AA), metabolism to thromboxane A2 (TXA2), and COX-2 expression in endothelial cells (ECs).24 25
PMP-borne AA facilitates platelet aggregation,25 monocyte:EC interaction through ICAM-1 expression,26 and monocyte chemotaxis. The
binding of PMP to leucocytes triggers leucocyte aggregation and phagocytosis.30 Microparticles derived from polymorphonuclear leucocytes
(PMNL-MPs) also activate ECs with enhanced cytoadhesion and cytokine expression.27
505
BJA Reid and Webster
Anionic phospholipids
Exoplasmic
Platelet
Endoplasmic
Exoplasmic
Microparticles
PMPs EMPs
Endoplasmic
Coagulation factor
binding
FIXa Tissue factor donors
FVa Coagulation factor
FVaXa FVIII FVa binding
Platelet aggregation
g
ULvWF PMNL-MPs
Thrombin Platelet aggregation TF
Fibrin plug
EC
Fig 3 Procoagulant potential of microparticles. Procoagulant phospholipids (including phosphatidylserine) are exposed on the exoplasmic
surface of platelet-derived microparticles (PMPs) during microparticle (MP) formation. Phosphatidylserine enhances factor VaXa (FVaXa)19
and tissue factor (TF) activity. Through processes partly dependent on the GPIIb/IIIa complex, PMPs adhere to the subendothelial matrix
and coaggregate with platelets.36 PMPs also express coagulation factor binding sites for factor IXa, Xa, and VIII (FIXa, FVa, and FVIII, respect-
ively).37 Endothelial-derived MPs (EMPs) potentiate platelet aggregation and thrombus formation by expression of ultra large von Willebrand
factor (ULvWF) antigen40 41 and coagulation factor binding sites.42 MPs including PMPs, EMPs, and leucocyte-derived MPs (PMNL-MPs) consti-
tute a circulating storage pool of blood-borne TF,11 where leucocytes carrying TF are concentrated to sites of vascular injury via interaction of
platelet P-selectin and PSGL-1 expressed on LMPs.39
506
Role of microparticles in sepsis BJA
Angiogenesis AA
Mitogenesis of
VSMC
Hyporeactivity
Hyperreactivity
Superoxide
generation
Ø NOS3
EC O2.–
Fig 4 Microparticles and endothelial (dys)function. Through transcellular delivery of arachidonic acid (AA) and endothelial cell (EC) metabolism
to thromboxane A2 (TXA2), platelet-derived microparticles (PMPs) induces vascular hyperreactivity on vascular smooth muscle cells (VSMC). In
vitro endothelial-derived microparticles (EMPs) increase superoxide anion production and reduce nitric oxide (NO) levels in ECs.54 Microparticles
(MPs) derived from T-lymphocytes (LymMPs) reduce NOS3 expression in conductance and resistance vessels, reducing NO production.55
LymMPs also induce vascular hyporeactivity through reduced NOS2 and COX-2 expression in VSMC.56
agents.56 The activation of transcription factor NF-kB drives matrix metalloproteinases (MMPs), MMP-2 and MMP-9, to
an up-regulation of inducible nitric oxide synthase (NOS2) enable vascular invasion of the basement membrane.67
and COX-2 leading to increased production of nitric oxide
and vasodilator prostanoids.56 Protective effects of microparticles in
In coronary artery disease, increased endothelium-derived health and disease
microparticle levels positively correlate with the degree of
endothelial dysfunction57 58 and high levels of circulating Anti-inflammatory and anticoagulant microparticles
endothelium-derived microparticles in patients with coronary As previously noted, the biological activity of microparticles
artery disease are associated with a worse clinical reflects their cellular origin, and cytoplasmic and membrane
outcome.59 Measurement of plasma endothelium-derived composition. Microparticles derived from leucocytes may in
microparticles predicts future cardiovascular events and fact induce protective, immunosuppressive effects at the
mortality in high-risk patients, including end-stage renal early stages of inflammation to down-regulate parallel proin-
disease.60 61 Taken together, plasma levels of endothelium- flammatory mechanisms.68 Recent findings suggest that
derived microparticles may present a novel biomarker for leucocyte-derived microparticles drive an anti-inflammatory
risk stratification and identification of patients at high risk macrophage response with release of transforming growth
of cardiovascular complications.62 factor b1 (TGF-b1), and inhibition of IL-8, interleukin-10
Microparticles may have some beneficial effects on (IL-10), and tumour necrosis factor a (TNF-a) to inhibit
vascular function. As previously discussed, platelet-derived macrophage activation.68 These microparticles contain the
microparticle-borne arachidonic acid induces COX-2 ex- anti-inflammatory protein Annexin 1.69 More recently, it
pression and vasodilatation through PGI2 production in the was demonstrated that monocyte-derived microparticles
endothelium.25 Both platelet- and endothelium-derived enhance peroxisome proliferator-activated receptor g
microparticles stimulate endothelial proliferation and induce (PPAR-g) protein expression in monocytes and macrophages,
angiogenesis both in vitro and in vivo.54 63 64 Microparticles which has anti-inflammatory properties.31 Endothelium-
isolated from human atherosclerotic plaques promote endo- derived microparticles may also be important in maintaining
thelial proliferation, in vivo neovascularization after CD40 liga- vascular integrity by stimulating vascular repair in vitro.62
tion, and plaque instability.65 66 Of note, endothelium-derived Thus, at least a subpopulation of microparticles may play a
microparticles at pathological but not physiological levels novel role in promoting inflammatory resolution.
