摘要:

Skeletal muscle protein wasting is a prominent feature of the metabolic response to sepsis. Persistent protein wasting leads to muscle dysfunction and prolongs recovery from the septic insult. Unfortunately, conventional nutritional support alone does not prevent the sepsis-induced weight loss and catabolism of muscle. Hence, mechanisms other than substrate deficiency appear to be involved in the derangements in protein metabolism during sepsis. The catabolism of muscle during sepsis results from a stimulation of proteolysis and an inhibition of protein synthesis. This review summarizes the mechanisms responsible for alterations in protein synthesis and degradation in muscle during sepsis at the biochemical level. The ability of hormones (insulin, insulin-like growth factor I, glucocorticoids) or cytokines (tumor necrosis factor, interleukin-1) to act as mediators of protein catabolism is also examined. Finally, we discuss the potential role of anticytokine therapies in preventing derangements in protein metabolism during sepsis. A picture is emerging which suggests that cytokines may influence skeletal muscle protein metabolism during sepsis both indirectly through inhibition of the regulatory actions of anabolic hormones on protein turnover, and directly through modulation of the protein synthesis and degradation enzymatic machinery.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The time course of nitric oxide (NO) production in posttrauma critical illness was monitored, and its relationship to posttrauma “sepsis/SIRS” and physiologic patterns was described. Eighty multiple trauma patients were studied (514 samples) during their course in the intensive care unit (Injury Severity Score 27.6; 36% deaths). Plasma NO was estimated from NO3+NO2by the Griess test and compared with that of 10 healthy controls (HC). At each sample period, the patient was categorized as having bacteremic sepsis (BAC), sepsis syndrome (SS), or systemic inflammatory response syndrome (SIRS), and classified by Physiologic State Severity Classification (PSSC) into normal stress response (A-State), metabolic insufficiency (B-State), or respiratory insufficiency (C2-State), each quantified by their physiologic “distance” from reference state of recovering trauma patients (R-State). A severity index (L2PDEATH), based on a logistic model of state distances from R-State, quantified probability of death. Deaths showed increased NO (p < .05) over survivors or HC by day 3 posttrauma. A fall in vascular tone in deaths was related to the increased NO (p < .0001). The level of NO was higher as sepsis worsened: BAC > SS > SIRS > HC (all simultaneous, p < .05). PSSC and L2PDEATH correlated with incidence > HC and level of NO. In conclusion, the severity of posttrauma critical illness was classified by PSSC and quantified by the L2PDEATH index. These reflect progressively increased NO levels and suggest worsening sepsis status. The reduced total peripheral resistance (TPR)-to-flow relationship (vascular tone) in deaths characteristic of the more severe septic PSSC states appeared related to the increased plasma NO.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

While the regulation of nitric oxide (NO) by inflammatory cytokines or lipopolysaccharide (LPS) has received considerable attention, NO modulation of cytokine expression has yet to be fully explored. The NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited interleukin (IL)-8 and IL-6 production in LPS-stimulated human whole blood in a dose-dependent manner. In the presence of 1 μg/mL LPS, L-NAME blocked IL-8 release (72 ± 4% inhibition at 20 mM (mean ± SEM, p < .05)) 24 h post-LPS without affecting cellular viability. IL-6 production was significantly inhibited only with the highest dose of L-NAME used. L-NAME inhibition of IL-8 production was also observed at the mRNA level. Conversely, direct exposure of whole blood to NO with the spontaneous NO liberator DETA NONOate caused a dose-dependent stimulation of IL-8, but had no effect on IL-6 release. IL-8 concentrations rose from 8.3 ± 1.9 ng/mL at 24 h to 31.7 ± 7.6 ng/mL at 72 h with a single stimulation of 10 mM DETA NONOate. The hydroxyl radical scavenger dimethyl sulfoxide (DMSO) prevented the DETA NONOate induction of IL-8, suggesting the participation of the hydroxyl radical in the NO-induced IL-8 production. These results provide important evidence substantiating a role for NO as a regulator of cytokine expression.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

We hypothesized that pulmonary vasorelaxation mediated by receptors that require generation of cyclic adenosine monophosphate (cAMP) is impaired in endotoxin-induced acute lung injury. The purpose of this study was to determine the effect of endotoxin on the following pathways of pulmonary vasorelaxation that require the generation of cAMP: 1) β-adrenoreceptor stimulation (response to isoproterenol, ISO), 2) P2purinoreceptor stimulation (response to adenosine diphosphate, ADP), 3) H2-histamine receptor stimulation (response to dimaprit), 4) adenosine A2receptor stimulation (response to adenosine, ADO), 5) type 2 E prostaglandin (EP2) receptor stimulation (response to prostaglandin E1, PGE1), and 6) direct adenylate cyclase stimulation (response to forskolin, FSK). We used isolated pulmonary artery rings harvested from rats injected with endotoxin or saline. We found that endotoxin impaired the response to β-adrenoreceptor stimulation (ISO) and P2purinoreceptor stimulation (ADP). Endotoxin converted the vasorelaxant effect of H2-histamine receptor stimulation (dimaprit) to vasoconstriction. On the other hand, the response to A2receptor stimulation (ADO) and EP2receptor stimulation (PGE.,) was normal. The dose response to direct adenylate cyclase stimulation (FSK) was the same as control except at a single concentration (10-7M). These data suggest that endotoxin causes selective impairment of pulmonary vasorelaxation through receptors coupled to cAMP generation. This impaired pulmonary vasorelaxation may contribute to the increased pulmonary vascular resistance seen in acute lung injury. These data may lead to therapy that will prevent or improve the pathophysiologic pulmonary circulation in acute lung injury.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The aim of this study was to investigate the influence of the activation of the complement and coagulation systems on bacterial clearance and killing capacity of the reticuloendothelial system in rabbits. To enable quantification of the clearance process, defined numbers of exogenous Escherichia coli (1.3 × 108colony-forming units) were injected intravenously, after complement activation with inulin-activated rabbit serum (n = 6), after complete defibrination with the snake toxin ancrod (n = 6), and in sham-operated animals (controls, n = 6). During the following 180 min observation period, parameters monitored were arterial pressure, fibrinogen, blood gases, and bacterial counts in blood and tissue samples of liver, kidney, spleen, and lung. Defibrination produced a significant delay in blood clearance (p < .05) compared with controls, coupled with up to four times higher bacterial counts in organ homogenates. Complement activation did not affect bacterial elimination kinetics, but was associated with accumulation ofE. coliin lung and kidney (up to 100-fold of control values, p < .001). The impaired bacterial clearance associated with increased organ colonization after activation of the complement and coagulation systems reflect reticuloendothelial system dysfunction, thus pointing toward a weaker resistance against bacterial infection.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The hamster cheek pouch was used to determine the role of platelet activating factor (PAF) and nitric oxide (NO) in leukocyte adhesion and microvascular leakage of FITC-dextran following systemic administration of endotoxin. Endotoxin (5 mg/kg, i.v.) or vehicle was administered to the hamster 15 min after systemic pretreatment with either a PAF antagonist (Abbott-87648, .1 mg/kg, i.v.) or a nitric oxide synthase inhibitor (L-NAME, 30 mg/kg, i.v.), or 60 min after dexamethasone pretreatment (4 mg/kg, i.p.). Endotoxin alone caused rapid leakage of FITC-dextran from the vascular compartment into the tissue. This leakage was not preceded by either increased leukocyte rolling or adhesion in postcapillary venules. Pretreatment with the PAF antagonist, as well as with dexamethasone, completely blocked endotoxin-induced leakage. L-NAME also blocked endotoxin-induced leakage; however, more than 50% of the hamsters treated with L-NAME died within 2 h after endotoxin administration. These results suggest that PAF and NO are important mediators of microvascular leakage during endotoxemia and that their actions are not dependent on leukocyte adhesion to postcapillary venular endothelium.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Dehydroepiandrosterone (DHEA), an endogenous immune modulator, reduces mortality after endotoxin (lipopolysaccharide (LPS)) administration in rodents. However, there have been no studies in clinically relevant large-animal models. A unique experimental model is used to study the effects of DHEA in resuscitated trauma and to evaluate the protective effect of DHEA on the systemic inflammatory response induced by a delayed LPS challenge. Anesthetized, ventilated pigs were instrumented and then subjected to local hind-limb trauma and 35% hemorrhage. After 1 h, animals were resuscitated with shed blood, supplemental Ringers solution, and in a randomized, blinded fashion, 4 mg/kg of DHEA or vehicle. Two additional groups received 10 mg/kg or 20 mg/kg of DHEA. Animals were dosed again at 24, 48, and 72 h. After 75 h,Escherichia coliLPS was administered. LPS caused a fall in DHEA levels (0.23 ± .05 ng/mL (60 min post-LPS) versus .94 ± 35 ng/mL (72 h), p = .01). DHEA levels 60 min post-LPS were significantly higher in treated animals (p < .002). After LPS, all groups manifested progressive septic symptoms with a hyperdynamic state and pulmonary failure. These symptoms were not blunted by the administration of DHEA. DHEA levels are suppressed by LPS in this two-stage model of trauma and delayed sepsis; however, exogenous DHEA administration fails to blunt the associated systemic inflammatory response and pulmonary failure.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Many studies have demonstrated that thyrotropin-releasing hormone (TRH) produces various beneficial effects in the treatment of shock. TRH has been proposed to reverse the cardiovascular depression of endogenous opioid peptides. Nevertheless, it remains unknown whether opioid receptors are truely involved in this process. We designed experiments to study the importance of δ andKopioid receptors in the beneficial effects of TRH in hemorrhagic shock in rabbits and on opiate receptors following hemorrhagic shock in rats. The results indicated that TRH (50 μg, i.c.v.) significantly improved the mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), and the maximal rate of ventricular systolic pressure changes (±dp/dtmax) during hemorrhagic shock in rabbits. This TRH effect was abolished by pretreatment with ICI174, 864 (50 μg, i.c.v.), a highly selective μ opioid receptor antagonist, but not by pretreatment with nor-binaltorphimine (Nor-BNI, 50 μg, i.c.v.), a highly selective K opioid receptor antagonist. The maximal binding capacity (Bmax) of brain δ and K opioid receptors significantly increased following hemorrhagic shock, but the receptor affinity (Kd) did not change. TRH (5 mg/kg, i.v.) decreased the number (Bmax) of brain δ opioid receptors significantly, but it did not influence the receptor affinity. TRH did not influence the Bmax or affinity of brain K opioid receptors. These findings suggest that opioid receptors play an important role in mediating the antishock property of TRH. TRH-induced down-regulation of the number of brain opioid receptors may be one of the important mechanisms by which TRH exercises its protective effects in the treatment of shock.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

To determine the influence of the site of infection on circulating endotoxin and hormonal release, male rats were prepared with arterial catheters and with either intravenous (i.v.) or intraperitoneal (i.p.) catheters under pentobarbital. Four days later, they were injected either i.v. or i.p. withEscherichia colisuspended in saline. Plasma was assayed for adrenocorticotropin (ACTH), corticosterone, and endotoxin activity. After ∼109colony-forming units (CFU) ofE. coli, plasma endotoxin in i.v. rats (496 ± 96 EU/mL) differed from that in i.p. rats (12.6 ± 3.6 EU/mL,p< .01). However, ACTH and corticosterone increased to the same extent in both groups. After ∼107CFU, plasma endotoxin in i.v. rats (9.15 ± 2.09 EU/mL) was greater than in i.p. rats (2.56 ± .42 EU/mL, p < .05), and ACTH and corticosterone increased more at 1 h in i.v. rats than in i.p. rats (p < .01). Additional rats given ∼0.3 × 109CFU i.p. had plasma endotoxin that did not differ from values measured after either ∼109CFU i.p. or ∼107CFU i.v. However, the ACTH responses in these three groups differed from one another (p < .01). ACTH was more strongly correlated to plasma endotoxin in i.v. rats (r = .915) than in i.p. rats (r = .528, p < .01 for difference from i.v. group). The weak relationship between plasma endotoxin and ACTH after i.p. inoculations suggests that peritoneal infections activate important pathways that are independent of the circulation.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Sustained exposure to radiofrequency radiation of millimeter wave (MMW) length produces hyperthermia and subsequent circulatory failure. This study sought to determine whether this phenomenon is altered by chronic pretreatment with the nitric oxide (NO) synthesis inhibitorNω-nitro-L-arginine methyl ester (L-NAME). Rats drank either 1) water, 2) water + L-NAME, or 3) water + L-NAME + L-arginine (at 20 and 50 times the dose of L-NAME) for 14 days. Ketamine-anesthetized rats were exposed to MMW until mean arterial blood pressure (MAP) fell to 75 mmHg, at which point MMW exposure was discontinued. MAP initially increased during exposure in all groups; the pressor response in L-NAME-treated rats was greater than that in water-drinking rats. Subsequently, MAP fell in all groups. The MMW exposure time required to reach MAP = 75 mmHg was significantly reduced in L-NAME-treated rats, although survival times (post-MMW) of L-NAME-treated and control rats were not statistically different. Coadministration of L-arginine abolished the enhanced pressor response produced by L-NAME, but did not completely reverse the shortened MMW exposure time in L-NAME-treated rats. Thus, chronic NO synthesis inhibition with L-NAME reduces the ability of rats to withstand 35 GHz microwave heating, suggesting that NO does not mediate the hypotension produced by this form of hyperthermia.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID