Rationale: Severe asthma is characterized by airway inflammatory responses associated with aberrant metabolism of arachidonic acid. Lipoxins (LX) are arachidonate-derived pro-resolving mediators that are decreased in severe asthma, yet mechanisms for defective LX biosynthesis and a means to increase LXs in severe asthma remain to be established.Objectives: To determine if oxidative stress and soluble epoxide hydrolase (sEH) activity are linked to decreased LX biosynthesis in severe asthma.Methods: Aliquots of blood, sputum, and bronchoalveolar lavage fluid were obtained from asthma subjects for mediator determination. Select samples were exposed to t-butyl-hydroperoxide or sEH inhibitor (sEHI) before activation. Peripheral blood leukocyte-platelet aggregates were monitored by flow cytometry, and bronchial contraction was determined with cytokine-treated human lung sections.Measurements and Main Results: 8-Isoprostane levels in sputum supernatants were inversely related to LXA 4 in severe asthma (r = 20.55; P = 0.03) and t-butyl-hydroperoxide decreased LXA 4 and 15-epi-LXA 4 biosynthesis by peripheral blood leukocytes. LXA 4 and 15-epi-LXA 4 levels were inversely related to sEH activity in sputum supernatants and sEHIs significantly increased 14,15-epoxy-eicosatrienoic acid and 15-epi-LXA 4 generation by severe asthma whole blood and bronchoalveolar lavage fluid cells. The abundance of peripheral blood leukocyte-platelet aggregates was related to asthma severity. In a concentration-dependent manner, LXs significantly inhibited plateletactivating factor-induced increases in leukocyte-platelet aggregates (70.8% inhibition [LXA 4 100 nM], 78.3% inhibition [15-epi-LXA 4 100 nM]) and 15-epi-LXA 4 markedly inhibited tumor necrosis factora-induced increases in bronchial contraction.Conclusions: LX levels were decreased by oxidative stress and sEH activity. Inhibitors of sEH increased LXs that mediated antiphlogistic actions, suggesting a new therapeutic approach for severe asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 00595114).

As the primary interface between the blood and various tissues of the body, the vascular endothelium exhibits a diverse range of roles and activities, all of which contribute to the overall health and function of the cardiovascular system. In this focused review, we discuss several key aspects of endothelial function, how this may be compromised and subsequent consequences. Specifically, we examine the dynamic regulation of arterial contractility and distribution of blood flow through the generation of chemical and electrical signaling events that impinge upon vascular smooth muscle. The endothelium can generate a diverse range of vasoactive compounds and signals, most of which act locally to adjust blood flow in a dynamic fashion to match tissue metabolism. Disruption of these vascular signaling processes (e.g. reduced nitric oxide bioavailability) is typically referred to as endothelial dysfunction, which is a recognized risk factor for cardiovascular disease in patients and occurs early in the development and progression of hypertension, atherosclerosis and tissue ischemia. Endothelial dysfunction is also associated with type-2 Diabetes and aging and increased mechanistic knowledge of the cellular changes contributing to these effects may provide important clues for interventional strategies. The endothelium also serves as the initial site of interaction for immune cells entering tissues in response to damage and acts to facilitate the actions of both the innate and acquired immune systems to interact with the vascular wall. In addition to representing the main cell type responsible for the formation of new blood vessels (i.e. angiogenesis) within the vasculature, the endothelium is also emerging as a source of extracellular vesicle or microparticles for the transport of signaling molecules and other cellular materials to nearby, or remote, sites in the body. The characteristics of released microparticles appear to change with the functional status of the endothelium; thus, these microparticles may represent novel biomarkers of endothelial health and more serious cardiovascular disease.

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