impair angiogenesis.54 The precise mechanism of angiogen- Novel findings suggest that activated protein C can induce
esis is unknown; however, endothelium-derived microparti- the formation and release of endothelial protein C receptor-
cles are known to express several proteases, including (EPCR) containing microparticles.70 EPCR-containing
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BJA Reid and Webster
microparticles contain functionally and actively bound syndrome (ARDS), where extrapulmonary infection can
protein C, a coagulation pathway inhibitor of factors Va and cause tissue factor-mediated coagulation and accumulation
VIIIa.70 Thus, raised levels of microparticles do not necessar- of neutrophils in the alveolar compartment.77 78 Models of
ily lead to thrombosis. Endothelium-derived microparticles sepsis involving bacterial products such as lipopolysaccharide
bearing anticoagulant activity may be beneficial in correcting (LPS) are well known to directly induce microparticle shed-
haemostatic imbalance to counterweigh thrombosis driven ding, and it has been suggested that these may then go on
by procoagulant microparticles.71 Thus, it is possible that in to cause the endothelial activation leading to the inflamma-
sepsis, these mechanisms are overwhelmed by the proin- tory response.79
flammatory and thrombogenic effects of microparticles
leading to a systemic inflammatory response to infection. Microparticles have a proinflammatory effect in
sepsis
Raised levels of platelet, granulocyte, and endothelium-
Microparticles in sepsis derived microparticles were first reported in patients with
Sepsis is a clinical syndrome characterized by a systemic in- meningococcal sepsis.20 Microparticles have procoagulant
flammatory response to infection.72 It is characterized by activity with thrombin generation in vivo via a tissue factor/
MPs
Arachidonic
Cytoadhesion and acid
phagocytosis
Thrombosis via a TF/FVIIa-
dependent mechanism Maintenance of
vascular tone
TF ||||
Hyporeactivity
Fibrin plug
Subendothelial matrix
≠ iNOS
Smooth muscle cells
Fig 5 Role of microparticles in sepsis. Elevated levels of platelet, endothelial cell (EC), and polymorphonuclear leucocyte (PMNL)-derived micro-
particles (MPs) are seen in sepsis.20 Platelet-derive MPs (PMPs) and PMNL-MPs are procoagulant with thrombin generation occurring via a tissue
factor (TF)/factor VIIa (FVIIa)-dependent pathway.20 PMNL-MPs demonstrate increased expression of adhesion molecules82 and EC-derived MP
(EMPs) adhere to leucocytes and increase phagocytic activity.83 MPs isolated from septic rats induce vascular hyporeactivity via NF-lB activa-
tion, enhanced expression of NOS2, and increased oxidative stress.86 Increased production of thromboxane A2 (TXA2) may compensate for
vascular hyporeactivity associated with hypotension in septic shock.87 88 Through differential effect on target tissues, microparticles induce
expression of enzyme systems related to inflammation and nitrative and oxidative stress.88 95
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Role of microparticles in sepsis BJA
oxidative activity.20 81 Paradoxically, circulating levels of space may be of prognostic significance. Indeed, higher
monocyte-derived microparticles are reduced in sepsis com- levels of leucocyte-derived microparticles in the blood and
pared with controls and may reflect monocyte deactivation bronchoalveolar lavage were associated with a better progno-
and dysfunction as previously described in severe sepsis.81 sis in patients with early-stage ARDS.78 This is in keeping with
In patients with sepsis, activated leucocytes enhance the notion that an initial, exaggerated, pulmonary inflamma-
the production of leucocyte-derived microparticles with tory response is associated with a worse outcome in ARDS.92
increased expression of adhesion molecules.82 Further, inter- Thus, a subpopulation of microparticles may play a protective
action between activated leucocytes and endothelium- role in the pathogenesis of ARDS and may serve as a novel bio-
derived microparticles through adhesion molecules is marker of prognostic significance.78
enhanced in patients with systemic inflammatory response
syndrome and these microaggregates increase oxidative Microparticles have differential effects on target
activity83 (Fig. 5). Microparticles may therefore serve as tissues in septic shock
important bioeffectors of inflammation and thrombosis in
Raised levels of circulating microparticles from platelets,
sepsis and contribute to tissue injury and organ dysfunction.
granulocytes, and endothelial cells have been identified in
patients with meningococcal septicaemia, septic shock,
509
BJA Reid and Webster
enables simultaneous detection, quantification, and pheno- 7 Allan D, Thomas P, Limbrick AR. The isolation and characterisa-
typing of microparticle subpopulations in one blood sample tion of 60 nm vesicles (‘nanovesicles’) produced during iono-
by detection of size and the binding of fluorescently labelled phore A23187-induced budding of human erythrocytes.
Biochem J 1980; 188: 881– 7
antibodies to cellular markers.98 The appropriate sampling
8 Hess C, Sadallah S, Hefti A, Landmann R, Schifferli JA. Ectosomes
conditions have been recently reported in a forum article.98
released by human neutrophils are specialised functional units.
In conclusion, although once felt to be inert remnants of J Immunol 1999; 163: 4564–73
cell destruction, microparticles are now considered to be a 9 Gasser O, Hess C, Miot S, Deon C, Sanchez JC, Schifferli JA. Char-
disseminated storage pool of bioactive effectors of inflam- acterisation and properties of ectosomes released by human
mation and immunity,20 21 thrombosis,22 23 and vascular polymorphonuclear neutrophils. Exp Cell Res 2003; 285: 243– 57
homeostasis.13 Microparticles are present in the blood at 10 Aupeix K, Hgel B, Martin T, et al. The significance of shed mem-
low levels in healthy individuals,16 and pathological states in- brane particles during programmed cell death in vitro, and in
cluding sepsis and DIC are associated with both an increase vivo, in HIV-1 infection. J Clin Invest 1997; 99: 1546– 54
in number and phenotypic change of circulating microparti- 11 Satta N, Toti F, Feugeas O, et al. Monocyte vesiculation is a pos-
sible mechanism for dissemination of membrane-associated
cles. Microparticles play an important role in endothelial dys-
procoagulant activities and adhesion molecules after stimula-
function.13 Microparticles may exhibit differential
tion by lipopolysaccharides. J Immunol 1994; 153: 3245– 55
510
Role of microparticles in sepsis BJA
25 Barry OP, Praticó D, Lawson JA, FitzGerald GA. Transcellular acti- membrane and expose catalytic surface assembly of the pro-
vation of platelets and endothelial cells by bioactive lipids in thrombinase enzyme complex. J Biol Chem 1990; 265: 3809– 14
platelet microparticles. J Clin Invest 1997; 99: 2118– 27 43 Brodsky SV, Malinowski K, Golightly M, Jesty J, Goligorsky MS.
