A new method of measuring intracellular Na and K using Li substitution was applied to a study of vascular smooth muscle and red cell Na changes in haemorrhagic shock. A rat haemorrhagic shock model was used. Controlled haemorrhage was allowed with a syringe reservoir and the arterial blood pressure was maintained at 30 mm Hg. In a pilot study, using 20 rats, the plasma Na and plasma K were monitored. A fall in plasma Na and a rise in plasma K were observed. Both returned towards normal following retransfusion and recovery for one hour. In vascular smooth muscle, significant changes in both cell Na and K occurred following a 2 hour period of haemorrhagic shock. The vascular smooth muscle cell Na in control animals was 27.0±1.5 mEq/kg dry weight and 42.7±1.4 mEq/kg dry weight in the shocked animals (P<0.001). The cell K was 127.8±6.0 in the control animals and 74.7±4.2 in the shocked animals. In red cell studies, significant increases in red cell Na were found. The red cell Na in controls was 7.09±0.29 mEq/litre cells, whilst in the shocked animals the red cell Na was 8.26±0.33 mEq/litre cells (P<0.025). This was associated with a small but not statistically significant fall in red cell K. In both sets of experiments, the plasma Na and K were monitored and similar changes to those of the pilot study were found. Following retransfusion and recovery for 1 hour in the vascular tissue study and 2 hours in the red cell study, no significant recovery of cellular Na or K occurred. The results of these studies are consistent with a significant impairment of cell membrane function in haemorrhagic shock. The importance of both normal vascular responses and red cell function following severe haemorrhage is obvious. The fact that both may be impaired may have important implications in relation to the treatment and prognosis of haemorrhagic shock. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

Acute Respiratory Distress Syndrome is a late cause of morbidity and mortality following hemorrhagic shock and resuscitation. Previous work in our laboratory showed that alveolar macrophages were primed for increased responsiveness to lipopolysaccharides, as evidenced by augmented inflammatory cytokine production. Recent studies have shown that macrophages can be polarized into two phenotypes, namely pro-inflammatory M1 and anti-inflammatory M2 macrophages, in response to various environmental cues. The major hypothesis to be tested in this thesis is that HS/R shifts the M1/M2 polarization of alveolar macrophages to favour a pro-inflammatory milieu in the lung. A biphasic shift in the phenotype of alveolar macrophages in response to HS/R characterized by an early reduction of M2 cells followed by a late up-regulation of M1 macrophages was observed. The administration of M2- polarizing PPAR&gamma; agonists prior to HS/R restored the M1/M2 balance of alveolar macrophages and reduced lung injury.

Acute Respiratory Distress Syndrome is a late cause of morbidity and mortality following hemorrhagic shock and resuscitation. Previous work in our laboratory showed that alveolar macrophages were primed for increased responsiveness to lipopolysaccharides, as evidenced by augmented inflammatory cytokine production. Recent studies have shown that macrophages can be polarized into two phenotypes, namely pro-inflammatory M1 and anti-inflammatory M2 macrophages, in response to various environmental cues. The major hypothesis to be tested in this thesis is that HS/R shifts the M1/M2 polarization of alveolar macrophages to favour a pro-inflammatory milieu in the lung. A biphasic shift in the phenotype of alveolar macrophages in response to HS/R characterized by an early reduction of M2 cells followed by a late up-regulation of M1 macrophages was observed. The administration of M2- polarizing PPAR&gamma; agonists prior to HS/R restored the M1/M2 balance of alveolar macrophages and reduced lung injury.

Thesis (M.S.)--University of Wyoming, 2007. / Title from PDF title page (viewed on Nov. 4, 2008). Includes bibliographical references (p. 63-68).

