摘要:

Transient sublethal hyperthermia and the recovery from this exposure to heat (heat shock preconditioning) provides a cytoprotective effect on oxidative insults through an intracellular protective response, heat shock response. The impact of heat shock preconditioning on hepatic microvascular failure, which is a causative determinant of ischemia/reperfusion-induced injury of the liver, was investigated by using intravital fluorescence microscopy. In Sprague-Dawley rats, normothermic ischemia was induced by totally clamping the hepatoduodenal ligament for 20 min, followed by 120 min of reperfusion. Heat shock preconditioning was performed by whole-body hyperthermia (42°C for 15 min) and subsequent 48 h recovery. In accordance with the prominent induction of heat shock protein 70 in the liver tissue, the postischemic decrease in sinusoidal perfusion rate and sinusoidal diameter, and the postischemic increase in the number of stagnant leukocytes in sinusoids and adherent leukocytes in postsinusoidal venules were significantly attenuated in the heat shock-treated animals. Furthermore, liver enzyme release (glutamate pyruvate trans-aminase and α-glutathione S-transferase) was significantly reduced and postischemic deterioration of bile production was attenuated. The 7-day survival rate after 20-minute ischemia was significantly improved from 50% to 80% (heat shock-nontreated group vs. heat shock-treated group,P< 0.05). These results indicate that heat shock preconditioning attenuates ischemia/reperfusion-induced hepatic injury by preventing postischemic microvascular disturbances, and that its protective effect is circumstantially associated with the concomitant induction of heat shock protein 70.

ISSN:1073-2322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Hypotension caused by hypovolemic, hemorrhagic shock induces disturbances in the immune system that may contribute to an increased susceptibility to sepsis. The effect of chemically induced hypotension on circulating cytokines and adhesion molecules has not been investigated yet. In 21 patients scheduled for resection of malignant choroidal melanoma of the eye the perioperative serum levels of the cytokines IL-1β, IL-6, IL-10, TNF-α, and the adhesion molecules sE-Selectin and slCAM-1 were investigated. Moderate hypothermia of 32°C was induced in all patients. In 14 patients profound hypotension (mean arterial blood pressure 35–40 mmHg, hypotension group) was induced by enalapril and nitroglycerin for a mean duration of 71 min. In 7 patients the tumor was not resectable, and hypotension was not induced (controls). We did not detect significant differences in serum levels of cytokines or sE-Selectin perioperatively in patients with profound hypotension compared with controls. In both groups IL-6 serum levels increased significantly and reached a maximum after rewarming (17 ± 6 and 16 ± 5 pg/dL, respectively,P< 0.001). IL-1β, IL-10, and TNF-α did not change perioperatively in both groups. On the first postoperative day slCAM-1 serum levels were significantly increased in both groups (mean increase of 96 and 54 ng/mL, respectively,P <0.01 andP <0.05). We conclude from this study that profound normovolemic arterial hypotension does not seem to have effects on serum levels of circulating IL-1β, IL-6, IL-10, TNF-α, and sE-Selectin. Perioperative moderate hypothermia may be the reason for the postoperative increase in slCAM-1 levels independent of the blood pressure.

ISSN:1073-2322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Using a zymosan-induced mouse model of multiple organ dysfunction syndrome (MODS), it has been shown that the absence of MIP-1α increased mortality fourfold, whereas the absence of C5 decreased mortality fourfold. The purpose of the present study was to determine the early events following zymosan injection in MIP-1α knockout and C5-deficient mice. B10.D2/nSnJ (C5-sufficient) and B10.D2/0SnJ (C5-deficient) and genetically matched MIP-1α +/+ and MIP-1α -/- mice were divided into 3 groups: Group 1 received no injection, Group 2 received intraperitoneal saline injection (1.0 mL), and Group 3 were given intraperitoneal zymosan (1mg/gm, 1.0 mL). Two hours, 24 h, and 48 h after injection, peritoneal exudate leukocyte counts, total WBC count, lung MPO levels, and organ histology were examined for signs of changes in cellular infiltration. An acute local and systemic inflammatory response characterized by an increase in the peritoneal leukocyte count, total WBC counts, and circulating neutrophil levels was observed within 2–48 h of zymosan injection. Lack of MIP-1α attenuated local recruitment of phagocytes into the peritoneal cavity, and absence of MIP-1α or C5 caused a decrease in circulating neutrophil levels. The presence or absence of either C5 or MIP-1α did not affect early pulmonary neutrophil sequestration. Organ histopathology suggested early neutrophil infiltration in the lung and spleen within 48 h. These studies indicate that MIP-1α and C5 play a critical role in modulating cellular changes associated with lethality in a zymosan model of MODS.

