摘要:

ABSTRACTAfter operations with cardiopulmonary bypass, patients often show early symptoms of the systemic inflammatory response syndrome (SIRS). Potential mediators of SIRS include the platelet-activating factor (PAF), which has been linked to septic shock and multiple organ dysfunction. We studied the effect of cardiac surgery on PAF acetylhydrolase, the PAF-degrading plasma enzyme, as well as the relationship between the enzyme and the postoperative state of the patients. PAF acetylhydrolase activity decreased by 38 ± 8% after instituting cardiopulmonary bypass because of plasma dilution and returned to near-preoperative levels within 6 h postsurgery. After that, enzyme levels decreased again, resulting in a 24 ± 12% reduction until at least 3 days postsurgery. Patients in poor postoperative condition (Acute Physiology Score >9) had a lower preoperative PAF acetylhydrolase activity than did normal patients (12 ± 4 vs. 17 ± 4 nmol min-1mL-1; p < .05). Likewise, patients who developed postoperative SIRS had a lower preoperative PAF acetylhydrolase activity than did patients without SIRS (12 ± 3 vs. 17 ± 4 nmol min-1mL-1; p < .05). The data suggest that PAF acetylhydrolase deficiency is among the factors associated with postoperative distress after cardiac surgery.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTThe role of nitric oxide (NO) on liver oxidative stress and tissue injury in rats subjected to tourniquet shock was investigated. This shock model differs from others in that injury is a consequence of remote organ damage. Liver oxidative stress becomes evident after hind limb reperfusion, as evidenced by the loss of total tissue thiols; by increases in tissue oxidized glutathione (GSSG), lipid peroxidation (LPO), plasma aminotransferases (alanine aminotransferase (ALT) and (aspartate aminotransferase (AST)), and plasma nitrites; and by a 36% loss in total superoxide dismutase (SOD) activity. Portal blood flow is reduced by 54.1 % after 2 h of hind limb reperfusion. Inhibition of NO synthesis with N±-nitro-L-arginine methyl ester or L-arginine methyl ester increased mean arterial blood pressure; further reduced portal blood flow; and aggravated liver injury as assessed by further loss in total thiols, increased LPO and GSSG content, and further increases in plasma ALT and AST. Total plasma nitrites were lower than in control animals, and total tissue SOD activity decreased by more than 80%. Treatment with the NO donor sodium nitroprusside reverted the decrease in portal blood flow and also reverted tissue thiol loss, LPO, and GSSG increases, as well as the loss of ALT and AST to plasma and of SOD activity to levels comparable to untreated control shock animals. As expected, plasma nitrites were greater than in tourniquet control animals. These data support the hypothesis that endogenous NO formation protects the rat liver from the consequences of oxidative stress elicited by hind limb reperfusion in rats subjected to tourniquet shock.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTInhibitors of nitric oxide synthase (NOS) attenuate the circulatory failure caused by endotoxin, but the role of NO in the development of multiple organ dysfunction and the relative contribution of NO produced by endothelial NOS and inducible NOS (iNOS) to organ injury remains unclear. Here we report for the first time that 1400W, a novel and highly selective inhibitor of iNOS activity, attenuates the delayed hypotension as well as the rise in the plasma levels of nitrite/nitrate caused by endotoxin in the rat. Inhibition of iNOS activity with 1400W administered either before or 2 h after endotoxin injection did not, however, attenuate the hepatocellular injury, renal dysfunction, or pancreatic injury in this model. Similarly, administration of another selective inhibitor of iNOS activity, L-NIL, 2 h after endotoxin injection abolished the rise in nitrite/nitrate and attenuated the delayed hypotension caused by endotoxin, but failed to ameliorate organ injury. Thus, selective inhibition of iNOS activity with 1400W attenuates the circulatory failure induced by endotoxin in the rat, but fails to influence the degree of organ injury/dysfunction.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTThe aim of the present study was to investigate the role of poly(ADP-ribose) synthetase in a nonseptic shock model, wherein oxyradicals, nitric oxide, and peroxynitrite are known to play a crucial role in the inflammatory process. DNA single-strand breakage and activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS) triggers an energy-consuming, inefficient repair cycle, which contributes to peroxynitrite-induced cellular injury. Here we investigated whether peroxynitrite production and PARS activation are involved in cytotoxicity in macrophages collected from rats subjected to zymosan-induced shock. Macrophages harvested from the peritoneal cavity exhibited a significant production of peroxynitrite, as measured by the oxidation of the fluorescent dye dihydrorhodamine 123. Furthermore, zymosan-induced shock caused a suppression of macrophage mitochondrial respiration, DNA strand breakage, activation of PARS, and reduction of NAD+cellular levels. In vivo treatment with 3-aminobenzamide (10 mg/kg intraperitoneally, 1 and 6 h after zymosan injection) or nicotinamide (50 mg/kg intraperitoneally, 1 and 6 