Bench-to-bedside review: circulating microparticles--a new player in sepsis?

Abstract

In sepsis, inflammation and thrombosis are both the cause and the result of interactions between circulating (for example, leukocytes and platelets), endothelial and smooth muscle cells. Microparticles are proinflammatory and procoagulant fragments originating from plasma membrane generated after cellular activation and released in body fluids. In the vessel, they constitute a pool of bioactive effectors pulled from diverse cellular origins and may act as intercellular messengers. Microparticles expose phosphatidylserine, a procoagulant phospholipid made accessible after membrane remodelling, and tissue factor, the initiator of blood coagulation at the endothelial and leukocyte surface. They constitute a secretion pathway for IL-1β and up-regulate the proinflammatory response of target cells. Microparticles circulate at low levels in healthy individuals, but undergo phenotypic and quantitative changes that could play a pathophysiological role in inflammatory diseases. Microparticles may participate in the pathogenesis of sepsis through multiple ways. They are able to regulate vascular tone and are potent vascular proinflammatory and procoagulant mediators. Microparticles' abilities are of increasing interest in deciphering the mechanisms underlying the multiple organ dysfunction of septic shock.

Figure 1

Structure of microparticles. Microparticles (MPs) are released from different cell types under physiological and pathological conditions. The plasma membrane is reorganised with active externalisation of phosphatidylserine (PhtdSer; a negatively charged phospholipid) and internalisation of phosphatidylcholine (insert). MPs bear intracytoplasmic and membrane-bound effectors from the originating cells, such as tissue factor (TF) and endothelial protein C receptor (EPCR) (endothelial cells and monocytes), CD-14 (monocytes) or glycoprotein (GP)_Iba-IX-V', P-selectin or integrins (platelets).

Figure 2

Microparticles and blood coagulation. (A) The plasma membrane of endothelial cells and monocytes is reorganised, with externalisation of phosphatidylserine - a negatively charged phospholipid - and encrypted tissue factor (TF) expression, allowing factor VII (FVIIa) activation and thrombin (FIIa) generation at the cell surface. Blebbing occurs, with release of microparticles (MPs) bearing TF, resulting in an increased surface for procoagulant reactions. Platelet adhesion and aggregation also occur with the release of MPs; platelets and MPs bear GP_Ibα', a cofactor for factor XI activation by thrombin, leading to the propagation phase with high levels of thrombin generation and fibrin formation. Endothelial TF-bearing MPs allow transfer of TF to PMNs, increasing TF dissemination and thrombotic microangiopathy or disseminated intravascular coagulopathy. (B) TF initiation of blood coagulation is quickly down-regulated by tissue factor pathway inhibitor (TFPI) on endothelial and monocytic cell surfaces, as on MPs. Endothelial protein C receptor (EPCR)-bound protein C is activated by the thrombin-thrombomodulin complex and activated protein C (APC) inhibits factor Va and factor VIIIa, limiting the propagation phase of thrombin generation. EPCR-bound APC also regulates NF-B, with cytoprotective effects on endothelial cells and monocytes. APC induces blebbing, with emission of EPCR-bearing MPs able to activate protein C, resulting in the dissemination of anticoagulant and antiapoptotic activities. LPS, lipopolysaccharide; PhtdSer, phosphatidylserine; PMN, polymorphonuclear.

Figure 3

Microparticles and inflammation in sepsis. During sepsis, microparticles (MPs) are shed from a variety of activated or apoptotic cells. MPs may be considered as both the cause and the consequence of inflammation through multiple amplification and regulatory loops affecting vascular cells and functions. Thus, MPs contribute to the spread of inflammatory and prothrombotic vascular status and they may affect the smooth muscle tissue through adhesion molecules, activation of NF-κB and the expression of inducible nitric oxide synthase and cyclooxygenase-2, with an increase in nitric oxide and vasodilator prostanoids, leading to arterial hyporeactivity. MPs form microaggregates with circulating neutrophil granulocytes and platelets and are involved in the modification of the oxidative status, markedly increasing oxidative activity. Subunits of NADPH oxidase have been identified in MPs associated with increased production of reactive oxygen species. AA, arachidonic acid; COX = cyclooxygenase; ICAM, intercellular cell adhesion molecule; iNOS, inducible NO-synthase; LPS, lipopolysaccharide; NO, nitric oxide; PAF, platelet activating factor; R, Rantes; ROS, reactive oxygen species; TF, tissue factor; VCAM, vascular cell adhesion molecule.