Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Effects of combined selective iNOS inhibition and peroxynitrite blockade during endotoxemia in pigs.
We investigated the effect of mercaptoethylguanidine (MEG, 3 mg kg(-1)h(-1)), a combined selective inducible nitric oxide synthase (iNOS) inhibitor, a peroxynitrite and oxygen free radical scavenger with cyclooxygenase-inhibitor properties on intestinal and hepatic perfusion, O2 exchange, and metabolism during long-term hyperdynamic porcine endotoxemia. MEG was started 12 h after onset of endotoxemia. At baseline and after 12, 18, and 24 h of endotoxemia, hepatic arterial and portal venous blood flow, ileal mucosal-arterial PCO2 gap, portal and hepatic venous lactate/pyruvate ratio, free glutathione (GSH), and 8-isoprostanes were measured. ⋯ MEG blunted the endotoxin-induced increase in expired NO and prevented the progressive fall in blood pressure without affecting cardiac output. It attenuated both systemic and regional venous acidosis without influencing the impairment of hepatosplanchnic metabolism nor counteracting the increase in GSH levels. In our model MEG failed to beneficially affect variables of oxidative stress.
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The morbidity and mortality from sepsis and multiple organ dysfunction syndrome (MODS) continues to be high. An increase in FcgammaRI+ (CD64+) monocytes was demonstrated in septic patients, and an association between cell number, their secretory activity, and poor outcome has been described. In the present investigation further characterization of CD64+ leukocytes has been attempted. ⋯ In healthy individuals CD64+ Neu and stimulated CD64+ Mo demonstrated increased ROS synthesis compared to matched CD64- cells (P = 0.001 and P = 0.042, respectively). Although ROS production by CD64+ leukocytes in sepsis was also increased compared to CD64- cells, significantly less ROS was generated compared to healthy subjects (P = 0.021). In conclusion, overexpression of CD64 on blood Mo and Neu from patients with sepsis and ARDS is associated with depressed PA and decreased oxidative response.
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Arginine stimulates lymphocyte function and is degraded by arginase, an enzyme that is abundantly present in red blood cells. Arginase impairs lymphocyte function and responses in vitro. Leakage of arginase from stored red blood cells may be involved in the lymphocyte dysfunction associated in allogenic blood transfusion. ⋯ This time dependent increase in arginase activity could be confirmed in the additional bags sampled (P < 0.0001, r = 0.78). The results for the first time show that arginase is released from red blood cells during storage for transfusion. Arginase infusion may play an important role in the immune suppression observed after blood transfusion.
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In the present study, by comparing the responses in wild-type mice (+/+) and mice lacking (-/-) the inducible (or type 2) nitric oxide synthase (iNOS), we investigated the role played by iNOS in the development of non-septic shock. A severe inflammatory response characterized by peritoneal exudation, high peritoneal levels of nitrate/nitrite, and leukocyte infiltration into peritoneal exudate was induced by zymosan administration in iNOS +/+ mice. This inflammatory process coincided with the damage of lung, liver, and small intestine, as assessed by histological examination. ⋯ Furthermore, a significant reduction of suppression of mitochondrial respiration, DNA strand breakage, and reduction of cellular levels of NAD+ was observed in ex vivo macrophages harvested from the peritoneal cavity of iNOS -/- mice subjected to zymosan-induced non-septic shock. In vivo treatment with aminoguanidine (300 mg/kg 1 and 6 h after zymosan administration) significantly prevents the inflammatory process. Taken together, our results clearly demonstrate that iNOS plays an important role in zymosan-induced non-septic shock.
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Biography Historical Article
Sepsis research: what did we do wrong? What would Semmelweis do today?