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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Nucleotide oligomerization domain (NOD) proteins recognize peptidoglycan fragments, resulting in up-regulation of transcription factors, and may enhance the inflammatory response to infection. Specifically, NOD2 has been shown to sense muramyl dipeptide (MDP), which is released during bacterial cell growth and replication. Activation of NOD2 by MDP enhances the inflammatory response caused by LPS (endotoxin). ⋯ When compared with animals receiving low-dose LPS alone, coadministration of MDP (10 mg kg(-1), i.v.) and LPS, or administration of MDP (10 mg kg(-1), i.v.) 24 h before LPS resulted in a significant increase in the degree of organ injury, cytokine release, and lung injury caused by LPS alone. Thus, our results demonstrate that the two bacterial wall components MDP and LPS work in concert to cause multiple organ injury and systemic inflammation. We hope that our results stimulate other studies designed to evaluate the effects of NOD ligands in animal models of inflammation.
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Because studies have shown that 17beta-estradiol (E2) produces anti-inflammatory effects after various adverse circulatory conditions, we examined whether administration of E2 before spinal cord injury (SCI) has any salutary effects in reducing SCI. Spinal cord injury was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. To gain a better insight into the mechanism of action of the anti-inflammatory effects of E2, the following end points of the inflammatory process were evaluated: (1) spinal cord inflammation and tissue injury (histological score); (2) neutrophil infiltration (myeloperoxidase activity); (3) expression of iNOS, nitrotyrosine, and COX-2; (4) apoptosis (terminal deoxynucleotidyltransferase-mediated UTP end labeling staining and Bax and Bcl-2 expression); and (5) tissue TNF-alpha, IL-6, IL-1beta, and monocyte chemoattractant protein 1 levels. ⋯ To elucidate whether the protective effects of E2 were mediated via the estrogen receptors, we investigated the effect of an estrogen receptor antagonist, ICI 182,780, on the protective effects of E2. ICI 182,780 (500 microg/kg, s.c., 1 h before treatment with E2) significantly antagonized the effect of the E2 and abolished the protective effect against SCI. Taken together, our results clearly demonstrate that administration of E2 before SCI reduces the development of inflammation and tissue injury associated with spinal cord trauma.
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There have been difficulties to demonstrate a relationship between endotoxin concentration and clinical response. One hypothesis for this difficulty might be that a fast increase in endotoxin concentration elicits a stronger biological response than a more gradual one of the same dose. The aim of the present study was to investigate the existence of such a response. ⋯ After 3 h, the endotoxin infusion was stopped, and the pigs were observed for another 3 h. The responses in TNF-alpha, core temperature, leukocytes, platelets, MAP, left ventricular stroke work index, mixed venous saturation, base excess, pH, and pulmonary compliance were greater in group I than in group II, whereas the IL-6 response did not differ between groups. The biological responses of inflammation, hypotension, hypoperfusion, and organ dysfunction are increased if the organism is exposed to a fixed amount of endotoxin more quickly.
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Shock and tissue hypoperfusion are common after asphyxia. We compared systemic and regional hemodynamic effects of epinephrine and dopamine in the treatment of shock and hypotension in asphyxiated newborn piglets resuscitated with 100% oxygen. Twenty-four piglets (1-3 days old; weight, 1.4-2.6 kg) were acutely instrumented to measure cardiac index (CI), carotid, mesenteric and renal arterial blood flows, and mean systemic (SAPs) and pulmonary arterial pressures (PAPs). ⋯ Epinephrine (0.3-1.5 microg kg(-1) min(-1)) for 2 h increased SAP and CI (with higher stroke volume) and decreased pulmonary vascular resistance (with reduced PAP-SAP ratio), whereas the responses with dopamine (10-25 microg kg(-1) min(-1)) were modest. Low-dose epinephrine improved mesenteric and carotid arterial flows, whereas the pressure-driven doses of epinephrine and dopamine increased carotid and mesenteric arterial flows, respectively. To treat shock in asphyxiated newborn piglets resuscitated with 100% oxygen, epinephrine exhibits an inotropic action compared with dopamine, whereas both catecholamines can increase carotid and mesenteric perfusion.