Role of microparticles in sepsis.

This review discusses the role of microparticles in inflammation, coagulation, vascular function, and most importantly, their physiological and pathological functions in sepsis. Microparticles are proinflammatory, procoagulant membrane vesicles released from various cell types. They are detectable in normal individuals and basal levels correlate with a balance between cell proliferation, stimulation, and destruction. Haemostatic imbalance leads to various pathological states of inflammation and thrombosis including cardiovascular disease and sepsis, where circulating microparticles display both an increase in number and phenotypic change. Microparticles, mainly of platelet origin enable both local and disseminated amplification of the haemostatic response to endothelial injury through exposure of phosphatidylserine, tissue factor, and coagulation factor binding sites. Surface expression of membrane antigens by microparticles facilitates cytoadhesion, chemotaxis, and cytokine secretion to drive a proinflammatory response. Microparticles behave as vectors in the transcellular exchange of biological information and are important regulators of endothelial function and angiogenesis. The extent to which circulating microparticles contribute to the pathogenesis of sepsis and disseminated intravascular coagulation is currently unknown. Microparticles may in fact be beneficial in early sepsis, given that activated protein C bound to endothelium-derived microparticles retains anticoagulant activity, and increased circulating microparticles are protective against vascular hyporeactivity. Elevated levels of microparticles in early sepsis may therefore compensate for the host's systemic inflammatory response. Importantly, in vivo, septic microparticles induce deleterious changes in the expression of enzyme systems related to inflammation and oxidative stress, thus they may represent important contributors to multi-organ failure in septic shock.

Melatonin and structurally similar compounds have differing effects on inflammation and mitochondrial function in endothelial cells under conditions mimicking sepsis.

BACKGROUND: Development of organ dysfunction associated with sepsis is due in part to oxidative damage to mitochondria. Melatonin regulates the sleep-wake cycle and also has potent antioxidant activity. The aim of this study was to determine the effects of melatonin and other structurally related compounds on mitochondrial function, endogenous glutathione (GSH), and control of cytokine expression under conditions mimicking sepsis. METHODS: Human endothelial cells were treated with lipopolysaccharide (LPS) plus peptidoglycan G (PepG) to simulate sepsis, in the presence of melatonin, 6-hydroxymelatonin, tryptamine, or indole-3-carboxylic acid. Nuclear factor κB (NFκB) activation, interleukin (IL)-6 and IL-8, total glutathione, mitochondrial membrane potential, and metabolic activity were measured. RESULTS: LPS and PepG treatment resulted in elevated IL-6 and IL-8 levels preceded by activation of NFκB (all P<0.0001). Treatment with all four compounds resulted in lower IL-6 and IL-8 levels, and lower NFκB activation (P<0.0001). Loss of mitochondrial membrane potential and endogenous glutathione was seen when cells were exposed to LPS/PepG, but these were maintained in cells co-treated with melatonin, tryptamine, or 6-hydroxymelatonin (P<0.05), but not indole-3-carboxylic acid. Metabolic activity decreased after exposure to LPS/PepG and was maintained by melatonin and 6-hydroxymelatonin at the highest concentrations only. CONCLUSIONS: We have shown that in addition to melatonin, other structurally related indoleamine compounds have effects on NFκB activation and cytokine expression, GSH, mitochondrial membrane potential, and metabolic activity in endothelial cells cultured under conditions mimicking sepsis. Further work is needed to determine whether these compounds represent therapeutic approaches for disrupting the oxidative stress-inflammatory response signalling pathway in sepsis.

Clinical investigation of athletes with persistent fatigue and/or recurrent infections.

OBJECTIVE: To investigate whether underlying medical conditions contribute to the fatigue and high incidence of infections that can occur during repeated intense training. METHOD: Forty one competitive athletes (22 male, 19 female) with persistent fatigue and/or recurrent infections associated with performance decrements had a thorough medical examination and a series of clinical investigations to identify potential medical causes. RESULTS: Conditions with the potential to cause fatigue and/or recurrent infections were identified in 68% of the athletes. The most common were partial humoral immune deficiency (28%) and unresolved viral infections (27%). Non-fasting hypoglycaemia was common (28%). Other conditions included allergic disease (15%), new or poorly controlled asthma (13%), upper airway dysfunction (5%), sleep disorders (15%), iron depletion (3%), and one case of a thyroid disorder. A positive antinuclear antibody was detected in 21% of the athletes, without any clinical evidence of autoimmune disorders. Evidence of Epstein-Barr virus reactivation was detected in 22% of the athletes tested. CONCLUSIONS: Athletes with recurrent infections, fatigue, and associated poor performance may benefit from a thorough investigation of potentially reversible underlying medical conditions, especially when these conditions cause disruption to training and competition. Unresolved viral infections are not routinely assessed in elite athletes, but it may be worth considering in those experiencing fatigue and performing poorly.