摘要:

Exposure of cultured human umbilical vein endothelial cells (HUVEC) to lipopolysaccharide (LPS) or interleukin 1 (IL-1) causes increased expression of adhesion molecules such as E-selectin and CD54 by HUVEC and consequently increased adherence of peripheral blood neutrophils. A recombinant amino-terminal fragment of bactericidal/permeability increasing protein (rBPI23) was shown to specifically block the LPS-induced adhesiveness of HUVEC for neutrophils. rBPI23also prevented the LPS-but not IL-1β-induced upregulation on HUVEC of E-selectin and CD54. Furthermore, this inhibition was evident even when the endothelial cells were exposed to LPS for up to 1–2 h prior to rBPI23addition. The inhibitory effects of an anti-CD14 monoclonal antibodies (mAb) were similar to those of rBPI23. Combination of the anti-CD14 mAb and rBPI23resulted inhibition greater than either one used alone. These studies demonstrate that rBPI23acts as a specific and potent inhibitor of soluble CD14-mediated LPS induction.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

This study assessed the hepatic acute phase response and cellular Ca2regulation in septic animals and in hepatoma cell linesin vitro. Sepsis was induced in male Sprague-Dawley rats by implanting in their abdominal cavities fecal pellets impregnated with liveEscherichia coliandBacteroides fragilis. 8 h after implantations, rats were treated with diltiazem (1.2 mg/kg) or superoxide dismutase (SOD) (5 x 103units/kg). After 24 h, plasma acute phase proteins (APP) were determined by immunoelectrophoresis, and hepatic APP-mRNAs by Northern blot hybridization. Effects of diltiazem, verapamil, or SOD on hepatic cells were determined in rat Reuber H-35 and human HepG2 hepatoma cells. Sepsis induced a significant increase in plasma APP and their hepatic mRNAs. Diltiazem and SOD reduced the sepsis-induced elevations in plasma lactate, the febrile response and mortality. APP expression in H-35 and HepG2 cells, stimulated by interleukin 1 (IL-1), IL-6, and dexamethasone, was inhibited by diltiazem or verapamil but not SOD. The results suggest that a heightened hepatic APP response in septic animals accompanies systemic/metabolic derangements and a significant animal mortality. Because diltiazem was previously shown to prevent sepsis-related disturbances in hepatic cellular Ca2regulation, its mediation of decrease in APP, systemic/metabolic response and mortality may be effected through modifications in cellular Ca2regulation. The data from hepatoma cells show an attenuation of the AAP can result from direct effects of a calcium blocker. However, whether the blocker primarily modifies cellular Ca2regulation and secondarily effects APP gene expression, or directly effects gene expression remains unknown.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

This study addressed the effect of catecholamine stimulation on substrate utilization for glu-coneogenesis, ureagenesis, and oxidation in perfused livers from septic rats. Livers were perfused with buffer containing 5 mM [14C]lactate and various concentrations of unlabeled alanine or pyruvate. Addition of alanine to lactate resulted in inhibition of gluconeogenesis and especially inhibition of gluconeogenesis from lactate. This effect was dependent upon the presence of the amino nitrogen, since the effect of pyruvate was to increase total gluconeogenesis with little effect on gluconeogenesis specifically from lactate except with phenylephrine stimulation of livers from sham-operated animals in which addition of pyruvate actually increased the rate of gluconeogenesis from lactate. Alanine itself was very poorly utilized as a gluconeogenic substrate. In contrast, the addition of alanine stimulated total oxygen consumption in both groups in the absence or presence of phenylephrine. This was the result of oxidation of added alanine in livers from sham animals, either with or without phenylephrine, and in septic animals without phenylephrine. However, in the presence of phenylephrine, the increase in total oxygen consumption was almost entirely the result of lactate oxidation. Pyruvate, on the other hand, uniformly stimulated oxygen consumption in both groups, with and without phenylephrine. Urea production was increased by alanine to a greater extent in the septic group compared to sham. However, while phenylephrine stimulated ureagenesis in the sham-operated group, it inhibited ureagenesis in the septic group. These results demonstrate that fundamental differences develop in livers from septic animals in their handling of nitrogenous and non-nitrogenous gluconeogenic substrates. These effects appear to be dependent upon the presence of the amino nitrogen group and are highly dependent upon the hormonal milieu.