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OBJECTIVES: To assess the effects of different doses and routes of Sulodexide on leukocyte-endothelium interaction and tissue perfusion in a model of venous hypertension and low blood flow. METHODS: Six weeks after venous hypertension induction, through external iliac vein ligature male hamsters (Mesocricetus auratus) received Sulodexide at 1, 2, or 4 mg/kg/day or saline (placebo) by subcutaneous or intramuscular routes during 2 or 4 weeks. After treatments, leukocyte rolling and adhesion, functional capillary density (FCD), and venular diameter were evaluated on the affected hindlimb. RESULTS: Subcutaneous and intramuscular treatments with Sulodexide after 2 and 4 weeks, significantly reduced leukocyte rolling and adhesion and increased FCD. Sulodexide did not affect venular diameter and intramuscular treatment was more effective in reducing leukocyte adhesion than the subcutaneous one. CONCLUSION: This preliminary study demonstrated that Sulodexide significantly decreased leukocyte-endothelium interaction and improved tissue perfusion in hamsters subjected to venous hypertension and low blood flow.

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Here we evaluated whether Natterins affect the leukocyte-endothelial cell interaction, hampering leukocyte mobilization and extravasation. Leukocyte-endothelial cell interactions were evaluated in venules of mouse cremaster muscle using intravital microscopy. We reported that low doses of Natterins interfere with the cell capturing, inhibiting the interaction of blood neutrophils with the post-capillary venules induced by the TLR4 agonist LPS, or the chemokine KC. Using endotoxemic mice challenged with LPS, we confirmed that Natterins reduce neutrophil accumulation in the peritoneum exudates. The rolling of leukocytes induced by KC or LPS was not impaired in Natterins-treated TLR2, MyD88 deficient or TLR4 mutant mice, indicating that TLR2- or TLR4-MyD88-mediated signals are required for the anti-inflammatory effect of Natterins. The inhibitory effect was not influenced by endogenous regulators of inflammation such as IL-10, corticosteroids, the HO-1 or the antagonist of the receptor of IL-1, nor by the disruption of their proteolytic activity. However, it was completely dependent on the activation of serine/threonine phosphatases and the PI3K signaling pathway, but independent on increased proteasome activity. This work started asking how the main toxins in the T nattereri venom contributes for the deficient influx of inflammatory leukocytes, which consequently drive to the delayed inflammatory reaction finalization in injured tissue; and finished demonstrating that Natterins can control the leukocyte-endothelial wall interactions in a mechanism dependent on negative signals derived from TLR2-TLR4/Myd88 signaling cascade. Interestingly, we confirmed that the antagonist effect of Natterins is mediated by the activation of serine/threonine phosphatases and by the key signaling PI3K molecule.

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OBJETIVO: Avaliar se a desnutrição no período neonatal produz prejuízos no recrutamento celular para o pulmão e na atividade oxidante-antioxidante de macrófagos alveolares em ratos adultos endotoxêmicos. MÉTODOS: Ratos machos Wistar (n=48) foram alimentados por mães cuja dieta, durante a lactação, continha 23 por cento de proteína no grupo nutrido e 8 por cento no grupo desnutrido. Após o desmame todos os animais foram recuperados com dieta normoprotéica. Entre 90 e 120 dias, a metade de cada grupo foi submetida à endotoxemia por meio da administração por via intraperitonial (v.i) de lipopolissacarídio na dose de 1mg/kg de peso corporal. Após 24 horas desse procedimento coletou-se o sangue para contagem total e diferencial de leucócitos e para a dosagem de óxido nítrico. Além do sangue coletou-se também o lavado broncoalveolar para contagem total e diferencial de leucócitos e, a partir de macrófagos isolados deste lavado, foram realizadas as dosagens de superóxido, óxido nítrico e superóxido dismutase. RESULTADOS: A desnutrição acarretou um déficit ponderal que persistiu até a idade adulta, além disso, reduziu a contagem total de leucócitos sangüíneos e o número de neutrófilos após o estímulo com lipopolissacarídio. A atividade oxidante-antioxidante foi alterada havendo diminuição da produção de superóxido, óxido nítrico e superóxido dismutase antes e após a indução da endotoxemia. CONCLUSÃO: Esses resultados sugerem que a desnutrição neonatal, mesmo após a recuperação nutricional, compromete o recrutamento celular para o pulmão e a atividade oxidante-antioxidante dos macrófagos alveolares em ratos adultos. A endotoxemia contribui para evidenciar essas seqüelas da resposta do hospedeiro frente a este modelo de desnutrição.

OBJECTIVE: The objective of this study was to assess if neonatal malnutrition impairs cell recruitment to the lungs and the oxidant-antioxidant activity of alveolar macrophages in adult endotoxemic rats. METHODS: Male Wistar rats (n=48) were divided into two groups and suckled by dams fed experimental diets containing a normal protein content of 23 percent (nourished group) and a low protein content of 8 percent (undernourished group) during lactation. After weaning, all animals received a normal protein diet. Between 90 and 120 days, half of each group was submitted to endotoxemia by intraperitoneal administration of 1mg/kg of body weight of lipopolysaccharide. Blood was collected 24 hours after this procedure for total and differential leukocyte count and measurement of nitric oxide. Bronchoalveolar lavage was also done to determine total and differential leukocyte count and measure superoxide, nitric oxide and superoxide dismutase in the macrophages isolated from this lavage. RESULTS: Malnourished animals remained underweight until adulthood. Furthermore, the following also decreased: total blood leukocyte count, number of neutrophils after lipopolysaccharide administration and production of superoxide, nitric oxide and superoxide dismutase before and after induced endotoxemia. CONCLUSION: These results suggest that neonatal malnutrition, even after nutritional recovery, compromises cell recruitment to lungs and the oxidant-antioxidant activity of alveolar macrophages of adult rats. Endotoxemia contributes to evidence these sequelae to the host response before this model of malnutrition.

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