摘要:

Interleukin-1 (IL-1) is one of several proinflammatory cytokines produced during infection, sepsis, and the systemic inflammatory response syndrome (SIRS) that serves to initiate the host inflammatory response and to integrate nonspecific immunity. Many of IL-1's biologic effects are beneficial to the host in times of stress, but when produced for extended periods of time or in excessive quantities, IL-1 contributes to morbidity and mortality. In fact, excessive IL-1 production has been directly linked to the development of hypotension, shock, multi-organ system failure, hematologic dyscrasia, and death in patients and animals with sepsis, SIRS, and septic shock. Recent research interest has focused on IL-1 inhibition to improve outcome in sepsis and septic shock. This article will review the role for IL-1 in sepsis and septic shock, and the function and status of the IL-1 receptors and IL-1 receptor antagonist in modulating IL-1 actions. The results of investigations of IL-1 inhibition in animal models and in human subjects with sepsis and septic shock will also be reviewed.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

In trauma or sepsis, monocytes and macrophages release mediators such as tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), and prostaglandin E2(PGE2). Although patients may be exposed to more than one stimulus, the effect of repetitive endotoxin (LPS) stimulation on human monocytes is poorly characterized. Human peripheral blood monocytes obtained from healthy volunteers were pretreated with endotoxin (LPS1) for 24 h. Cultures were then restimulated for 24 h with a second, activating LPS stimulus (LPS2) at various concentrations and supernatant mediators (TNF, IL-1, IL-6, and PGE2) measured. Serum cytokine levels of normal monocyte donors were compared to basal and LPS-stimulated cytokine release of their monocytesin vitro.LPS2increased all mediators in a dose-dependent manner in the absence of LPS1pretreatment. LPS1significantly increased LPS2-triggered monocyte secretion of IL-1, IL-6, and PGE2, but inhibited TNF release. Cell-associated TNF and IL-1 were also inhibited and enhanced in parallel with supernatant levels of the respective cytokines. Serum cytokine levels were low, showed wide variation, and correlated poorly within vitroLPS-triggered cytokine production. Human monocyte mediator production is differentially regulated by endotoxin pretreatment. Provocativein vitrotesting of monocytes could identify prior LPS exposure and may be more useful than serum cytokine measurements.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Thymic programmed cell death (PCD) or apoptosis (Ao) is elevated during inflammation by a variety of stressorsin vitro(i.e., glucocorticoids, tumor necrosis factor (TNF), prostanoids, etc.), however, little or no information is available concerning its presence in polymicrobial sepsis. To establish whether or not PCD is accelerated in the thymus following the onset of sepsis, thymocytes were harvested from C3H/HeN mice at 1, 4, 12, and 24 h following cecal ligation and puncture (CLP; to induce sepsis) or Sham-CLP (Sham), and assessed for changes in thymocyte viable cell yield, increased Ao+ cells based on FACS analysis (propidium iodide staining) or by evidence of fragmentation of the genomic DNA. The results indicate that at 1 h post-CLP there were no marked changes in any of these parameters. However, by 4 h post-CLP the percentage of Ao+ thymocytes increased and the septic mouse genomic DNA exhibited trace amounts of fragmentation. These changes increased in the septic animals cells through both 12 and 24 h. Alternatively, thymic viable cell yield did not significantly decrease until 12 h. Marked changes in systemic mediators, corticosterone and TNF, were also detected in septic mouse blood at all time points. In an effort to determine the contribution of these two agents to the induction of the accelerated PCD seen here, mice were randomized to receive either RU-38486 (11β-[ρ-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one (Mifepristone); a steroid receptor blocker), polyethylene glycol (PEG)-(rsTNF-R1)2(a TNF inhibitor) immediately following CLP. The decline in viable thymocyte cell yield induced by sepsis (CLP) was not seen with RU-38486, but was present in PEG-(rsTNF-R1)2-treated mice. Furthermore, RU-38486, unlike PEG-(rsTNF-R1)2, treatment markedly decreased the percentage of cells which were Ao+ as well as the extent of DNA fragmentation. Thus, sepsis-induced PCD in the thymus is not a response to TNF but appears to be controlledin vivoby corticosteriods released after the onset of sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Inflammatory cytokines and acute-phase proteins are closely interrelated, and their levels of production by various cells are increased by thermal injury. It was hypothesized that burn-mediated increases in the production of TNF and IL-6 by Kupffer cells and the production of acute phase proteins by hepatocytes are paralleled by increases in the corresponding message RNA levels in these cells. The mRNA expression of the cytokines, IL-6 and TNFα, and acute phase proteins, α-1 acid glycoprotein (α-1 AGP), and albumin in liver tissue were determined in rats 24 h after thermal injury. Also IL-6 and TNFα fromin vitrocultured Kupffer cells, and α-1 AGP and albumin fromin vitrocultured hepatocytes, and the serum levels of these proteins, were determined. An increased expression of IL-6 mRNA in liver tissue from animals of the burned group was accompanied by an elevation of IL-6 released from cultured Kupffer cells and by increased serum levels of this cytokine. Thermal injury caused a decrease in TNF mRNA but no change in the production of this cytokine by Kupffer cells, and TNF could not be found in the serum. Also, an increase in α-1 AGP mRNA expression following thermal injury was consistent with the increase of α-1 AGP production by hepatocytes and with the elevated serum level of this acute phase protein. Thermal injury caused no change in albumin mRNA expression or in thein vitroproduction of this negative acute phase protein, however, the serum level of albumin increased. The results suggest that thermal injury may cause alterations in the cytokine and acute phase protein mRNA levels in liver, which may cause alterations in the cellular production and serum levels of the corresponding proteins. An increase in IL-6 production, mediated by thermal injury, may be beneficial to the immune response but may lead to an overwhelming inflammatory response.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Small-volume resuscitation with 7.2% NaCl/10% dextran 60 (HHS) restores cardiovascular stability faster than all other therapeutic modalities currently known. This study was undertaken to elucidate the effects of HHS on the brain, specifically on the formation of posttraumatic brain edema. HHS was administered to anesthetized albino rabbits with or without a focal cryogenic brain lesion and hemorrhagic shock. Specific gravity of small tissue samples was determined 4 h after injury and values were topographically assembled to form a color-coded map of both hemispheres, allowing for a high resolution mapping of brain edema. Cerebral blood flow on the side of the lesion, as assessed by the H2clearance method, increased transiently after injury but remained unchanged from baseline during shock and after infusion of HHS, indicating intact cerebrovascular autoregulation. The cryogenic lesion without subsequent HHS infusion resulted in significant brain edema formation in grey and white matter of the exposed hemisphere. In injured animals resuscitation with HHS led to a global reduction of brain water content in both hemispheres. We conclude that small-volume resuscitation with HHS does not worsen posttraumatic brain edema. To the contrary, our results show that it decreases cerebral water content even in regions close to the injury. This makes it worthwhile to investigate the benefits of HHS for the treatment of intracranial hypertension.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Because the activation state of macrophages may alter their response to endotoxin, we compared phospholipid arachidonic acid content, and synthesis of eicosanoids and tumor necrosis factor by resident and thioglycollate-elicited rat peritoneal macrophages. Thioglycollate elicitation increased macrophage phospholipid mass twofold, increased the relative percentages of 16:0–20:4 diacylglycero-phosphocholine (PtCho) and 18:0–20:4 diacylglycerophosphoethanolamine (PlsEtn), and decreased the relative percentages of 18:0–20:4 alkenylacylglycerophosphoethanolamine (PlsEtn) and 18:0–20:4 alkyl-acylglycerophosphocholine (PakCho) compared with resident peritoneal macrophages. Thioglycollateelicited macrophages synthesized significantly less thromboxane B2, 6-keto-prostaglandin F1α, and prostaglandin E2and more tumor necrosis factor (TNF) activity in response to both endotoxin and A23187 than did resident macrophages. These results suggest that thioglycollate elicitation decreases specific arachidonic acid-containing molecular species in PlsEtn and PakCho, which may, in part, explain the decrease in eicosanoid and increase in TNF synthesis by thioglycollate-elicited macrophages. The differences between resident and thioglycollate-elicited macrophages in the synthesis of the eicosanoids and TNF activity was not altered by increasing either the concentration of either stimulus or the incubation time.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Nitric oxide (NO) may influence the hemodynamic response to hemorrhage. To test this hypothesis, the NO synthesis inhibitorNω-nitro-L-arginine methyl ester (L-NAME) was administered to conscious, dehydrated swine during a 37% blood volume hemorrhage and a 180 min recovery period without fluid resuscitation. L-NAME (.75 mg/kg bolus plus constant infusion of .75 mg/kg/h) was given via a central intravenous catheter during the bleed. The selectivity and specificity of L-NAME as a NO synthesis inhibitor in pigs was validated in pilot studies. The present study shows that inhibition of NO synthesis with L-NAME had no significant effect on the major hemodynamic parameters during and after hemorrhage when compared to dehydrated and euhydrated control groups. Only stroke volume and A-Vo2were significantly different from controls. Mortality was 83% for the L-NAME group and 44% for controls at 180 min of recovery (NS). The results suggest that NO synthesis inhibition provides no hemodynamic benefit during hemorrhage in dehydrated, conscious swine.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The cardiovascular response to endotoxemia was evaluated in an awake, intravascular volume-resuscitated canine model. The animals were chronically instrumented for ultrasonic crystal dimension analysis and pressure measurements of the left ventricle (LV), aorta, right atrium (RA), and pulmonary artery (PA) and for cardiac output (CO) measurement. Lipopolysaccharide (Escherichia coli011:B4) (LPS) was administered intravenously either as an acute, high dose bolus (5 mg/kg; n = 5), a high dose bolus after complete β-blockade with propranolol (n = 3), or a chronic, low dose infusion (5 μg/kg/h; n = 7). Relative to baseline values, cardiac contractility was increased after acute high dose LPS bolus, however this effect was negated by β-blockade. Chronic, low dose LPS infusion produced an increase in cardiac contractility at 1 h, a return to baseline by 4 h, and maximal contractile depression by 24 h. No change was seen in LV compliance after the high dose LPS bolus. The LV end diastolic volume was decreased by the high dose LPS bolus. This change was blocked by propranolol administration. Chronic LPS administration was accompanied by a decrease in LV compliance and an increase in LV end diastolic volume. Other cardiovascular indices (heart rate, CO, systemic vascular resistance) changed in a fashion similar to human sepsis. These findings confirm that endotoxemia in conscious canine subjects causes changes in cardiovascular function similar to that seen in human and animal models of sepsis. This study also allows us to explain some of the discrepancies between earlier studies of human sepsis and animal models in which the appropriate clinical conditions and an intact neuro-endocrine axis were not maintained.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Prostaglandins of the E series (PGE1, PGE2) have well-described immunosuppressive (anti-inflammatory) as well as vasodilator (pro-inflammatory) actions. The net effect on an acute inflammatory response would depend on the dose, timing, and site of action. Egg phosphatidyl liposomes are novel drug delivery vehicles that can alter thein vivodisposition of PGE1. The purpose of this study was to explore the therapeutic potential of PGE1, with or without liposome encapsulation, on the systemic inflammatory response evoked by endotoxin following trauma. Anesthetized pigs received a soft tissue injury + hemorrhage, and fluid resuscitation after 1 h. In one series, whole blood was incubated with PGE1(0, 40, or 200 μg/mL) andEscherichia coliendotoxin (LPS; 0, 1, 5, or 10 μg/mL)in vitroand neutrophil CD18 adherence receptor density was measured with immunomonitoring. In another series, LPS (5 μg/kg) was administered 3 days following trauma to animals pretreated with either phosphate-buffered saline (PBS) + PGE1, (62 ng/kg/min x 40 min, 2.5 μg/kg total, n = 8), PBS (n = 12), liposomes alone (Lipo, n = 10) or liposome-encapsulated PGE1(Lipo + PGE, n = 7). This PGE1dose had minimal effects on blood pressure in baseline conditions. Hemodynamics, cell differential counts, plasma cortisol, and plasma tumor necrosis factor (TNF) were measured for 3 h post-LPS. LPSin vitrocaused a dose-related increase in neutrophil CD18 expression that was not altered by < 200 μg/mL PGE1before or after trauma. LPSin vivoincreased pulmonary vascular resistance and heart rate and both were blunted by PGE1: .73 ± .14 vs. .40 ± .06 mmHg/mL/min/kg, PBS vs. PBS + PGE1, ρ = .0167 and 128 ± 7 vs. 93 ± 9 beats/min, PBS vs. PBS+PGE1, ρ = .0020, respectively. In addition, stroke index (and therefore cardiac efficiency) was improved with PGE1+ PBS vs. PBS (ρ = .0024). These cardiovascular effects were eliminated when PGE1was liposome encapsulated. Plasma TNF was increased to 300–600 pg/mL following LPS and there was no effect of PGE1or liposomes, but the LPS increased plasma cortisol to 7.8 ± .8 vs. 4.0 ± 1.0 μg/100 mL for PBS vs. PBS + PGE1(ρ = .0732) and 8.5 ± 2.1 vs. 2.9 ± 1.1 μg/100 mL for Lipo vs. Lipo + PGE1(ρ = .0131). Conclusions are as follows: 1) PGE1reduced the LPS-evoked cortisol increase and improved cardiac function, but had no detectable effect on the evoked TNF spike or neutropenia; 2) Liposome encapsulation eliminated the cardiac, but not the cortisol-lowering, effect; 3) the relative lack of PGE1on LPS-evoked acute inflammation could reflect a desensitization to its immunosuppressive actions. Alternatively, the results are consistent with the interpretation that PGE1is not a primary regulator for acute inflammation, but is rather one of a myriad of pro- and anti-inflammatory factors that balance the process.

ISSN:1073-2322    

出版商:OVID    

年代:1995

数据来源: OVID