摘要:

ABSTRACT—Despite intensive investigation, the pathogenesis of post‐injury multiple organ failure (MOF) remains elusive. Laboratory and clinical research strongly suggests that the gastrointestinal tract (i.e., the gut) plays a pivotal pathogenic role. Since its inception in 1988, the Trauma Research Center (TRC) at the University of Texas‐Houston Medical School (UTHMS) has focused its efforts on elucidating the role of the gut in post‐injury MOF. On the basis of our observations and those of others, we believe that 1) shock with resulting gut hypoperfusion is an important inciting event, 2) the reperfused gut is a source of proinflammatory mediators that can amplify the early systemic inflammatory response syndrome (SIRS) and thus contribute to early MOF, 3) early gut hypoperfusion causes an ileus in both the stomach and small bowel that sets the stage for progressive gut dysfunction so that the proximal gut becomes a reservoir for pathogens and toxins that contribute to late sepsis‐associated MOF, and 4) late infections cause further worsening of this gut dysfunction. Thus, the gut can be both an instigator and a victim of MOF. The purpose of this article is to provide the rationale behind these beliefs and to provide a brief overview of the ongoing research projects in the TRC at UTHMS.

ISSN:1073-2322    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ABSTRACT—The DNA binding activity of the transcription factor, NF‐&kgr;B, is regulated by the phosphorylation and degradation of its inhibitory protein, I&kgr;B, and post‐translational modification involving redox reaction of a cysteine residue (Cys62) of NF‐&kgr;B. We addressed the role of the redox state of endothelial cells in modulating TNF&agr;‐induced NF‐&kgr;B activity. The effects of TNF&agr; on DNA‐binding activity of NF‐&kgr;B and expression of mRNA encoding ICAM‐1 (an NF‐&kgr;B‐activated gene) were studied in human pulmonary artery endothelial (HPAE) cells under basal conditions and after decreasing the intracellular glutathione (GSH) concentration. HPAE cells were treated with buthionine sulfoximine (BSO) (16 h), an inhibitor of GSH synthesis, which caused concentration‐dependent decreases in GSH concentration. Stimulation of control cells with TNF&agr; resulted in reactive oxygen species (ROS) generation and activation of NF‐&kgr;B binding to the ICAM‐1 promoter and ICAM‐1 transcription. However, stimulation of GSH‐depleted cells with TNF&agr; resulted in ROS accumulation secondary to the decreased ROS buffering capacity, and marked impairment of NF‐&kgr;B‐binding activity and ICAM‐1 mRNA expression. Exposure of BSO‐treated cells to the reducing agent dithiothreitol (DTT) before TNF&agr; treatment or supplementation of nuclear extract (isolated after TNF&agr; challenge of BSO‐treated cells) with DTT significantly augmented the effect of TNF&agr; on NF‐&kgr;B‐binding activity and ICAM‐1 mRNA expression. Thus the oxidative modification of NF‐&kgr;B secondary to the loss of ROS buffering capacity may regulate NF‐&kgr;B binding to ICAM‐1 promoter, and thereby ICAM‐1 transcription in endothelial cells.

ISSN:1073-2322    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ABSTRACT—Laboratory studies of uncontrolled hemorrhage demonstrate that under resuscitation (UR) improves short‐term survival, but at the expense of tissue perfusion. The long‐term effects of UR have not been studied. The purpose of this study was to evaluate survival and the incidence of end‐organ injury (EOI), 3 days following moderate and severe UR of uncontrolled hemorrhage. Thirty‐four swine (14‐24 kg) were assigned to 4 groups: Groups I, II, and III were hemorrhaged to a pulse pressure = 5 mmHg in the presence of a 4‐mm aortic tear: Group I (control; n = 6) was not resuscitated; Group II (n = 11) was severely under resuscitated (MAP [mean arterial pressure] = 40 mmHg) for 75 min; Group III (n = 9) was moderately under resuscitated (MAP = 60 mmHg) for 75 min. After 75 min, the aortotomy was repaired, and animals were resuscitated to baseline physiologic parameters. Group IV (sham; n = 8) was instrumented, but not hemorrhaged. Seventy‐two‐hour mortality was 100%, 36%, 22%, and 0% for Groups I through IV (P= .001 Fisher's exact). Cardiac indices, serum bicarbonate, and systemic oxygen delivery were significantly lower in Group II as compared to Group III during the 75 min of UR (P< 0.05; repreated measures ANOVA). By 72 h, physiologic parameters in surviving animals had returned to baseline levels. Measures of kidney, liver, neurologic, and pulmonary function did not change from baseline. There was no histologic evidence of EOI. In this model, 75 min of UR did not result in EOI. There was a trend toward greater survival, and tissue perfusion was better preserved with moderate as compared to severe UR.

ISSN:1073-2322    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ABSTRACT—The gut primes neutrophils (PMNs) during injury, which can then induce distant organ damage after a second insult. ICAM‐1 is an important adhesion molecule in PMN attachment to the vascular endothelium. Parenteral nutrition (TPN) decreases gut levels of interleukin (IL)‐4 and IL‐10, two cytokines that are normal inhibitors of ICAM‐1 expression. TPN also increases gut ICAM‐1 expression and PMN accumulation. Since glutamine (GLN) and bombesin (BBS) prevent TPN‐associated impairment of mucosal immunity, we hypothesized that GLN and BBS would modulate organ ICAM‐1 expression in association with normalization of IL‐4 and IL‐10 levels. Forty‐four mice were fed chow, TPN, or GLN‐TPN (isonitrogenous 2% GLN‐enriched TPN). After 5 days of diets, ICAM‐1 expression was quantified in organs using the dual radiolabeled monoclonal antibody technique. In the next experiment, 29 mice were fed chow, TPN, or BBS‐TPN (BBS 15 &mgr;g/kg TID) for 5 days to measure organ ICAM‐1 expression. Total IL‐4 and IL‐10 levels were measured with ELISA from intestinal homogenates of another set of 52 mice fed chow, TPN, GLN‐TPN, or BBS‐TPN. TPN significantly increased ICAM‐1 expression in the lung, kidney, and intestine compared with chow mice. GLN‐TPN decreased intestinal, but not lung, ICAM‐1 expression, while BBS‐TPN reduced pulmonary, but not gut, ICAM‐1 levels. GLN‐ and BBS‐TPN returned gut IL‐4 levels to normal, but failed to increase IL‐10 levels. GLN and BBS had different effects on organ ICAM‐1 expression induced by lack of enteral nutrition. Mechanisms other than recovery of IL‐4 alone may be responsible for gut ICAM‐1 expression.

ISSN:1073-2322    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ABSTRACT—Addison's crisis is the most serious complication of adrenal insufficiency. To elucidate the mechanism of this disorder following infection, the role of TNF in adrenalectomized murine models of Addison's crisis and Addison's disease (chronic hypoglucocorticoidism) were examined. Adrenalectomy conferred a 40‐fold increased sensitivity to the lethal effects of lipopolysacharride (LPS) (P< .001). Enhanced sensitivity to LPS was found to increase with duration of adrenal insufficiency (P< .02). Enhanced lethality to heat‐killedStreptococcus pneumoniawas also demonstrated (P< 0.02). Necropsy of endotoxinkilled adrenalectomized mice demonstrated similar pathologic findings to those found by others when the control mice were administered a lethal dose of either LPS or TNF. Adrenalectomized TNF receptor la and lb double null mice were demonstrated to be resistant to the lethal effects of LPS (P< 0.02). Pretreatment with anti‐TNF, but not control antisera, was found to prevent death in LPS‐treated wild‐type adrenalectomized mice as well (P< 0.02). Studies into the mechanism by which TNF was precipitating Addison's crisis demonstrated enhanced sensitivity to TNF (3‐fold;P< 0.02), and a marked increase in serum TNF concentration (approximately 5‐fold;P< 0.001) following LPS challenge. The effect of TNF upon long‐term survival in adrenalectomized mice was examined in TNF‐receptor la‐ and lb‐deficient mice. Deficiencies in either the TNF‐receptor la or lb was noted to confer a survival advantage relative to colony controls following adrenalectomy (P< 0.02). In summary, both LPS‐induced Addison's crisis and chronic adrenal insufficiency are disorders of TNF disregulation. Based upon these data, therapeutic strategies targeted at controlling TNF in adrenal insufficiency are suggested.