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We determined the oxidant activity in lung airways, parenchyma, and systemic tissues in response to smoke inhalation, comparing lipid peroxidation with physiologic and histologic change. Adult sheep were given a controlled amount of cooled smoke from burned cotton toweling, containing a uniform particle diameter of 3–4 μm. The mean peak carboxyhemoglobin was 45 ± 4%. Animals were monitored unanes-thetized for 24 h and killed. Severe respiratory failure was noted, as a result of airways mucosal ulceration, submucosal edema, and atelectasis, along with increased airways fluid, but minimal alveolar edema. Airway fluid malondialdehyde (MDA) content was threefold greater than plasma. However, airways mucosa and lung parenchymal tissue, lipid peroxidation, and oxidized glutathione were not increased, suggesting the only direct oxidant activity was present only at the airways surface. Other factors besides oxidants are likely to be involved in the lung injury. However, a marked systemic oxidant stress was noted as evidenced by a significant increase in liver tissue MDA and decrease in reduced glutathione and catalase activity. The tissue oxidant stress also corresponded with a 75% increase in systemic oxygen consumption and an increase in soft tissue vascular permeability. We conclude that: 1) the only direct lung oxidant stress after smoke was noted in airways fluid, while lung tissue lipid peroxidation was not seen despite severe airways injury and atelectasis, and 2) major systemic physiologic changes, as evidenced by increased systemic oxygen demands and systemic micro-vascular permeability are seen with smoke exposure in addition to evidence of systemic tissue oxidant stress. The likely source of the oxidant activity was a smoke-induced systemic inflammation.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Renovascular hypertension alters endothelial-dependent mechanisms to affect the response of small arterioles in skeletal muscle to sepsis. Small arteriole responses to sepsis differ between skeletal muscle and small intestine in normotensives. Our study now shows that renovascular (1K1C) hypertension alters small arteriole responses in the small intestine to Escherichia coli sepsis. Large arterioles (A1, A2) constricted by 10–20% in the small intestine of both normotensive and hypertensive rats during both high and low cardiac output sepsis. Small arterioles (premucosal A3and preserosal A4) constricted during high cardiac output sepsis in normotensive but not hypertensive rats. Small A3and A4arterioles dilated (20–40%) during low cardiac output sepsis in hypertensives; but only A3and not A4arterioles dilated in normotensives during low cardiac output sepsis. Acetylcholine, which releases endothelial-derived relaxing factor in skeletal muscle, dilated both premucosal A3and preserosal A4in both normotensive and hypertensive rats. Thus, hypertension alters small arteriole responses to sepsis in both skeletal muscle and small intestine, but apparently by different mechanisms.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We have previously shown a direct relationship (r= .97) between the fall in arterial blood pressure and the increase in skeletal muscle oxygen extraction (MVO2) during canine endotoxemia. Since it is well known that hypotension activates the sympathetic system, the primary aim of these experiments was to determine if the increase in MVO2during endotoxemia is a result of elevated levels of catecholamines due to increased sympathetic neural and/or humoral activity (sympathoadrenal system). Canine gracilis muscles were vascularly isolated and perfusedin situat a constant flow (6–7 ml/min/100 g). Endotoxemia was induced by a 30 min intravenous infusion ofEscherichia coliendotoxin (2 mg/kg), which induced a 50% reduction in arterial pressure. Perfusion pressure, mean arterial pressure, and arteriovenous oxygen difference (a-v O2) were continuously measured. We found 1) no significant difference between the amount of O2extracted by an innervated or a denervated muscle during endotoxemia; 2) the intra-arterial infusion of norepinephrine or epinephrine into a denervated gracilis muscle (plasma molar concentrations of; 10-11, 10-9, 10-7, and 10-5) failed to increase MVO2to the level observed during endotoxemia; 3) pretreatment of a muscle with pro-pranolol to block skeletal muscle β-adrenergic receptors, did not suppress the endotoxin-induced rise in MVO2. We concluded that the increase in MVO2seen after the administration of endotoxin is not due to either increased sympathetic nerve activity or elevated levels of circulating catecholamines. We speculate that the increased MVO2during endotoxemia is caused by nonadrenergic mediators released by endotoxin rather than the hypotensive stimulus.