ISSN:1073-2322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Tyrosine phosphorylation pathways are essential components of the process of macrophage activation and the resultant production of inflammatory mediators such as tumor necrosis factor (TNF) and nitric oxide (NO). Several lines of evidence suggest that members of thesrcfamily of protein tyrosine kinases play important roles in macrophage activation by gram-negative bacterial lipopolysaccharide (LPS) or the cytokine interferon-gamma (IFN-α), but targeted disruption of three members of thesrcfamily (hck, fgr, andlyn) in mice failed to demonstrate a requirement for these particular kinases in macrophage activation. We report that the pyrazolopyrimidine PP1, asrcfamily-selective tyrosine kinase inhibitor, potently inhibits the production of TNF and inducible nitric oxide synthase (iNOS) in RAW 264.7 murine macrophages stimulated with LPS, rIFN-α, or LPS + rIFN-α. Furthermore, the tested concentrations of PP1 inhibit LPS- and rIFN-α-mediated tyrosine phosphorylation of thehcktyrosine kinase and its putative substrate,vav, but fail to block rIFN-α-mediated JAK2 tyrosine phosphorylation. These findings provide additional support for a model of macrophage activation involving one or moresrc-related kinases. Selective inhibitors of this signaling pathway should be studied in animal models of sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Sepsis-induced microvascular leukocyte/endothelial cell interaction may result in a deterioration of capillary perfusion that finally leads to septic organ dysfunction. The aim of the present study was to characterize a novel, sublethal, two-hit model of chronic systemic sepsis that allows the repeated analysis of microcirculation by intravital microscopy. In Syrian golden hamsters the effect of a single i.v. endotoxin (LPS, 2 mg/kg,E. coli) injection (SH-LPS group, n = 5 animals) vs. a double LPS injection (DH-LPS group, n = 6 animals) was analyzed. After monitoring baseline parameters (t1), measurements were performed at 30 min (t2), 3 h (t3), 8 h (t4), 24 h (t5), 48 h (t6), 56 h (t7) and 72 h (t8) (both groups) after initial LPS exposure. In DH-LPS animals, a second LPS injection (2 mg/kg) was given at t6(48 h). Intravital fluorescence microscopy was performed in a dorsal skin fold chamber preparation and allowed determination of leukocyte-endothelial cell interaction (leukocyte rolling and sticking), and measurement of functional capillary density (FCD), which served as a measure of capillary perfusion. The first LPS injection comparably altered leukocyte/endothelial cell interaction and capillary perfusion in both groups (t1-t6,P> 0.05, MANOVA). Between t6and t8leukocyte adherence decreased in SH-LPS animals, whereas in DH-LPS animals adherence remained constantly elevated (SH-LPS: −53.0 ± 6.2% between t6and t8vs. DH-LPS: −3 ± 5;P< 0.05). The ongoing inflammatory response in DH-LPS animals was associated with a progressive deterioration of FCD, whereas FCD remained constant in SH-LPS animals (DH-LPS: −71.5 ± 17% between t6and t8vs. SH-LPS: 3.0 ± 13%;P< 0.05). In parallel, coagulatory parameters were found significantly altered only in DH-LPS animals but not in SH-LPS animals. We conclude that “double hit” LPS exposure is an appropriate model (i) to analyze repeatedly over time microcirculatory disorders under conditions of persistent endotoxemia-induced inflammatory response, and (ii) to prove the effectiveness of novel anti-inflammatory strategies.

ISSN:1073-2322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Polymorphonuclear leukocytes (PMN) play a crucial role in the primary immunological defense against infectious agents. PMN activation and function is influenced in a paracrine manner by cyto-kines and bacterial products. While cell-cell communication has been demonstrated between PMN and other cell types, little data is available addressing PMN-PMN communication. Therefore, the aim of this study was to determine whether PMN were able to affect PMN functionin vitroin a cell-contact independent manner, and whether IL-1β influenced this effect. Conditioned medias (CM) were prepared by incubating PMN in HBSS ± IL-1β for 1–4 h. Incubation of fresh PMN in these conditioned medias had little or no effect on the expression of cell surface FcαR expression or oxidative metabolism. However, incubation of PMN in CM-IL1α, but not control CM, increased phagocytotic activity and suppressed apoptosis. Additionally, CM-IL 1α, but not control CM, slowed the changes in Mac-1 and CR1 cell surface expression that occurred in HBSS within 2 h of incubation. Finally, control CM down-regulated the cell surface expression of PSGL-1; an effect that was not observed with CM-IL1α. In conclusion, we demonstrate that PMN are able to communicate with and influence the immunological function of other PMN independent of cell-cell contact, and that this influence is regulated by cytokines such as IL-1β. The major impact of this paracrine regulation is to down-regulate PMN apoptosis with the potential for an upregulated inflammatory response.