h after zymosan injection) significantly inhibited the decrease in mitochondrial respiration and the activation of PARS, and partially restored the cellular level of NAD+. In a separate group of experiments, In vivo pretreatment with NG-nitro-L-arginine methyl ester, a nonselective inhibitor of nitric oxide synthesis (10 mg/kg intraperitoneally, 15 min before zymosan administration), reduced peroxynitrite formation and prevented the appearance of DNA damage, the decrease in mitochondrial respiration, and the loss of cellular levels of NAD+. Our study suggests that formation of peroxynitrite and subsequent activation of PARS may alter macrophage function in inflammatory processes and inhibition of nitric oxide, and that PARS may be a novel pharmacological approach to prevent cell injury in inflammation.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTPeroxynitrite (a potent oxidant produced by nitric oxide and superoxide) and hydroxyl radical, reactive oxidants produced during hemorrhagic shock, are potent triggers of DNA single-strand breakage. DNA injury triggers the activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS), which contributes to cellular injury. Hemorrhagic shock is associated with early vasomotor paralysis as well as with early derangements in the cellular metabolic status. Here we have tested whether activation of PARS contributes to the vasodilatation and early mortality in a rat model of severe hemorrhagic shock. In anesthetized rats hemorrhaged to a mean arterial blood pressure of 35 mmHg, pretreatment with the PARS inhibitor 5-iodo-6-amino-1,2-benzopyrone significantly improved survival rate. Furthermore, an inhibitor of nitric oxide biosynthesis (NG-methyl-L-arginine) and the cell-permeable superoxide dismutase mimetic Mn(lll)tetrakis(4-benzoic acid) porphyrin also offered a significant protection in terms of hypotension and acute mortality. However, the selective inhibitor of the inducible nitric oxide synthase, mercaptoethylgua-nidine, failed to affect blood pressure or mortality. The present data suggest that PARS activation plays a role in the pathophysiology of hemorrhagic shock. Early production of peroxynitrite (produced by nitric oxide from constitutive nitric oxide synthase) and hydroxyl radical may induce DNA single-strand breakage, which is the immediate trigger of PARS activation.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTThe aim of this study was to evaluate the effect of dextran (Dx) 1 versus Dx 60 (molecular weights 1,000 and 60,000) on microvascular disturbances and tissue injury in striated muscle after ischemia/reperfusion (I/R). Experiments were performed using a 4 h pressure-induced ischemia model in the hamster dorsal skinfold chamber. Three groups (n = 6) of animals received a continuous infusion (45 min, 3 ±L/mon) of either Dx 1 or Dx 60 (total dose 5 mg/kg) or saline solution beginning 15 min before reperfusion. Intravital fluorescence microscopy allowed for quantification of functional capillary density, leukocyte adherence, extravasation of fluorescein isothiocyanate-Dx, and nonviable (propidium-positive) cell count before ischemia and .5, 2, and 24 h after reperfusion. Experiments were terminated with tissue preservation for electron microscopy. Postischemic functional capillary density was significantly improved by Dx 60 (at 24 h, 88% vs. 51 % in controls). In animals receiving postischemic Dx 1 or Dx 60, leukocyte adherence was significantly reduced (at .5 h, 44% and 58%, respectively) as compared with controls, whereas macromolecular extravasation was unchanged. Nonviable cell count was significantly decreased by both Dx fractions (at 24 h, Dx 1, 75%; Dx 60, 87%), indicating a reduction of tissue injury, which was also confirmed by electron microscopy. These results provide evidence that Dx 60 at 5 mg/kg attenuates I/R injury more effectively than Dx 1. Leukocytes play a major role in the development of I/R injury, but macromolecular extravasation does not always correlate with the leukocyte-endothelium interaction and the manifestation of I/R injury.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTAlthough cardiac function is depressed during endotoxic shock, it remains controversial whether the ventricular contractility and structure are altered during sepsis. To resolve this issue, rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). At 2, 5, and 10 h after CLP (i.e., the early, hyperdynamic stage of sepsis) or 20 h after CLP (the late, hypodynamic stage of sepsis, based on the depressed tissue perfusion), in vivo left ventricular contractility parameters such as maximal rate of the left ventricular pressure increase (+dP/dtmax) and decrease (-dP/dtmax), maximal rate of “pressure-normalized” change in ventricular pressure (dP/dtmax/P), and ventricular peak systemic pressure were determined using a Digi-Med± Heart Performance Analyzer±. In additional groups of animals, ultrastructure of the cardiac muscle in the left ventricle was examined at 5, 10, or 20 h after CLP, using a transmission electron microscope. The results indicate that +dP/dtmaxand dP/dtmax/P increased significantly at 2–10 h after CLP. The values of -dP/dtmaxand ventricular peak systemic pressure increased significantly at 2 and 5 h after the onset of sepsis, respectively. These in vivo ventricular contractility parameters, however, were not