Functions, Old and New

Early interest in MP stemmed from their procoagulant activity (PCA), which remains relevant to this review for reasons noted below. Their PCA was attributed to the reversal of normal membrane asymmetry, meaning that normally in-facing and anionic phospholipids (PL) such as phosphatidylserine (PS) flip to the plasma side. These PL exhibit PCA by serving as sites for the assembly of the vitamin K-dependent clotting factors into active complexes, promoting coagulation via tissue factor (TF) pathway.

Recent work, however, calls for revision of this paradigm. It has been shown that MP exert PCA primarily by amplifying the contact pathway, not the TF pathway [18, 19], confirmed in our laboratory. The contact pathway is closely tied to the complement and kinin systems, suggesting involvement in previously unexpected pathways of inflammation.

The second major function to be recognized was a role in inflammation. There are two aspects to this role, the first being as biomarkers. It is generally observed that circulating MP of several lineages increases in response to inflammation induced experimentally by administration of lipopolysaccharide (LPS), zymosan, or overt infection. For example, we examined a variety of MP phenotypes in sepsis, especially endothelial MP (EMP) subtypes, and determined that a strong inflammatory response favored survival, concluding that inflammation was not associated with mortality [20]. In addition, MP can function to transport agents which can induce or modulate inflammation, e.g., cytokines and bioactive lipids. This topic, cell-cell signaling, was reviewed as of 2007 [21] and is updated in the following sections.

The third major function of MP has come to light only in the last decade, being the transport of functional RNA, DNA, and other functional transcripts, to be reviewed. Some key references in this area were cited in section “Exosomes: Distinctly Different?”.

Formation and Fate

The biochemical details of these topics remain poorly understood. It is well known that a rise in cytoplasmic calcium will trigger release of MP, therefore, the use of calcium ionophores such as A23187 are often used to induce vesiculation ex vivo. With regard to mechanisms of clearance of MP, this topic has become very complex in recent years and will be reviewed separately in another forum. However, limited studies of several MP lineages find that all have short half-life in circulation,

<10 min, e.g., [15]. Progress in understanding biochemical mechanisms has been made [22-24]. A major advance has been the identification of the mechanism of membrane “flip-flop” causing reversal of membrane asymmetry, related to MP shedding [25, 26]. This was previously attributed to presumed enzymes called flip- pase, floppase, or PL translocase, now known to be an ion channel.

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