26 Barry OP, Praticó D, Savani RC, FitzGerald GA. Modulation of Plasminogen activator inhibitor-1 promotes formation of endo-
monocyte –endothelial cell interactions by platelet microparti- thelial microparticles with procoagulant potential. Circulation
cles. J Clin Invest 1998; 102: 136– 44 2002; 106: 2372–8
27 Mesri M, Altieri DC. Endothelial cell activation by leukocyte 44 Combes V. Circulating endothelial microparticles in Malawian
microparticles. J Immunol 1998; 161: 4382–7 children with severe falciparum malaria complicated with
28 Mesri M, Altieri DC. Leukocyte microparticles stimulate endothe- coma. J Am Med Assoc 2004; 291: 2542–3
lial cell cytokine release and tissue factor induction in a JNK1 45 Falati S, Liu Q, Gross P, et al. Accumulation of tissue factor into
signalling pathway. J Biol Chem 1999; 274: 23111–8 developing thrombi in vivo is dependent upon microparticle P-
29 Forlow S, McEver RP, Nollert MU. Leukocyte– leukocyte interac- selectin glycoprotein ligand 1 and platelet P-selectin. J Exp
tions mediated by platelet microparticles under flow. Blood Med 2003; 197: 1585–98
2000; 95: 1317–23 46 Geisbert TW, Young HA, Jahrling PB, Davis KJ, Kagan E,
30 Jy W, Mao WW, Horstman LL, Tao J, Ahn YS. Platelet microparti- Hensley LE. Mechanisms underlying coagulation abnormalities
cles bind, activate and aggregate neutrophils in vitro. Blood Cells in Ebola haemorrhagic fever: overexpression of tissue factor in
Mol Dis 1995; 21: 217–31 primate monocytes/macrophages is a key event. J Infect Dis
511
BJA Reid and Webster
correlate with cardiovascular outcomes. Eur Heart J 2011; 32: proinflammatory IL-1b-rich microparticles. J Immunol 2011;
2034–41 186: 5489– 96
60 Nozaki T, Sugiyama S, Koga H, et al. Significance of a multiple 80 Aras O, Shet A, Bach RR, et al. Induction of microparticle- and
biomarkers strategy including endothelial dysfunction to cell-associated intravascular tissue factor in human endotoxe-
improve risk stratification for cardiovascular events in patients mia. Blood 2004; 103: 4545– 53
at high risk for coronary heart disease. J Am Coll Cadiol 2009; 81 Itakura Y, Ogura H, Tanaka H, et al. Paradoxical cytoskeleton and
54: 601– 8 microparticle formation chances in monocytes and poly-
61 Amabile N, Boulanger CM, Guerin A, Tedgui A, London G. Circu- morphonuclear leukocytes in severe systemic inflammatory re-
lating endothelial microparticles: a novel biomarker for cardio- sponse syndrome patients. J Trauma 2003; 55: 1125–32
vascular death and cardiovascular events in end-stage-renal 82 Fujimi S, Ogura H, Tanaka H, et al. Activated polymorphonuclear
disease. Circulation 2009; 120: S1010 leukocytes enhance production of leukocyte microparticles with
62 Dignat-George F, Boulanger CM. The many faces of endothelial increased adhesion molecules in patients with sepsis. J Trauma
microparticles. Arterioscler Thromb Vasc Biol 2011; 31: 27 –33 2002; 52: 443– 8
63 Kim HK, Song KS, Chung JH, Lee KR, Lee SN. Platelet microparti- 83 Ogura H, Tanaka H, Koh T, et al. Enhanced production of endo-
cles induce angiogenesis in vitro. Br J Haematol 2004; 124: thelial microparticles with increased binding to leukocytes in
376– 84 patients with severe systemic inflammatory response syndrome.
64 Brill A, Dashevsky O, Rivo J, Gozal Y, Varon D. Platelet-derived J Trauma 2004; 56: 823–31
512
Role of microparticles in sepsis BJA
97 Morel O, Toti F, Morel N, Freyssinet JM. Microparticles in endothe- 101 Huber J, Vales A, Mitulovic G, et al. Oxidized membrane
lial cell and vascular homeostasis: are they really noxious? Hae- vesicles and blebs from apoptotic cells contain biologi-
matologica 2009; 94: 313–7 cally active oxidized phospholipids that induce monocyte–
98 Jy W, Horstman LL, Jimenez JJ, et al. Measuring circulating endothelial interactions. Art Thromb Vasc Biol 2002; 22:
cell-derived microparticles. J Thromb Haemost 2004; 2: 1842–51 101– 7
99 Boulanger CM, Amabile N, Tedgui A. Circulating microparticles: a 102 Patel KD, Zimmerman GA, Prescott SM, McIntyre TM. Novel
potential prognostic marker for atherosclerotic vascular disease. leukocyte agonists are released by endothelial cells exposed
Hypertension 2006; 48: 180– 8 to peroxide. J Biol Chem 1992; 267: 15168– 75
100 Mack M, Kleinschmidt A, Bruhl H, et al. Transfer of the chemo- 103 Del Conde I, Shrimpton CN, Thiagarajan P, Lopez JA. Tissue
kine receptor CCR5 between cells by membrane-derived micro- factor-bearing microvesicles arise from lipid rafts and fuse
particles: a mechanism for cellular human immunodeficiency with activated platelets to initiate coagulation. Blood 2005;
virus 1 infection. Nat Med 2000; 6: 769–75 106: 1604– 11
513