Circulating Microparticles from Patients with Septic Shock Exert Protective Role in Vascular Function

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Abstract
Rationale: Sepsis is an archetypal condition with molecular links between inflammation and coagulation. Both events can be orchestrated by the interaction between circulating and vascular cells that under activation release microparticles. Objectives: We characterized circulating microparticles from both nonseptic subjects and patients with septic shock and evaluated their contribution to vascular function. Methods: Circulating microparticles and their cell origin were measured in blood from 36 patients with septic shock and 18 nonseptic subjects by flow cytometry. Microparticles were then injected intravenously into mice and vascular reactivity was assessed in aorta. Expression and activity of enzymes involved in nitric oxide (NO) and cyclooxygenase metabolite production were analyzed. Measurements and Main Results: Circulating levels of microparticles and platelet- and endothelial-derived microparticles were increased in septic patients. Surprisingly, septic microparticles enhanced the sensitivity of contraction of mouse aorta in response to serotonin. Interestingly, septic microparticles enhanced the contraction of aorta from lipopolysaccharide-treated mice. This effect was linked neither to increased calcium entry nor to Rho kinase inhibitor–sensitive mechanisms. In addition, the effect of septic microparticles was not modified either by NO-synthase or cyclooxygenase-2 inhibitors, and was not associated with NO or O2− overproduction. The nonselective cyclooxygenase-2 inhibitor indomethacin reduced, and the specific thromboxane A2 antagonist SQ-29548 abolished, aortic contraction in mice treated with nonseptic and septic microparticles. The effect of septic microparticles was associated with increased thromboxane A2 production, and was sensitive to a selective thromboxane A2 antagonist. Conclusions: We provide evidence that increased circulating microparticles are protective against vascular hyporeactivity accounting for hypotension in patients with septic shock.

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