Hemorrhagic shock is a clinical syndrome involving widespread cellular dysfunction and resulting in injury to many organs. Resuscitation from hemorrhagic shock is similar to reperfusion after ischemia, but differs in that some blood flow persists during shock. Ischemia-reperfusion produces oxygen radicals in many organs, including the liver of the rat and the human. The hypothesis of this project was that oxygen radicals are produced and cause hepatic injury during resuscitation from hemorrhagic shock. The production of oxygen radicals within the liver should cause lipid peroxidation and tissue injury. Manipulation of defenses against oxygen radicals should decrease the hepatic injury caused by hemorrhagic shock and resuscitation. The blood pressure of Sprague-Dawley rats was reduced to 35-40 mm Hg by blood withdrawal for two hours, followed by reinfusion of withdrawn blood. Plasma alanine aminotransferase (ALT) levels rose and injury to hepatocytes and non-parenchymal cells was found on transmission electron microscopy. The presence of lipid peroxidation was determined by quantitation of ethane exhalation and hepatic content of thiobarbituric acid reactive substances (TBARS). Ethane exhalation was elevated during the hypotensive phase and after resuscitation. Hepatic TBARS levels were elevated after resuscitation only. The same hemorrhagic shock protocol was used to determine the effect of antioxidant manipulation on hepatic injury. The antioxidants superoxide dismutase, catalase, or deferoxamine produced no reduction in hepatic injury. The administration of phorone reduced hepatic non-protein sulfhydryl content and increased plasma ALT levels nine fold at 24 hours after resuscitation. The development of lipid peroxidation and the exacerbation of liver injury by the administration of phorone suggest that oxygen radicals are produced in the liver during hemorrhagic shock and resuscitation. However, the administration of antioxidants provided no protection. Therefore, it seems unlikely the oxygen radicals are involved in the pathogenesis of liver injury in this model. It is possible that the lipid peroxidation occurs after the cell is irreversible injured.

Thesis (M.S.)--University of Wisconsin--Madison, 1982. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Made available in DSpace on 2014-06-11T19:30:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-12-19Bitstream added on 2014-06-13T20:00:44Z : No. of bitstreams: 1 silva_ae_dr_botfm.pdf: 677283 bytes, checksum: 81300198b62fe55885f8b966cdd716bf (MD5) / Os anestésicos inalatórios halogenados podem apresentar papel importante na patogênese das alterações cardiocirculatórias e renais durante o choque hemorrágico por alterarem, de maneira dose dependente, os mecanismos de defesa compensatórios. O presente estudo teve como objetivo comparar os efeitos de uma concentração alveolar mínima (CAM) de halotano, sevoflurano e isoflurano sobre o sistema cardiovascular e renal em cães submetidos a choque hemorrágico e reposição volêmica com o sangue retirado do animal. O estudo aleatório foi realizado em trinta cães, sem raça definida, distribuídos em três grupos de acordo com o anestésico inalatório halogenado utilizado durante a anestesia, em concentrações eqüipotentes de uma CAM: GH (n=10) - halotano a 0,89%; GS (n=10) - sevoflurano a 2,4%; e GI (n=10) - isoflurano a 1,4%. Todos os cães foram ventilados mecânicamente, esplenectomizados e submetidos a sangramento, com retirada em torno de 40% do volume sangüíneo, visando manter a pressão arterial média de 40 a 50 mm Hg durante 45 minutos. A seguir, os cães foram submetidos à expansão volêmica com o sangue removido. Os atributos hemodinâmicos foram determinados no momento controle, após 45 minutos de hemorragia, e 15 e 60 minutos após a reposição sangüínea. Os atributos renais foram medidos nos mesmos momentos, exceto no período hemorrágico, pela ausência de diurese. No momento controle, a maioria das variáveis hemodinâmicas e renais foram semelhantes entre os grupos, com exceção da fração de filtração, cujos valores foram menores no grupo GI, em relação aos grupos GH e GS (p < 0,05), e da osmolalidade urinária, cujos valores foram maiores no grupo GS, em comparação com o grupo GH (p < 0,05). Após a hemorragia... / Halogenated anesthetics may play an important role in the pathogenesis of cardiovascular and renal changes during hemorrhagic shock because they modify, in a dose-dependent manner, compensatory defense mechanisms. The aim of the present study was to compare the effects of a minimum alveolar concentration (MAC) of halothane, sevoflurane and isoflurane on the cardiovascular and renal systems of dogs subjected to hemorrhagic shock followed by restoration of blood volume with shed blood. Thirty mongrel dogs were randomly distributed into three groups according to the halogenated anesthetic used for anesthesia. They were anesthetized with halothane (H group; n=10), sevoflurane (S group; n=10) or isoflurane (I group; n=10) and anesthesia was maintained at 1.0 MAC: 0.89%, 2.4%, and 1.4%, respectively. All the dogs were mechanically ventilated, splenectomized and subjected to bleeding with 40% blood reduction to keep mean arterial pressure between 40 and 50 mm Hg for 45 min. Thereafter, the dogs were resuscitated with shed blood. The hemodynamic attributes were determined at the control moment, after 45 min of hemorrhage, 15 and 60 min after restoration of blood volume. The renal attributes were determined at the described moments, except during the hemorrhage period, for lack of diuresis. At the control moment, most of the hemodynamic and renal variables were similar among the groups, except for the filtered fraction, Introdução e Literatura 11 which was lower in GI than in groups GH and GS (p < 0.05), and for urinary osmolarity, which was higher in GS compared to GH (p < 0.05). After hemorrhage, the hemodynamic attributes decreased, without significant differences among the groups (p > 0.05). Fifteen minutes after resuscitation, most of the hemodynamic and renal attributes were... (Complete abstract click electronic access below)

