摘要:

Tumor necrosis factor-α (TNF) exerts numerous influences which, in association with severe infection, subserve both detrimental as well as beneficial host responses. The current review addresses recent insights into the structure and function of this pleiotropic cytokine, with a particular emphasis upon cellular and organ system consequences of sepsis-induced TNF activity. A comparison of responses elicited by endotoxin or TNF administration are discussed as are mechanisms of endogenous TNF regulation, such as soluble receptors, anti-inflammatory cytokines, and counter-regulatory responses. A review of past and future clinical strategies for altering TNF activity during sepsis is also provided.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The effects of oligotide, an oligodeoxyribonucleotide analog, were investigated in an experimental model of traumatic shock. Pentobarbital-anesthetized rats subjected to Noble-Collip drum trauma and receiving only the vehicle (i.e., Krebs-Henseleit solution) developed a severe form of traumatic shock characterized by marked hypotension (61 ± 6 mmHg), a survival time of 115 ± 21 min, endothelial dysfunction, significant increases in plasma free amino-nitrogen concentration (ρ < .001) as well as elevated intestinal myeloperoxidase activity. In contrast, oligotide given intravenously (15 mg/kg bolus + 10 mg/kg/h infusion for 5 h) resulted in a significant prolongation of survival time to 209 ± 31 min (ρ < .01), a significant and sustained increase in mean arterial blood pressure, a significant attenuation of plasma free amino-nitrogen concentration (ρ < .01), and intestinal myeloperoxidase activity (ρ < .05). Furthermore, oligotide significantly preserved superior mesenteric artery (SMA) endothelial function as seen by the relaxation response of isolated SMA rings to acetylcholine (71 ± 5% vs. 36 ± 5%, ρ < .01 compared to untreated trauma rats). Moreover, oligotide in a concentration-dependent manner attenuated unstimulated human neutrophil adherence to either thrombin or trauma-activated SMA endotheliumin vitro(ρ < .001). Thus, our data suggest that the mechanism of the protective effect of oligotide in traumatic shock is improving endothelial function and diminishing neutrophil accumulation leading to reduced tissue injury.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Studies indicate that hepatocellular dysfunction occurs at 2 h after cecal ligation and puncture (CLP, i.e., sepsis model) despite the increased cardiac output (CO) and hepatic perfusion. It, however, remains unknown whether hepatocellular function is depressed earlier than the onset of hyperdynamic circulation in sepsis. To determine this, rats were subjected to sepsis by CLP. At .5, 1, 1.5, or 2 h after CLP, CO was measured by dye dilution. Hepatocellular function (i.e., maximum velocity of indocyanine green clearance and the efficiency of the active transport) was determined using anin vivoindocyanine green clearance technique. Microvascular blood flow was measured by laser Doppler flowmetry. To determine whether there is any association between hemodynamics and prostaglandins (PGs), plasma levels of PGE2and PGI2were measured by radioimmunoassay. The results indicate that hepatocellular function decreased significantly as early as 1.5 h after CLP. Cardiac output and microvascular blood flow in the liver and small intestine, however, increased and vascular resistance decreased at 2 h after CLP. Thus, hepatocellular dysfunction occurs earlier than the occurrence of hyperdynamic circulation during sepsis. Although circulating PGE2levels were not altered, plasma PGI2increased significantly at 2 h after CLP. The elevated circulating PGI2levels, therefore, may be partially responsible for the decreased vascular resistance and increased tissue perfusion at 2 h after CLP. Our findings also suggest that cellular dysfunction, observed in the very early stage of sepsis, is not due to any hyperdynamic circulation/hypermetabolism-related events, but may be associated with the release of proinflammatory cytokines.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Tumor necrosis factor (TNF) plays a well known role during the development of multiple organ failure, in part due to its role for the expression of adhesion molecules on endothelial cells, thereby contributing to inflammatory reactions. The purpose of this study was to investigate the effects of TNF on leukocyte-endothelial interactions in the liver as a key organ during the systemic inflammatory response syndrome. In Sprague-Dawley rats (n = 6/group) hemorrhagic shock was induced by reduction of the mean arterial blood pressure (MAP) to 40 mmHg for 45 min; resuscitation was initiated by retransfusion of shed blood (60%) and Ringer's lactate. At 1 and 5 h after resuscitation, intravital microscopy of the liver was performed after injection of acridine orange as marker of leukocytes in sham-control animals and in shock animals pretreated with anti-TNF monoclonal antibody (2 mg/kg b.w. TN3; Celltech, Slough, UK) or NaCl .9% 2 h prior to shock induction, respectively. At constant systemic hemodynamic conditions in all groups (e.g., normal MAP), sinusoidal diameters and sinusoidal blood flow were comparably decreased to approximately 75% of control values in all shock groups. Significant differences were observed particularly in respect to permanent adherent leukocytes with 31.8 ± 4.7% in the shock/NaCl group and 20.7 ± 2.6% (mean ± S.E., ρ < .05) in the shock/TN3 group 5 h after resuscitation following hemorrhagic shock. Consistently higher adhesion rates were observed in the portal regions compared to pericentral regions of the liver lobules. Moreover, elevated TNF plasma levels 5 h after onset of resuscitation in the shock/NaCl group (534 ± 354 pg/mL) were significantly reduced by anti-TNF pretreatment in the shock/TN3 group (47 ± 16 pg/mL, ρ < .05). The results of the study indicate that TNF plays an important role for regulation of intrahepatic leukocyte adhesion after hemorrhagic shock in the rat. Attenuation of TNF-induced leukocyte adhesion in the liver may reduce liver dysfunction or dysregulation after hemorrhagic shock.