ISSN:1073-2322    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ABSTRACT—We investigated the cardiovascular consequences of acute intoxication by the organophosphate poison, mevinphos (Mev), and delineated the underlying mechanism. Based on on‐line power spectral analysis of systemic arterial pressure (SAP) signals in rats anesthetized and maintained by propofol, we identified two distinct phases after intravenous administration of Mev (160 or 320 &mgr;g/kg). Phase I was characterized by transient hypertension and mild tachycardia, concurrent with an increase in the very high‐frequency (BVHF; 5‐9 Hz), high‐frequency (BHF; 0.8‐2.4 Hz), low‐frequency (BLF; 0.25‐0.8 Hz), and very low‐frequency (BVLF; 0‐0.25 Hz) components of SAP signals. Phase II exhibited significant hypotension, a reversal of the BVHF and BVLF power to control levels, and further reduction in the power density of both BHF and BLF components to below baseline. Microinjection of Mev (2 &mgr;g) into the bilateral nucleus reticularis ventrolateralis (NRVL), the medullary origin of sympathetic neurogenic vasomotor tone, essentially duplicated those phasic cardiovascular changes. Similarly, sympathoexcitatory NRVL neurons exhibited respectively an elevation and a decline in their spontaneous activities during Phase I and Phase II Mev intoxication. We conclude that the progressive accumulation of acetylcholine over time induced by a direct inhibition of Mev on cholinesterase in the NRVL may be responsible for the phasic changes in cardiovascular events over the course of acute Mev intoxication. Whereas the initial amount of acetylcholine is excitatory to NRVL neurons, overstimulation by the amassed acetylcholine results instead of an inhibitory action.

ISSN:1073-2322    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ABSTRACT—Studies indicate that polymicrobial sepsis in humans and animals is characterized by a biphasic response, which is dominated early by proinflammation, but over time develops into a state of generalized anti‐inflammation (depressed Th1 cell response and decreased macrophage (M0) capacity to release proinflammatory cytokines). However, with respect to the macrophage, it remains unknown what mechanism(s) controls this change. In this regard it is well documented that the p38 mitogen activated protein kinase pathway (MAPK) plays a central role in the regulation of M&phis; functions. However, the contribution of p38 MAPK activation to the loss of these M&phis; functions in polymicrobial septic animals remains unknown. To determine this we induced polymicrobial sepsis in C3H/HeN male mice using cecal ligation and puncture (CLP). Twenty‐four hours post‐CLP, during the late, immune‐suppressed stage of sepsis, splenic and peritoneal M&phis; were harvested, stimulated with lipopolysaccharide (LPS), and the activation of p38 MAPK assessed. In M&phis; from CLP mice, p38 MAPK activity was markedly increased. To determine the extent that these changes in p38 MAPK had an impact on M&phis; immune function, cells were pretreated with 10 &mgr;M of the p38 MAPK inhibitor, SB203580, or with DMSO vehicle, and subsequently stimulated with LPS. IL‐10, IL‐6, IL‐12, and nitric oxide release was determined. Our results indicate that with LPS stimulation alone, there was a marked increase in the release of the anti‐inflammatory mediator, IL‐10 after CLP. Alternatively, proinflammatory IL‐12 and IL‐6 release was suppressed. Treatment with SB203580 suppressed the increase in IL‐10 release seen after CLP, while partially restoring IL‐12 secretion. IL‐6 release was partially restored only in splenic macrophages treated with SB203580. To the extent that thesein vitrofindings could be translated to anin vivosetting, we assessed thein vivoeffects of p38 MAPK inhibition on survival. Mice were given 100 mg of SB203580/kg body weight or saline vehicle (intraperitoneal) either immediately post‐CLP or 12 h post‐CLP. Delayed administration of SB203580 significantly improved survival, while also preventing the increased NO and IL‐10 release and improving IL‐12 release by macrophages. These results suggest that p38 MAPK pathway plays a critical role in the induction of an immune‐suppressive macrophage phenotype, and that inhibition of p38 MAPK markedly improves survival following polymicrobial sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ABSTRACT—Alterations of the ATP‐dependent Ca2+uptake in the cardiac sarcoplasmic reticulum (SR) during the 2 hemodynamically distinct phases of sepsis were investigated. Sepsis was induced by cecal ligation and puncture (CLP). Control rats were sham‐operated. The SR vesicles were isolated by sucrose gradient centrifugation. The results show that the rates of ATP‐dependent Ca2+uptake in the cardiac SR were unaffected during the early hyperdynamic phase, whereas they were decreased by 41‐46% (P< 0.01) during the late hypodynamic phase of sepsis. Analysis of the kinetics of Ca2+transport indicates that during the late phase of sepsis, the Vmaxvalues of Ca2+pump for ATP and Ca2+were decreased, whereas the affinities of Ca2+pump for ATP and Ca2+were unaffected. Magnesium stimulated, whereas vanadate inhibited the ATP‐dependent Ca2+uptake, but the Mg2+‐stimulated and the vanadate‐inhibited Ca2+uptake activities were significantly lower during the late sepsis. Phosphorylation of SR by the cAMP‐dependent and the calmodulin‐dependent protein kinases stimulated the ATP‐dependent Ca2+uptake in the control and the early septic experiments, whereas it failed to stimulate Ca2+uptake in the late sepsis. The extent of the phosphorylation‐stimulated Ca2+uptake activities was reduced by 65‐69% (P< 0.01) during the early sepsis, and they were completely abolished during the late sepsis. These data indicate that the ATP‐dependent Ca2+uptake in cardiac SR was impaired during the late hypodynamic phase of sepsis. The impaired Ca2+uptake during late sepsis was associated with a defective phosphorylation of SR proteins. Because the ATP‐dependent Ca2+uptake by cardiac SR plays an important role in the regulation of contraction‐relaxation coupling, our findings may contribute to the understanding of the pathogenesis of altered cardiac function during the progression of sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ABSTRACT—Starling's law is a description relating the energy released by the contracting ventricle to the end diastolic fiber length. The peak systolic pressure during isovolumic contraction is an example of this relationship; Sunagawa and coworkers (12) termed that pressure Pmax. It may also be estimated during ejecting beats. Here we compare the variable Pmax at a given end diastolic volume with that of end systolic elastance as an indicator of ventricular function, changes in either being indicative of changesin the inotropic state of the heart. We specifically investigate 2 points on the end systolic pressure‐volume relationship (ESPVR) plot: 1) the Pmax, EDV point, obtained from the concept of the maximum pressure, Pmax, the pressure an isovolumically contracting ventricle would produce at a given end diastolic volume (EDV); and 2) the end systolic pressure, end systolic volume point. Both points would be expected to shift proportionally with changes in the slope of ESPVR. Data were obtained from 2 published reports in humans in the literature and from a group of 5 dogs subjected to a wide range of preloads and afterloads. High correlations (>0.9) were obtained for changes in the slope of ESPVR and the Pmax, EDV points. The latter, a more readily obtainable variable from single ejecting beats, is proposed as a version of Starling's law, the changes in which are directly comparable with the changes in end systolic elastance. The changes in the end systolic pressure, end systolic volume points, were not as reliable (<0.7).

ISSN:1073-2322    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ABSTRACT—Hypothermia (HT) is used in certain surgical procedures to reduce metabolism and protect the brain, but in trauma victims accidental HT is considered harmful. Recent animal studies indicate that HT has protective effects in hemorrhagic shock. The aim of the present study was to examine how induced HT modifies the hemodynamic pattern in hemorrhagic shock. Twenty pigs with a body weight of between 17 and 24 kg (mean 20.8) were anesthetized, 50% of their blood volume was withdrawn, and hypothermia (30°C) was induced in half of them (HT group) while the others served as controls. Central hemodynamics was monitored during 4 h via an arterial line and a pulmonary artery catheter. Blood samples were obtained for measurement of leukocyte and platelet counts. Three of the control pigs died while all the animals in the HT group survived the experiment. The hemorrhage resulted in a marked increase in heart rate and a drop in cardiac output and mean arterial pressure. HT slowed the heart rate and induced a further reduction of cardiac output, which parallelled the depression of the core temperature, while the stroke volume did not change in any of the groups. A significant decrease in mean arterial pressure and the leukocyte count became apparent 2 h after the induction of HT. HT aggravated the hypokinetic situation resulting from hemorrhagic shock but without increasing the mortality.

ISSN:1073-2322    

出版商:OVID    

年代:2001

数据来源: OVID