ISSN:1073-2322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

In the process of developing a model ofEscherichia coliendotoxin-induced acute lung injury and shock in specific pathogen-free pigs, the effects of pretreatment with metyrapone (a cortisol-synthesis inhibitor) were examined. Metyrapone was administered 1.5 h before start of endotoxin infusion at t = 0 h (MET-ETOX group, n = 6). At the end of the experiments (t = 4 h) a bronchoalveolar lavage (BAL) was performed. Control animals received only endotoxin (CON-ETOX group, n = 6) or metyrapone (MET-CON group, n = 4). The following results are presented as means ± SEM. It was found that metyrapone successfully blocked endogenous cortisol synthesis (plasma cortisol levels were 41.0 ± 5.9 nM in MET-ETOX vs. 339.0 ± 37.7 nM in CON-ETOX at t = 4 h,P< 0.01). At t = 4 h the MET-ETOX animals had substantially increased systemic hypotension compared to the CON-ETOX group (mean arterial pressure 26.7 ± 4.3 vs. 77.7 ± 12.2 mmHg,P< 0.01), decreased dynamic lung compliance (10.9 ± 0.7 vs. 13.7 ± 0.6 mL/cmH2O,P< 0.01), increased percentage of BAL neutrophils (28.4 ± 6.5 vs. 6.6 ± 1.8,P< 0.01), pulmonary edema (BAL total protein 0.82 ± 0.21 vs. 0.42 ± 0.09 mg/mL,P< 0.05), elevated levels of interleukin-8 (1924 ± 275 vs. 324 ± 131 pg/mL,P< 0.01) and acidosis (pH 7.11 ± 0.03 vs. 7.23 ± 0.06,P< 0.05). The MET-ETOX group also showed an increased pulmonary hypertension between 2 and 3 h after start of endotoxin infusion and a trend toward significantly increased levels of plasma interleukin-8 (P= 0.052). Arterial pCO2, pO2/FiO2, plasma endothelin-1, plasma TNFα, and blood leukocytes were not markedly influenced by the plasma cortisol levels. Nitric oxide production did not seem to be altered by endotoxin infusion in this model, in contrast to other animal studies; this discrepancy could be thought to be due to endotoxin-dosage differences or species differences. It is concluded that if endogenous cortisol production is blocked by metyrapone, the reactions occurring as a result of the endotoxin-induced acute lung injury and shock are greatly enhanced and that therefore pretreatment with metyrapone might be an important addition to this model with specific pathogen-free pigs.

ISSN:1073-2322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

We investigated the acute effects of endotoxemia on left ventricular (LV) contractility, relaxation, diastolic properties, and mechanical energetics in closed-chest calves. Twelve male calves (4 to 10 days old) were anesthetized with α-chloralose and instrumented to measure the LV pressure-volume relationship. Calves (n = 6) in the control group remained hemodynamically stable for 4 h. Calves (n = 6) administered endotoxin (0.1 ug/kg, O55:B5, i.v., over 0.5 h) had increased heart rate, mean pulmonary artery pressure, LV contractility (end-systolic elastance), chamber stiffness, and mechanical efficiency, no change in LV relaxation, and decreased mean systemic arterial pressure, cardiac output, and LV stroke work and pressure-volume area. Endotoxin-induced changes were maximal att= 0.5 h, after which time all hemodynamic variables gradually returned towards baseline values. Intravenous administration of isoproterenol (0.02 αg.kg-1.min-1) alone or combined with phenylephrine (5 αg.kg-1.min-1) att= 4 h produced similar increases in heart rate, end-systolic elastance, and cardiac output in control and endotoxin-treated groups. Our findings indicate that circulatory dysfunction, rather than LV dysfunction, predominates during acute endotoxemia (4 h) in chloralose-anesthetized, closed-chest neonatal calves.

ISSN:1073-2322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Zymosan, a non-bacterial agent, causes inflammation by inducing the production of a variety of cytokines and pro-inflammatory mediators, wherein reactive oxygen species including nitric oxide and peroxynitrite are known to play a crucial role in the inflammatory process. The current study was designed to investigate the protective effect of melatonin, a radical scavenger and antioxidant, on non-septic shock induced by zymosan in the rat. Four groups of rats (controls, melatonin-injected [5 mg/kg α 6], zymosaninjected [500 mg/kg], and zymosan + melatonin) were used in this experiment. Thiobarbituric acid reactive substances (malondialdehyde [MDA] + 4-hydroxyalkenals [4-HDA]), as an index of lipid peroxidation, were measured in the liver, lung, small intestine (ileum), kidney and pancreas. Twenty-four hours after zymosan administration, MDA + 4-HDA levels were significantly increased in the liver, lung, small intestine, and kidney while the increase in the pancreas was not statistically significant compared to levels in control rats. The percentage increases in lipid peroxidation products were 34.3%, 39.2%, 48.5%, 32.5%, and 17.4% for the liver, lung, small intestine, kidney, and pancreas, respectively. In animals given melatonin 30 minutes before zymosan, and 5 more times after zymosan (i.e., every 4 hours), the increase in MDA + 4-HDA levels was reduced in all organs studied. There was also a significant increase in the volume of peritoneal exudate in zymosan-treated rats that was reduced when the zymosan-shocked rats received melatonin. After zymosan administration, immunohistochemical and histological examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific “footprint” of peroxynitrite, and tissue damage in the liver, lung, and small intestine of zymosan-shocked rats. Again, melatonin treatment reduced both nitrotyrosine immunoreactivity and tissue damage associated with zymosan administration.

ISSN:1073-2322    

出版商:OVID    

年代:1999

数据来源: OVID

ISSN:1073-2322    

出版商:OVID    

年代:1999

数据来源: OVID