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We have developed anin vitrorat hepatocyte model in which cytokines inhibit fatty acid oxidation. Cytokine administration resulted in decreased fatty acid oxidation, ketone body production and acetyl CoA/CoA ratios. The inhibitory effects of TNF on fatty acid oxidation were enhanced by either IL-1 or IL-6 TNF (20 U/ml) + IL-6 (30 ng/ml) produced maximal inhibition, whereas IL-1 enhanced inhibition at submaximal TNF concentrations. The key to our model is that substrate input into the tricarboxylic acid cycle in the form of either alanine or pyruvate was required for cytokine mediated inhibition of fatty acid oxidation. Alanine or pyruvate may serve as a source for increased production of malonyl CoA, a potent inhibitor of fatty acid oxidation. We hypothesize that cytokines cause an inappropriate switch from fatty acid oxidation to fatty acid synthesis which has serious consequences for energy levels in the liver and can lead to end organ failure.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Intact peritoneal macrophage (Mø) function is critical to successful localization of intra-abdominal infection. Peritoneal macrophage antigen presentation capacity (APC), interleukin-1 (IL-1) expression, and immune-associated (la) antigen expression and abscess formation were determined following cecal ligation and puncture. APC and IL-1 expression were measured by coculture with a T-helper cell clone and by measuring subsequent proliferation, la expression was determined in blood, peritoneal Mø, and splenocytes using anti-la monoclonal antibody stain and flow cytometric analysis. Significant reductions in both la expression and APC were found 1 and 4 days after CLP with no change in IL-1 expression. Muramyl dipeptide, which enhances Mø phagocytosis, partially abrogated the depression in antigen presentation but did not affect la expression. Peritoneal Mø la expression and APC, but not IL-1 expression, were depressed after experimental peritonitis. The recovery of Mø function by day 14 coincides with clinical recovery and abscess formation, and restoration of early Mø depression may improve outcome.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The unique arrangement of large numbers of fixed tissue macrophages, endothelial, and pa-renchymal cells along hepatic sinusoids as well as their key role in the acute phase response makes the liver a primary target organ in endotoxemia. Pathogenesis of hepatic failure in endotoxemia is incompletely understood, but microcirculatory failure as well as leukocyte-endothelial interaction in response to inflammatory mediators may relate to it. Using intravital fluorescence microscopy, sinusoidal widths, leukocyte flow velocity, and sublobular leukocyte (white blood cell (WBC)) adhesion characteristics 1 h after randomized intravenous application of 0, 0.1 1, or 5 mg/kg b.w. Escherichia coli endotoxin O 111 B4 (ETX) were evaluated in female Sprague-Dawley rats (n = 6–8/group). Whereas the bolus injection of ETX caused only minor concurrent macrohemodynamic effects, a significant increase of permanent WBC adhesion especially in periportal areas (0 mg, 2.1 ± 0.7%; 0.1mg, 16.2–3.6%**; 1 mg, 15.5 ± 1.0%**; 5 mg, 13.2 ± 2.3%* (**p< .01, *p< .05, compared to vehicle)) was found in all groups 60 min after ETX challenge. In contrast, an increase of WBC margination in midzonal and pericentral regions was only seen with the higher doses of 1 or 5 mg/kg ETX, respectively. The sublobular pattern of WBC margination is consistent with the concept of regulation of WBC adhesion by inflammatory mediators released by lipopolysaccharide-stimulated Kupffer cellsin vivo. We propose that overwhelming the detoxifying capacity of predominantly periportally located Kupffer cells with large amounts of ETX may lead to activation of pericentral-located resting macrophages paralleled by a rise of adhering leukocytes.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

There is increasing evidence of an association between intestinal injury and the development of a septic state and distant organ failure. Since this phenomenon can occur in the absence of detectable systemic bacterial translocation (BT), we tested the hypothesis that shock-induced intestinal injury will result in the gut becoming a cytokine-generating organ by measuring interleukin 6 (IL-6) and tumor necrosis factor (TNF) levels in the portal blood, cardiac blood, and intestinal lymph of rats subjected to sham, 30, 60, or 90 min of hemorrhagic shock (30 mm Hg). These blood and lymph samples, as well as the mesenteric lymph nodes (MLN), spleens, and livers, were cultured for translocating bacteria. Although all the portal and cardiac blood samples were sterile, the portal blood levels of TNF and IL-6 were increased to a greater extent than simultaneously obtained cardiac blood samples in rats subjected to 60 or 90 min of shock (p < .05). The lymph IL-6 levels increased but were similar between the groups. BT was limited to the MLN and occurred in a dose-dependent fashion with 38, 63, and 100% of the animals having culture-positive MLNs after 30, 60, or 90 min of shock, respectively. In conclusion, after hemorrhagic shock, the gut appears to become a cytokine liberating organ even in the absence of detectable bacteria in the portal circulation.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID