The apoptosis clearance signal phosphatidylserine inhibits leukocyte migration and promotes inflammation resolution in vivo.

Previous studies have shown that phagocytosis of apoptotic cells can tune the macrophage phenotype and trigger the resolution of inflammation. This mechanism is largely dependent on the recognition of phosphatidylserine (PS) residues on the outer membrane of dying cells. Therefore, we sought to assess the effects of PS-containing liposomes (mimics of apoptotic cells) on the leukocyte migration profile during the inflammatory process in vivo. Inflammation was induced by carrageenan injection into air pouches created on the dorsal region of mice, as this model enables convenient access to the exudates for further investigation. Mice were treated with PBS, PS-containing or phosphatidylcholine (PC)-containing liposomes (10, 30 or 100 mg/kg intraperitoneally [i.p.]). Starting 8 h after carrageenan injection, the level of leukocyte infiltration was monitored over three days. The PS-containing, but not PC-containing, liposomes reduced the polymorphonuclear (PMN) and mononuclear (MN) leukocyte influx into the inflamed pouches in a dose-dependent fashion. Most notably, these effects could also be adoptively transferred; that is, they were also found in mice injected with a liposome-free peritoneal lavage obtained from the mice that had received the intraperitoneal PS-liposome treatment. The effect of treatment with the PS-induced soluble mediators (PS-ISMs) was found to be dependent on the presence of peritoneal macrophages and was susceptible to heat, trypsin degradation, and cycloheximide treatment. The PS-containing liposomes promoted the reduction of PMN leukocyte influx by triggering the release of anti-inflammatory autacoids with a proteinaceous nature that were produced de novo after PS exposure.

Opioid analgesics in experimental sepsis: effects on physiological, biochemical, and haemodynamic parameters.

Cecal ligation and puncture (CLP) is the sepsis model that more closely resembles the human pathology, but it is likely to cause suffering to experimental animals. However, it is not clear whether the use of analgesia may affect some parameters evaluated in experimental sepsis research. Therefore, we investigated the effects of fentanyl and tramadol in experimental sepsis in the rat. The following parameters were evaluated: body temperature, body weight, water and food ingestion, mortality, analgesia, blood leukocytes, mean arterial blood pressure, vascular reactivity to phenylephrine, lung myeloperoxidase activity, and plasma levels of IL1-ß, glutamic-oxaloacetic, glutamic-pyruvic, lactate, creatinine and urea. While producing significant analgesia, the opioids modify minimally the parameters, with the exception of sepsis-induced hypotension and mortality. Although fentanyl and tramadol can minimize pain and the general suffering of animals submitted to CLP surgery, their effects on cardiovascular parameters as well as in the mortality indicate that their use in experimental sepsis must be done with caution and with all the proper control groups.

Anti-atherogenic effects of a phenol-rich fraction from Brazilian red wine (Vitis labrusca L.) in hypercholesterolemic low-density lipoprotein receptor knockout mice.

Moderate wine intake (i.e., 1-2 glasses of wine a day) is associated with a reduced risk of morbidity and mortality from cardiovascular disease. The aim of this study was to evaluate the anti-atherosclerotic effects of a nonalcoholic ethyl acetate fraction (EAF) from a South Brazilian red wine obtained from Vitis labrusca grapes. Experiments were carried out on low-density lipoprotein (LDL) receptor knockout (LDLr⁻/⁻) mice, which were subjected to a hypercholesterolemic diet and treated with doses of EAF (3, 10, and 30 mg/kg) for 12 weeks. At the end of the treatment, the level of plasma lipids, the vascular reactivity, and the atherosclerotic lesions were evaluated. Our results demonstrated that the treatment with EAF at 3 mg/kg significantly decreased total cholesterol, triglycerides, and LDL plus very low-density lipoprotein levels compared with control hypercholesterolemic mice. The treatment of mice with EAF at 3 mg/kg also preserved the vasodilatation induced by acetylcholine on isolated thoracic aorta from hypercholesterolemic LDLr⁻/⁻ mice. This result is in agreement with the degree of lipid deposit on arteries. Taken together, the results show for the first time that the lowest concentration of an EAF obtained from a red wine produced in southern Brazil significantly reduced the progression of atherosclerosis in mice.

An ethyl acetate fraction obtained from a Southern Brazilian red wine relaxes rat mesenteric arterial bed through hyperpolarization and NO-cGMP pathway.

A number of studies suggest that moderate consumption of red wine may be more effective than other alcoholic beverages in decreasing the risk of coronary heart disease (CAD). In this study, we investigated the effect of a crude extract (CE), as well as an ethyl acetate fraction (EAF) obtained from a Brazilian red wine in the mesenteric arterial bed (MAB) from rats. Our results showed that after the tonus of MAB was increased with phenylephrine (PE), increasing concentrations of CE induced a concentration-dependent relaxation; moreover, EAF was more potent in relaxing the MAB when compared with CE. In vessels depolarized with KCl (80 mM) or treated with the Na(+)/K(+)-ATPase pump inhibitor, ouabain (OUA; 100 microM), or with the K(+) channel blockers: barium (BaCl(2), 100 microM) and tetraethylammonium (TEA; 500 microM), the effect of EAF was significantly reduced. However, this effect was not altered by the ATP-dependent K(+) (K(ATP)) channel blocker, glibenclamide (GLI; 100 microM) as well as Charybdotoxin (ChTx 10 nM), a nonselective inhibitor of K(Ca) channels of large and intermediate conductance plus Apamin (Apamin 100 nM), a specific inhibitor of K(Ca) channels of small conductance. The residual vasodilator effect of EAF observed in vessels pretreated with L-NOARG (100 microM), 1H-[1,2,4,] oxadiazolo[4,3-alfa]quinoxalin, ODQ (10 microM) or KCl (80 mM), given separately, was reduced by the administration of KCl (40 mM) plus L-NOARG (100 microM). The present study demonstrates that the vasodilator effect of EAF is partially dependent upon membrane hyperpolarization in combination with nitric oxide (NO) release.