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Excessive microvascular permeability is a serious complication involved in traumatic injury and inflammatory diseases. Alcohol intoxication can exacerbate the physiological derangements produced by microvascular endothelial barrier dysfunction in such disease conditions. Sphingosine-1-phosphate (S1P) has known endothelial barrier-protective properties, and has been shown to ameliorate microvascular leakage in a model of combined alcohol intoxication and hemorrhagic shock and resuscitation (HSR). However, whether the barrier-protective properties of S1P extend to endothelial cells of the blood-brain barrier (BBB) is unclear. The mechanisms of S1P-induced barrier protection during alcohol intoxication or HSR are also unknown. In the current study, we tested the hypothesis that S1P could enhance endothelial barrier during alcohol intoxication or hemorrhagic shock by preserving the integrity of junction proteins and the endothelial glycocalyx, and protecting mitochondrial function. Cultured primary human brain microvascular endothelial cell (HBMEC) monolayers were used to characterize endothelial-specific mechanisms of S1P protection of the BBB during alcohol treatment. Transendothelial electrical resistance (TER) and apparent permeability coefficients for albumin, dextran-4 kDa, and sodium fluorescein were used as indices of barrier function. Junctional localization was determined by immunofluorescence confocal microscopy. We also used an established in vivo rat model of conscious HSR and assessed microvascular leakage, endothelial glycocalyx integrity, and mitochondrial function by intravital microscopy. Cultured rat intestinal microvascular endothelial cell (RIMEC) monolayers were used to test the ability of S1P to protect against glycocalyx shedding and endothelial barrier dysfunction caused by direct disruption of mitochondrial integrity due to inhibition of mitochondrial complex III. The results show that alcohol significantly impaired HBMEC TER and increased solute permeability, which was reversed with application of S1P after alcohol treatment. Alcohol caused the formation of gaps between cells. Treatment with S1P (after alcohol) increased junctional localization. Our in vivo results show that S1P protects against HSR-induced hyperpermeability, preserves the expression of adherens junctional proteins, and protects against glycocalyx degradation. S1P treatment during HSR also protects against mitochondrial membrane depolarization. Besides that, S1P protects RIMECs against mitochondrial dysfunction-induced endothelial barrier dysfunction and glycocalyx degradation by acting through mitochondrial complex III. Our results indicate that S1P may be useful for restoring BBB function during alcohol intoxication. Moreover, S1P protects against HSR-induced mitochondrial dysfunction in endothelial cells, which in turn improves the structure of the endothelial glycocalyx after HSR and allows for better junctional integrity to prevention of excess microvascular permeability.

Bibliography: p. 137-154. / 154 p. : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis details a series of studies in patients, in human volunteers and in large animals. Haemodynamics and left ventricular systolic and diastolic mechanics are reported during lactic acidosis, during therapies for lactic acidosis, and during hyperdynamic and hypovolemic shock. The study has the unifying hypothesis that cardiac dysfunction is important in hyperdynamic and hypovolemic shock and is not caused by lactic acidosis. / Thesis (M.D.)--University of Adelaide, Dept. of Anaesthesia and Intensive Care, 1997?