significantly different from shams at 20 h after CLP. Ultrastructural examination showed that enlarged T-tubules were prominent during the hyperdynamic stage of sepsis, which was correlated with the increased cardiac contractility. Although focal and moderate hypertrophy as well as expanded intermyocyte junctions could be observed occasionally, myocardial cells did not appear to be compromised at 20 h after CLP. Thus, the transition from the hyperdynamic to hypodynamic circulation during sepsis does not appear to be due to any depression in myocardial function because cardiac contractility and structure are not compromised even during the late, hypodynamic stage of sepsis. However, further investigation is required to determine whether cardiac function is depressed at the terminal stage of polymicrobial sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTPre-exposure of THP-1 cells to low concentrations of endotoxin (lipopolysaccharide, LPS) down-regulates thromboxane (Tx) A2, an arachidonic acid (AA) metabolite, production in response to a subsequent LPS stimulation. To further delineate the mechanisms of LPS-induced down-regulation of TxA2, we examined expression of prostaglandin H synthase (PGHS)-2 mRNA, changes in PGHS activity, and content of PGHS-1 and −2. Pre-exposure to LPS (1 ±g/mL for 18 h to desensitize cells) inhibits production of TxB2, the stable metabolite of TxA2, in response to secondary stimulation of LPS (10 ±g/mL), when compared with LPS-stimulated naive cells (p < .05, n = 5). LPS (10 ±g/mL) induced expression of PGHS-2 mRNA at 1 and 2 h in naive cells, but this expression was decreased in the LPS-desensitized cells. However, exogenous AA (16 ±M) or phorbol myristic acid (PMA), 3 ±M) stimulated greater TxB2production in the LPS-desensitized cells than in the naive cells (p < .05). Protein content of PGHS-1 and −2 were examined by Western blot analysis, using antibodies specific for PGHS-1 and PGHS-2. Densitometric analysis demonstrated a significant increase in PGHS-2 induction in LPS-stimulated naive cells (405 ± 174%) over its respective basal group (p < .05, n = 5). PGHS-1 was constitutively present, but there was no significant difference in quantity between naive and LPS-desensitized basal or LPS-stimulated groups. Thus, despite the reduction in expression of PGHS-2 mRNA, these composite data demonstrate that down-regulation of PGHS activity (assessed with exogenous AA or PMA) cannot be responsible for the inhibition of AA metabolism observed in LPS desensitization.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTWe sought to understand the mechanism of metabolic acidosis that results in acute resuscitated endotoxic shock. In six pentobarbital-anesthetized dogs, shock was induced by Escherichia coli endotoxin infusion (1 mg/kg) and was treated with saline infusion to maintain mean arterial pressure > 80 mmHg. Blood gases and strong ions were measured during control conditions and at 15, 45, 90, and 180 min after endotoxin infusion. The mean saline requirement was 1833 ± 523 mL over a 3 h period. The total acid load from each source was calculated using the standard base deficit. The mean arterial pH decreased from 7.32 to 7.11 (p < .01); pco2and lactate were unchanged. Saline accounted for 42% of the total acid load. However, 52% of the total acid load was unexplained. Although serum Na+did not change, serum Cl-increased (127.7 ± 5.1 mmol/L vs. 137.0 ± 6.1 mmol/L; p = .016). We conclude that saline resuscitation alone accounts for more than one-third of the acidosis seen in this canine model of acute endotoxemia, whereas lactate accounts for less than 10%. A large amount of the acid load can be attributed to differential Na+and Cl-shifts from extravascular to vascular spaces.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTSystemic organ blood flow was longitudinally determined with fluorescent microspheres after severe thermal injury in unanesthetized sheep. After chronic instrumentation, 20 sheep were subjected to combined injury with 40% body surface area third-degree burn and 48 breaths of cotton smoke insufflation. During the next 72 h of the experimental period, all animals were resuscitated with Ringer's lactate following the Parkland formula. To test the effect of systemic administration of ibuprofen, animals were assigned to the control group (n = 11) or the ibuprofen group (n = 9). In the ibuprofen group, animals received ibuprofen as a 12 mg/kg bolus injection 1 h after injury and 6 mg/kg/h as a continuous infusion for the next 47 h. After this combined injury, animals exhibited a biphasic hemodynamic alteration, with an initial shock period and a later hyperdynamic period, a phenomenon often seen in severely burned patients. Among multiple organs, the splanchnic organs exhibited more dominant and sustained decreases in regional blood flow, whereas heart and kidney blood flow were maintained at more than 90% of baseline level even in the initial hypovolemic phase. In the postresuscitation period, no organ except the heart showed increased regional blood flow, despite a more than 20% increase in cardiac output. Ibuprofen had effects on early recovery from the initial shock period, and it improved intestinal organ blood flow, suggesting a potential benefit of this drug for severe thermal injury.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID