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A Small Step Forward

July 8, 2011

Microparticles

“The purpose of the present communication is to provide evidence for the occurrence in normal plasma, serum, and fractions derived therefrom of coagulant material in minute particulate form, sedimentable by high-speed centrifugation and originating from platelets, but distinguishable from intact platelets.  It is suggested that this material, hereafter referred to as ‘platelet-dust,’ is responsible for [the progressive increase in coagulation in stored plasma].”

So wrote the British physician Dr. Peter Wolf nearly 45 years ago.  Wolf’s “platelet dust” eventually morphed into the more modern-sounding “microparticle” and the following working definition.  A microparticle is a bubble-like vesicle, smaller than a micrometer (the average width of a human hair is 80 micrometers) that is released by the endothelial cells that line our blood vessels and the red and white blood cells that circulate through them.  Thereafter the facts grow as murky as, well, platelet dust.  Scientists remain uncertain why cells shed microparticles and, more importantly, whether the vesicles have a positive or adverse effect on a range of biological processes, from inflammation to blood coagulation.  Further complicating matters, microparticles seem to contain, like the biological equivalent of a gift sampler, an assortment of biochemicals.  But the assortment varies, depending on a microparticle’s cell of origin and the stimulus that initiates its formation.

Scientists have begun to crack into the various microparticles to better characterize their biochemical cargo and thus biological functions.  In the May 15 issue of The Journal of Immunology: Cutting Edge section, NIDCR grantees and colleagues report an important new find.  They show that microparticles derived from circulating white blood cells called polymorphonuclear (PMN) leukocyte cells taken from inflammatory exudates contain specialized, pro-resolution lipid mediators that help to halt acute inflammation.  The implication being, the microparticles deliver the lipid mediators to signal the inflammatory sites to promote resolution.

“For example,” the authors noted, “the levels of microparticle-associated hydroxydocosahexaenoic acids, namely 14-HDHA and 17-HDHA, were high during the initiation phase of the acute inflammatory response, decreased during the peak of inflammation, and accumulated in resolution, the phase in which potent anti-inflammatory and proresolving lipid mediators are biosynthesized to help bring about homeostasis to the tissues.”

The finding, however, raised an intriguing possibility.  If PMN-derived microparticles are inherently anti-inflammatory and can signal resolution, as their data showed, could these vesicles be employed like Trojan horses to construct and deliver other bioengineered, pro-resolution nanoparticles?  If so, the approach would further enhance the resolution phase and mimic the body’s own novel healing mechanisms.  But because the microparticles are natural occupants of the circulatory system, they would deliver their payload without triggering the toxic side effects that many man-made biomaterials now prompt.

To test the idea, the researchers harnessed microparticles from human PMNs and used them to construct nanoparticles that they enriched with either aspirin-triggered resolvin D1 or a lipoxin A4 analog, both well established pro-resolution lipid mediators.  They then administered their novel nanomedicines intravenously to mice with experimentally induced inflammation of a temporomandibular joint (TMJ).  These large, ball-and-socket joints connect the jaw to the skull on both sides of the head and are the site of a range of sometimes chronic and painful disorders in people.

In their proof-of-principle study, the scientists found that a dose of just 10 nanograms of microparticle-bearing resolvin D1 and the lipoxin A4 analog protected against TMJ inflammation.  They reached this conclusion based on:

  • The “drastically reduced” infiltration of PMN white blood cells into the TMJ, an indication that the immune response has ratcheted down and prevented the onset of inflammation induced joint damage.
  • Endogenous microparticles stimulated scavenging immune cells called macrophages to dispose of dead white blood cells, a major hallmark of a pro-resolving mediator.
  • Their earlier studies that showed resolvins dramatically attenuate pain.

The researchers concluded, “These findings indicate that humanized nanoparticles, termed nano-proresolving medicines, are mimetics of endogenous resolving mechanisms, possess potent beneficial bioactions, can reduce nanotoxicity, and offer new therapeutic approaches.”

 

  • Norling LV, Spite M, Yang R, Flower RJ, Perretti M, Serhan CN. Cutting edge:  Humanized nano-proresolvng medicines mimic inflammation-resolution and enhance wound healing. J Immunol. 2011 May 15;186(10):5543

 

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This page last updated: February 26, 2014