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Three cyclo-oxygenase inhibitors (ibuprofen, indomethacin, and high dose aspirin) and two inhibitors of thromboxane biosynthesis (imidazole and low dose aspirin) were used to evaluate the role of prostaglandins and thromboxane in the release of calcitonin gene-related peptide (CGRP) during endotoxicosis. Endotoxin (lipopolysaccharide B fromSalmonella Enteritidis, 5 mg/kg, intravenously) was administered to rats lightly anesthetized with ether during injection. After 3 h, endotoxin significantly elevated plasma CGRP levels by 3-fold. Ibuprofen (50 mg/kg, subcutaneously), indomethacin (10 mg/kg, subcutaneously) and high dose aspirin (100 mg/kg, intraperitoneally (i.p.)), but not imidazole (30 mg/kg, i.p.) or low dose aspirin (15 mg/kg, i.p.), significantly blocked endotoxin-induced CGRP elevations, suggesting that a prostaglandin, but not thromboxane, served as a mediator of CGRP release during endotoxicosis. Because endotoxin-induced production of prostaglandins is greatly diminished in endotoxin-tolerant rats (following multiple exposures to low dose endotoxin), we tested whether endotoxin-induced CGRP release also becomes diminished in tolerant rats. Accumulation of plasma CGRP was greatly diminished in endotoxintolerant rats exposed to endotoxin (5 mg/kg, intravenously), consistent with a mediator role for prostaglandins in the CGRP release during endotoxicosis.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Systemic and pulmonary circulation kinetics for51Cr-erythrocytes and111In-leukocytes were measured in rats during experimental hemorrhagic shock and normotension with or without pretreatment with the antirolling agent fucoidin. Leukocyte margination was expressed as transit factors (white blood cell transit time/red blood cell transit time) for polymorphonuclear and mononuclear cells. There was an increased pooling of leukocytes in the pulmonary and systemic vascular beds during shock with a maximum after 60 min when the transit factors had increased 2.90–3.72 times in the pulmonary vascular bed and 2.00–3.52 times in the systemic vascular bed for mononuclear and polymorphonuclear cells, respectively. High preshock pooling levels lead to a more pronounced increase in pooling during shock. Pretreatment with fucoidin significantly reduced the pooling increase in the systemic vascular bed. Granulocyte oxidative activity (nitro blue tetrazolium test) invariably increased during shock and was not affected by fucoidin.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Endothelial cell (EC) injury is observed in clinically important pathological processes, including bacterial endotoxemia. We hypothesized that such pathological processes may exhibit target organ heterogeneity due to organ-specific heterogeneity of endothelial cells. To test this hypothesis, endothelial cells of aorta (AO), pulmonary artery (PA), left ventricle (LV), and right ventricle (RV) were cultured from individual sheep and exposed to bacterial endotoxin. Marked heterogeneity in endotoxin-induced cytotoxicity was observed. AOEC were the most sensitive, followed by PAEC, LVEC, and RVEC. This cytotoxicity was manifested as programmed cell death (apoptosis). All cells were able to express both interleukin-6 and endothelin-1 (ET-1) transcripts. Following exposure to bacterial endotoxin, interleukin-6 transcripts accumulated in all cells, whereas ET-1 expression was constant or slightly decreased. These data suggest that organ-specific heterogeneity of EC responsiveness to endotoxin is a potential determinant of organ-specific resistance to endotoxin and other mediators of injury.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

A quantitative liver test based on the formation of the lidocaine metabolite monoethylglycinexylidide (MEGX), was used to evaluate the effect of hemorrhagic shock at 40 mmHg for 90 min on Sprague-Dawley rats. After 2 h of stabilization, lidocaine was injected (2 mg/kg). A second group received volume resuscitation with Ringer's lactate over 1 h (15 mL/kg) after shock, and after 1 h of stabilization lidocaine was administered. These groups were compared to control animals. Blood samples were drawn at 0 time (baseline), prior to lidocaine injection, and at 10, 15, 30, and 60 min after lidocaine injection. MEGX values in shocked animals were significantly lower than in the control group; in animals receiving volume resuscitation, levels were higher than the shocked animals without resuscitation, but did not reach control levels. Thus, shock produced a significant depression of hepatocyte function, which was partially reversed by Ringer's lactate resuscitation. The MEGX test appears to be a suitable tool for clinical evaluation and therapeutic intervention after shock.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The potential role of reactive oxygen species generated by Kupffer cells and neutrophils was investigated in a model of endotoxin-enhanced liver injury after hepatic ischemia. Male Fischer rats were subjected to 20 min ischemia and reperfusion of up to 24 h; .5 mg/kgSalmonella enteritidisendotoxin was injected at 30 min of reperfusion. The animals developed severe liver injury resulting in 50% hepatocellular necrosis at 24 h. Isolated Kupffer cells and neutrophils from the postischemic liver generated 10-fold more superoxide than cells from control livers. Treatment with gadolinium chloride (GdCl3) selectively reduced the capacity of Kupffer cells to generate superoxide by 65% and attenuated liver injury by 73% at 4 h and 58–69% at 24 h. Monoclonal antibodies against neutrophil adhesion molecules (CD11/CD18) had no effect on the early injury but reduced hepatocellular necrosis by 90–95% at 24 h. The antioxidant Trolox and the iron-chelator deferoxamine attenuated liver injury by 71 and 80%, respectively. It is concluded that Kupffer cells are mainly responsible for the initial injury, and neutrophils are the dominant cytotoxic cell type during the later phase. Reactive oxygen generated by both cell types is critical for this pathogenesis.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID