摘要:

The immune response to trauma, shock, and/or sepsis appears to exhibit a bimodal response, in which there is an early exaggerated inflammatory response, giving way over time to a state of hyporesponsiveness or immune dysfunction. This state of immune dysfunction is frequently associated with increased infectious complications and/or mortality, seen following shock or trauma. In this article, we present an overview of some of those changes that have been seen with respect to the process of major histocompatibility class II (MHC class II) antigen presentation by macrophage, a key component of the overall host immune response to foreign bacterial and/or fungal pathogens encountered following shock/ trauma (with a particular emphasis on hemorrhagic shock as a component of traumatic shock). With respect to the overall process of antigen presentation, defects (dysfunction) are evident not only in models of shock and sepsis, but also in traumatized patients. Studies of the capacity of a monocyte's/macrophage's ability to present antigen indicate that defects can be detected, not only in those steps involved in antigenic processing, but also in MHC class II molecule expression and accessory molecule function (or its inhibition) following shock. Those changes in the macrophage's capacity to process antigen seen during the first 24 h after hemorrhagic shock appear to be associated with the cell's metabolic response to regional hypoxia and/or the shift to proinflammatory mediator release (tumor necrosis factor, interleukin [IL]-1, IL-6, etc.). This initial acute response to shock appears to act as the nidus for chronic anti-inflammatory mediator release (prostaglandin E2, transforming growth factor-β, IL-10, IL-4, nitric oxide, etc.), which may mediate the sustained depression of the antigen-presenting cell's function.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

A phase I pharmacokinetic and safety clinical trial of rBPI23, a recombinant amino terminal fragment of bactericidal/permeability-increasing protein, was conducted in healthy male volunteers. rBPI23was administered as a 5 or 30 min infusion at doses of .1 to 1 mg/kg. The pharmacokinetics of rBPI23in human subjects were described by a bi-exponential disposition function with evidence of concentration-dependent kinetics. The α half-life increased significantly with increasing dose, from 4–5 min at .1 mg/kg to 7–8 min at 1 mg/kg. The β half-life varied between 18 and 29 min regardless of dose and the clearance varied from 5 to 10 mL/min/kg. Very little, if any, of the administered rBPI23was excreted intact in the urine. Electrocardiograms, ionized calcium concentration, prothrombin and partial prothrombin times, hematologic parameters, and blood chemistries remained normal. Furthermore, no antibody response to rBPI23was observed in any of the subjects.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We investigated the effect of alterations in buffer oxygen tensions from normoxia (Po2= 180–200 mmHg) to hypoxia (Po2< 30 mmHg) and then reoxygenation (Po2> 140 mmHg) on the GPLD-pathway by measuring phosphatidylethanol formation in the presence of ethanol and subsequent NADPH oxidase activation and O-2production in polymorphonuclear leukocytes (PMN). Experiments were performed with PMN stimulated with either interleukin (IL)-8, tumor necrosis factor (TNF)-α, or IL-1β in the presence or absence of fibronectin. Hypoxia exerted a downregulating effect on this pathway and reoxygenation restored GPLDactivation to levels seen during normoxia; however, supraphysiological concentrations of cytokines were able to reverse this pattern. Changes in GPLDactivation correlated best with changes in O-2production during the hypoxia to hypoxia/reoxygenation transition induced by TNF-α-Fn and IL-1β ± Fn. Thus, changes in oxygen tension can directly modulate the extent of the PMN response to stimulation by IL-8, TNF-α, or IL-1β, and activation of the GPLD-pathway appears to be highly sensitive to hypoxia and hypoxia/reoxygenation.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We evaluated the effects of hemorrhagic shock/resuscitation (S/R) on hepatic reticuloendothelial system function, using an in vivo assay that discriminantly quantitates its two essential components, phagocytic clearance and phagocytic killing of double-labeled Escherichia coli injected intravenously. Rats were subjected to hemorrhagic shock at mean arterial pressure at 50 ± 5 torr for 2 h, resuscitated, and survived. Hepatic phagocytic clearance was significantly decreased immediately following and 6 h after S/R, compared with sham-shocked rats, but recovered to normal levels after 24 h. Although hepatic killing efficiency was increased initially, and transiently depressed 6 h later, it was strikingly upregulated after 24 h. As a consequence, net hepatic killing was transiently suppressed at 0 and 6 h, but upregulated after 24 h. Pre-treatment with proinflammatory agonists, including endotoxin, IFN-γ, or IFN-γ + TNF-α enhanced both hepatic killing efficiency and net hepatic killing. These observations suggest that although hepatic killing function is initially impaired after the onset of S/R, it is strikingly upregulated 24 h later, simulating both the initial immunosuppression, and the later hyperinflammatory response to systemic S/R that could lead to multiple organ dysfunction syndrome.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The liver is unique for its large resident macrophage (HMΦ) population as a potential source of immunoregulatory cytokines. The present study was designed to determine HMΦ function in a rat model of cholestasis (CBDL). Northern blot analysis of TNF-α mRNA showed a profound difference in the dose response to bacterial lipopolysaccharide (LPS) between sham and CBDL HMΦ. Sham HMΦ demonstrated an 8-fold difference in induction of TNF-α mRNA versus CBDL HMΦ. TNF-α secretion, determined by enzyme-linked immunosorbent assay, was significantly higher from LPS-activated sham HMΦ versus the same cells activated with Gram-positive bacterial peptidoglycan while CBDL HMΦ were more responsive to peptidoglycan than to LPS. These results demonstrate stimulus- and response-specific functional alterations in the HMΦ population during acute cholestatic injury. We speculate that these functional alterations are phenotypically induced in acute liver injury resulting in responses that are not characteristic of normal HMΦ.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We evaluated the effects on survival of three different strategies for blocking the actions of nitric oxide (NO) during Gram-negative sepsis in rats. Male Sprague-Dawley rats underwent placement of a jugular vein catheter and i.p. implantation of a gelatin capsule containing a paste (.11 ± .01 g final weight) consisting of sterile rat feces mixed with a suspension (.2 mL) of viable Escherichia coli (strain sm18; 5.7 ± 105colony-forming units) in saline. Beginning at T = 6 h, all animals received i.v. ampicillin (85 mg/kg every 12 h) until death or the administration of five doses. At the same time points, pairs of animals received an i.v. dose of either an experimental treatment agent or an appropriate control substance. The following experimental regimens were tested: 5 mg/kg per dose of S-methylisothiourea sulfate (SMT), a selective inhibitor of the inducible isoform of nitric oxide synthase (NOS); 10 mg/kg per dose or 25 mg/kg per dose of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of the inducible and constitutive isoforms of NOS; 200 mg/kg per dose of cross-linked human hemoglobin (HGB), an NO scavenger. SMT significantly prolonged survival in septic rats, although cumulative survival at T = 168 h was approximately equivalent in SMT- or saline-treated animals. In contrast, HGB and the higher dose of L-NAME significantly shortened survival times. At T = 20 h, arterial Po2was significantly lower in rats treated with HGB as compared to time-matched controls. We conclude that SMT, a compound with reported activity as a selective inhibitor of the inducible isoform of NOS, prolongs survival in a rat model of antibiotic-treated Gram-negative sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The aim of the present study was to test the hypothesis that pulmonary microvascular reactivity is depressed in sepsis and that inducible nitric oxide synthase (iNOS) contributes to the vascular hyporeactivity. Rats were made septic by cecal ligation and puncture. After 16 h, pulmonary vascular reactivity was evaluated by measurement of perfusion pressures while the vasculature was challenged with angiotensin II and KCI. The results showed that vascular reactivity was significantly depressed in lungs from septic rats in comparison to sham-operated controls. Pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 100 μM) restored the depressed vasoreactivity while the nitric oxide (NO) synthase substrate L-arginine (1 mM) reversed the contraction-restoring effect of L-NAME. NO production in lungs from septic rats increased about 4-fold in comparison to sham-operated controls. iNOS protein was expressed in lung tissues, mainly the resistance vessels, from septic rats but not from sham-operated controls. Reverse transcription and polymerase chain reaction also showed a strong induction of iNOS mRNA in lung tissues from septic rats. These results suggest that increased iNOS expression and NO production may contribute to depressed pulmonary vascular reactivity in sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Hypertonic saline with or without colloidal solution has been successfully used for treating hemorrhagic shock in animal experiments and clinical studies. Due to its various effects at systemic, organ, and microcirculatory levels, the substance appears to be a promising candidate for improving tissue oxygenation in sepsis. We therefore investigated the hypothesis that infusion of hypertonic saline would further improve O2delivery, O2extraction, and O2uptake in hyperdynamic septic shock patients already stabilized by adequate volume and catecholamine infusion. Twenty-one patients received 2–4 mL/kg body weight of hypertonic saline in hydroxyethyl starch within 15 min. This hypertonic saline infusion caused a rapid significant increase in O2delivery by 14% but only a marginal increase in O2consumption (7% by cardiovascular Fick [p < .05], 4% by respiratory gases [n.s.]). Hypertonic saline increased the already elevated cardiac output by 24%. The pulmonary capillary wedge pressure increased from 14 ± 3 to 23 ± 3 mmHg and pulmonary shunt fraction increased 15%, but arterial PO2did not fall. Except for the increase in pulmonary capillary wedge pressure, none of the cardiovascular changes lasted longer than 60 min. Plasma sodium levels increased from 138 ± 25 to 163 ± 38 mmol/L and normalized within 24 h. In these hyperdynamic septic patients, hypertonic saline infusion produced a transient increase in circulation, but no evidence of a substantial increase in O2consumption. Either there was no significant O2debt due to the already elevated O2delivery levels at baseline (700 mL/min/m2) or the global O2measurements we used were not able to detect discrete regional hypoxia.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

During endotoxin shock mean arterial pressure (MAP) and cardiac output (CO) fall, and the latter is redistributed. To evaluate whether these changes are solely caused by the low output, or are also based on endotoxin itself, we compared regional hemodynamic changes during endotoxemia with those in a nonendotoxemic state of decreased CO in anesthetized rats. In group E (n = 10) endotoxin Escherichia coli O127:B8 (8 mg-kg-1) was infused from t = 0 till t = 60 min. In group B (n = 10) the same decrease of CO and MAP was obtained as in group E by inflating a balloon in the inferior caval vein, distal to the renal veins, from t = 0 till t = 60 min. We measured MAP, CO (thermodilution), central venous pressure, heart rate, organ blood flow, and redistribution of CO (microspheres), arterial lactate and glucose, and hematocrit. MAP and CO decreased (p < .05) in both groups (by 30 and 50%, respectively at t = 60). Heart rate, hematocrit, arterial lactate, and arterial glucose were significantly higher (p < .05) in group E (by 17,12,180, and 55%, respectively). Blood flow to most organs had similarly decreased in both groups. The decreased intestinal blood flow lead to macroscopic damage only in group E. Blood flows (absolute or as percentage of CO) to heart, hepatic artery, and diaphragm, however, had significantly increased in group E while blood flows to skin, skeletal muscle, and stomach had decreased more in group E. Except for the heart these differences could be explained by increased work load (detoxification: liver; hyperventilation: diaphragm, muscle) and thus to a more pronounced redistribution at the expense of skin and muscle blood flow. Regional hemodynamic changes during endotoxemia thus could largely be attributed to decrease of CO and redistribution of the circulating blood volume. In the heart, endotoxin seemed to exert effects independent of the hypodynamic state. This was also true for the intestinal damage and the rise in hematocrit and arterial lactate.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We tested the hypothesis that diaspirin cross-linked hemoglobin (DCLHb; Baxter Healthcare Corp.) would improve blood pressure, organ perfusion, and mortality during sepsis. Rats were catheterized to assess general hemodynamics (protocol 1) or regional blood flow (protocol 2). Sepsis was induced by intraperitoneal introduction of a cecal slurry (100 mg/kg). In protocol 1, rats received either 100 or 250 mg/kg DCLHb, or albumin at 1, 2, or 4 h after sepsis induction. Hemodynamics were recorded at these times and daily for 72 h. DCLHb increased blood pressure, prevented 72 h leukocytosis, and reduced mortality, but the timing of DCLHb administration was crucial. In protocol 2 only moribund septic animals received 100 mg/kg DCLHb or iso-oncotic albumin i.v. Hemodynamics and regional organ blood flows were measured at baseline, immediately before and after treatment, and at 24 h. DCLHb immediately increased blood pressure with no changes in cardiac output, heart rate, or regional perfusion. DCLHb increased regional perfusion to vital areas at 24 h (compared to albumin group). Distribution of cardiac output in albumin-treated rats was significantly skewed toward skeletal muscle at a time when cardiac output was significantly lower as compared with DCLHb treated animals. In conclusion, DCLHb safely elicited a pressor response, and improved regional perfusion to selected tissues. However, DCLHb benefits were best obtained when given within a specific time frame.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID