PubMed Health⌕ Search

Biomedical subjects

A B Nathens

Publications and source records attributed to A B Nathens.

At least 19 recordsLinked to original sources
PubMed2001

Relationship between trauma center volume and outcomes.

CONTEXT: The premise underlying regionalization of trauma care is that larger volumes of trauma patients cared for in fewer institutions will lead to improved outcomes. However, whether a relationship exists between institutional volume and trauma outcomes remains unknown. OBJECTIVE: To evaluate the association between trauma center volume and outcomes of trauma patients. DESIGN: Retrospective cohort study. SETTING: Thirty-one academic level I or level II trauma centers across the United States participating in the University Healthsystem Consortium Trauma Benchmarking Study. PATIENTS: Consecutive patients with penetrating abdominal injury (PAI; n = 478) discharged between November 1, 1997, and July 31, 1998, or with multisystem blunt trauma (minimum of head injury and lower-extremity long-bone fractures; n = 541) discharged between June 1 and December 31, 1998. MAIN OUTCOME MEASURES: Inpatient mortality and hospital length of stay (LOS), comparing high-volume (>650 trauma admissions/y) and low-volume (</=650 admissions/y) centers. RESULTS: After multivariate adjustment for patient characteristics and injury severity, the relative odds of death was 0.02 (95% confidence interval [CI], 0.002-0.25) for patients with PAI admitted with shock to high-volume centers compared with low-volume centers. No benefit was evident in patients without shock (P =.50). The adjusted odds of death in patients with multisystem blunt trauma who presented with coma to a high-volume center was 0.49 (95% CI, 0.26-0.93) vs low-volume centers. No benefit was observed in patients without coma (P =.05). Additionally, a shorter LOS was observed in patients with PAI and New Injury Severity Scores of 16 or higher (difference in adjusted mean LOS, 1.6 days [95% CI, -1.5 to 4.7 days]) and in all patients with multisystem blunt trauma admitted to higher-volume centers (difference in adjusted mean LOS, 3.3 days [95% CI, 0.91-5.70 days]). CONCLUSIONS: Our results indicate that a strong association exists between trauma center volume and outcomes, with significant improvements in mortality and LOS when volume exceeds 650 cases per year. These benefits are only evident in patients at high risk for adverse outcomes.

Academic Medical Centers↗
PubMed2001

Timing of urgent thoracotomy for hemorrhage after trauma: a multicenter study.

HYPOTHESIS: It is possible to quantify an amount of thoracic hemorrhage, after blunt and penetrating injury, at which delay of thoracotomy is associated with increased mortality. DESIGN: A retrospective case series. SETTING: Five urban trauma centers. STUDY SELECTION: Patients undergoing urgent thoracotomy (within 48 hours of injury) for hemorrhage (excluding emergency department thoracotomy). DATA EXTRACTION: Respective registries identified patients who underwent urgent thoracotomy. Injury characteristics, initial and subsequent chest tube outputs, time before thoracotomy, and outcomes were evaluated. MAIN OUTCOME MEASURE: Death. RESULTS: One hundred fifty-seven patients (36 with blunt and 121 with penetrating injuries) underwent urgent thoracotomy for hemorrhage between January 1, 1995, and December 31, 1998. Mortality correlated with mean (+/- SD) Injury Severity Score (38 +/- 19 vs 22 +/- 12.6 for survivors; P<.01) and mechanism (24 [67%] for blunt vs 21 [17%] for penetrating injuries; P<.01). Mortality increased as total chest blood loss increased, with the risk for death at blood loss of 1500 mL being 3 times greater than at 500 mL. Blunt-injured patients waited a significantly longer time to thoracotomy than penetrating-injured patients (4.4 +/- 9.0 h vs 1.6 +/- 3.0 h; P =.02) and also had a greater total chest tube output before thoracotomy (2220 +/- 1235 mL vs 1438 +/- 747 mL; P =.001). CONCLUSIONS: The risk for death increases linearly with total chest hemorrhage after thoracic injury. Thoracotomy is indicated when total chest tube output exceeds 1500 mL within 24 hours, regardless of injury mechanism.

Adult↗
PubMed2001

Relevance and utility of peritoneal cultures in patients with peritonitis.

BACKGROUND: The pathogenic organisms responsible for the manifestations of secondary peritonitis have been well characterized through almost 30 years of experimental and clinical studies. Enteric gram-negative organisms and anaerobes predominate, with Escherichia coli and Bacteroides fragilis, respectively, being the most frequent isolates. This flora is remarkably consistent across patients and institutions. As a result of this consistency and the availability of well-established effective empiric antimicrobial regimens, many surgeons believe that cultures of peritoneal exudates in patients with peritonitis offer no useful information and no clinical benefit. METHODS: Review of pertinent antibiotic and management trials in the management of intraabdominal infection. RESULTS: There is increasing evidence that identification of organisms resistant to the chosen empiric antibiotic regimen portends a higher likelihood of failure. What is not clear is whether postoperative changes in the regimen in accordance with sensitivity patterns of the isolates offers any clinical advantage. In most circumstances, the data provided allow for simplification of the antibiotic regimen. CONCLUSION: The potential for reducing antibiotic exposure and the value of information derived from surveillance of microbial sensitivity patterns support the routine performance of peritoneal cultures.

Ascitic Fluid↗
PubMed2001

Payer status: the unspoken triage criterion.

BACKGROUND: The cost of uncompensated trauma care is a significant barrier to trauma system development. Trauma center designation may burden an institution with an unprofitable mix of underinsured, severely injured patients. Concerns about inadequate reimbursement may motivate interhospital transfers on the basis of insurance status rather than medical necessity, potentially undermining the effectiveness of the system. We set out to explore whether this phenomenon exists in a mature trauma system. METHODS: Trauma patients receiving definitive care at Level III or IV trauma centers were compared with patients transferred from these centers to the only Level I regional center. Insurance status was classified as either commercial or noncommercial. Logistic regression was used to determine the independent predictors of transfer after adjusting for differences in injury severity. RESULTS: Only 12% of 2,008 patients initially evaluated at Level III/IV centers were transferred to the Level I center, an indicator of the effectiveness of prehospital triage protocols in the region. The presence of specific complex injuries, younger age, male gender, and insurance status were all associated with an increased likelihood of transfer. Insurance status was an independent predictor of transfer: patients without commercial insurance were 2.4 (95% confidence interval, 1.6-3.6) times more likely to be transferred to a Level I facility than patients with commercial insurance after adjusting for differences in injury severity. CONCLUSION: Insurance status influences the decision to transfer to higher levels of care. These findings suggest that the financial burden of a trauma system may be inequitably distributed. This inequitable distribution may be necessary for trauma system sustainability and calls for the development of disproportionate reimbursement strategies to support regional referral centers.

Adolescent↗
PubMed2001

Antioxidants increase lipopolysaccharide-stimulated TNF alpha release in murine macrophages: role for altered TNF alpha mRNA stability.

Through their effects on gene activation, antioxidants have been reported to modulate cellular expression of several proinflammatory cytokines and adhesion molecules, an effect mediated by preventing translocation of the transcription factor nuclear factor-kappa B (NF-kappa B) into the nucleus. In addition, modulation of the intracellular redox state may have profound effects on cell activation and subsequent gene expression distinct from effects on NF-kappa B; these effects may account for the divergent effects of antioxidants on cytokine gene expression in various reports. In the present studies, we evaluated the effect of the antioxidant, pyrrolidine dithiocarbamate (PDTC), on murine and human myeloid cell tumor necrosis factor alpha (TNF alpha) gene and protein expression. PDTC-enhanced LPS-induced TNF alpha secretion in cells derived from a murine macrophage cell line (J774.1), as well as in primary murine peritoneal macrophages by 4-fold. The effect was both stimulus and species dependent, as TNF alpha secretion was attenuated by PDTC in human THP-1 cells and in murine cells stimulated with zymosan. Northern analysis demonstrated that these effects were evident at the level of mRNA expression. Electrophoretic mobility shift assays confirmed the down-regulatory effect of PDTC on human myeloid NF-kappa B activation, whereas in murine cells no such inhibitory effect was evident. Evaluation of TNF alpha mRNA stability in murine cells demonstrated that the potentiating effect of PDTC on TNF alpha mRNA expression was due to an increase in mRNA half-life from 37 to 93 min. Together, these data suggest that the effect of antioxidants on gene expression are both stimulus and species dependent and illustrate a novel mechanism whereby redox manipulation might modulate TNF alpha expression in vivo.

Animals↗
PubMed2001

The relationship between trauma center volume and outcome.

In spite of the limited direct evidence available, increasing data support a positive volume-outcome association in trauma care. When coupled with the extensive indirect data suggesting that regions with organized systems of trauma care are associated with lower trauma-related mortality rates than regions where the number of centers and their level of commitment are unlimited and untested, there is little doubt that experience improves outcome and that volume plays a critical role in the accrual of experience. Although regionalization of trauma care has the inevitable consequence of increased prehospital transport times, particularly in rural areas remote from large trauma centers, some states have designed inclusive systems where a large number of smaller centers have been verified and designated as lower level trauma centers (i.e., level 3-5). The process of trauma center verification holds these smaller volume centers to a standard of care such that the quality of care of the trauma patient may exceed that of other, less-regulated aspects of medical or surgical care. Several reports have suggested that trauma outcomes in smaller rural level 3 centers or centers with dedicated trauma programs with appropriate, functional triage protocols are comparable to national norms, thus reflecting the importance of commitment to outcome. These data suggest that quality of care does not only follow volume, particularly when stipulations and requirements are clear regarding the process of care and ongoing quality assurance.

Hospital Mortality↗
PubMed2000

The effect of organized systems of trauma care on motor vehicle crash mortality.

CONTEXT: Despite calls for wider national implementation of an integrated approach to trauma care, the effectiveness of this approach at a regional or state level remains unproven. OBJECTIVE: To determine whether implementation of an organized system of trauma care reduces mortality due to motor vehicle crashes. DESIGN: Cross-sectional time-series analysis of crash mortality data collected for 1979 through 1995 from the Fatality Analysis Reporting System. SETTING: All 50 US states and the District of Columbia. SUBJECTS: All front-seat passenger vehicle occupants aged 15 to 74 years. MAIN OUTCOME MEASURES: Rates of death due to motor vehicle crashes compared before and after implementation of an organized trauma care system. Estimates are based on within-state comparisons adjusted for national trends in crash mortality. RESULTS: Ten years following initial trauma system implementation, mortality due to traffic crashes began to decline; about 15 years following trauma system implementation, mortality was reduced by 8% (95% confidence interval [CI], 3%-12%) after adjusting for secular trends in crash mortality, age, and the introduction of traffic safety laws. Implementation of primary enforcement of restraint laws and laws deterring drunk driving resulted in reductions in crash mortality of 13% (95% CI, 11%-16%) and 5% (95% CI, 3%-7%), respectively, while relaxation of state speed limits increased mortality by 7% (95% CI, 3%-10%). CONCLUSIONS: Our data indicate that implementation of an organized system of trauma care reduces crash mortality. The effect does not appear for 10 years, a finding consistent with the maturation and development of trauma triage protocols, interhospital transfer agreements, organization of trauma centers, and ongoing quality assurance.

Accidents, Traffic↗
PubMed2000

Effectiveness of state trauma systems in reducing injury-related mortality: a national evaluation.

BACKGROUND: Regional trauma systems were proposed 2 decades ago to reduce injury mortality rates. Because of the difficulties in evaluating their effectiveness and the methodologic limitations of previously published studies, the relative benefits of establishing an organized system of trauma care remains controversial. METHODS: Data on trauma systems were obtained from a survey of state emergency medical service directors, review of state statutes and a previously published trauma system inventory. Injury mortality rates were obtained from national vital statistics data, whereas motor vehicle crash (MVC) mortality rates were obtained from the Fatality Analysis Reporting System. Mortality rates were compared between states with and without trauma systems. RESULTS: As of 1995, 22 states had regional trauma systems. States with trauma systems had a 9% lower crude injury mortality rate than those without. When MVC-related mortality was evaluated separately, there was a 17% reduction in deaths. After controlling for age, state speed laws, restraint laws, and population distribution, there remained a 9% reduction in MVC-related mortality rate in states with a trauma system. CONCLUSION: These data demonstrate that a state trauma system is associated with a reduction in the risk of death caused by injury. The effect is most evident on analysis of MVC deaths.

Accidents, Traffic↗
PubMed2000

Effect of an older sibling and birth interval on the risk of childhood injury.

OBJECTIVE: Certain family structures have been identified as putting children at high risk for injury. To further define children at highest risk, we set out to explore the effect of an older sibling and birth interval on the risk of injury related hospital admission or death. METHODS: Data were analyzed using a case-control design. Cases and controls were identified by linking longitudinal birth data from Washington state (1989-96) to death certificate records and hospital discharge data obtained from the Washington State Comprehensive Hospital Abstract Reporting System and frequency matched in a 1:2 ratio on year of birth. Cases consisted of singleton children 6 years of age or younger who were hospitalized or died as a result of injury during the years 1989-96. Multivariate logistic regression was used to identify and adjust for confounding variables. RESULTS: There were 3145 cases and 8371 controls. The adjusted odds ratio for injury in children with an older sibling was 1.50 (95% confidence interval 1.37 to 1.65). The effect was greatest in children under 2 years of age, and in those with a birth interval of less than two years. As the number of older siblings increased, so did the risk of injury, with the highest risk in children with three or more older siblings. CONCLUSION: These data suggest that the presence of an older sibling is associated with an increased risk of injury. The risk is highest in those with very short birth intervals. Potential mechanisms for this increased risk may relate to inadequate parental supervision. Pediatricians and other care providers need to be alert to these identifiable risk factors and then direct preventive strategies, such as home visits and educational programs, toward these families.

Birth Certificates↗
PubMed1999

Selective decontamination of the digestive tract in surgical patients: a systematic review of the evidence.

OBJECTIVE: To determine the comparative efficacy of selective decontamination of the digestive tract in critically ill surgical and medical patients, and in selected subgroups of surgical patients with pancreatitis, major burn injury, and those undergoing major elective surgery and transplantation. DATA SOURCES: The MEDLINE database was searched from January 1966 to December 1996 using the terms "decontamination or prophylaxis," "intensive care units," and "antibiotics." The search was limited to English-language studies evaluating the efficacy of selective decontamination of the digestive tract in human subjects. STUDY SELECTION: The primary review was restricted to prospective randomized trials. DATA EXTRACTION: End points of interest included rates of nosocomial pneumonia, bacteremia, urinary tract infection, wound infection, mortality, and length of intensive care unit stay. Methodologic quality of individual studies was assessed using a previously described model. DATA SYNTHESIS: Odds ratios (ORs) together with their (95% confidence interval [Cls]) were reported and determined using the Mantel-Haenszel method. Mortality was significantly reduced with the use of selective decontamination of the digestive tract in critically ill surgical patients (OR, 0.7, 95% CI, 0.52-0.93), while no such effect was demonstrated in critically ill medical patients (OR, 0.91; 95% CI, 0.71-1.18). The greatest effect was demonstrated in studies where both the topical and systemic components of the regimen were used. Rates of pneumonia were reduced in both subsets of patients, while those of bacteremia were significantly reduced only in surgical patients. CONCLUSIONS: Selective decontamination of the digestive tract notably reduces mortality in critically ill surgical patients, while critically ill medical patients derive no such benefit. These data suggest that the use of selective decontamination of the digestive tract should be limited to those populations in whom rates of nosocomial infection are high and in whom infection contributes notably to adverse outcome.

Antibiotic Prophylaxis↗
PubMed1999

Redox manipulation using the thiol-oxidizing agent diethyl maleate prevents hepatocellular necrosis and apoptosis in a rodent endotoxemia model.

Manipulation of the intracellular redox state has been shown to alter cell activation pathways with resultant changes in cellular function. Previous studies have suggested that thiol oxidation, using the glutathione-depleting agent diethyl maleate (DEM), was able to inhibit endothelial cell activation. We hypothesized that this agent might exert beneficial effects following endotoxemia in the rat, a model in which transendothelial migration of neutrophils is central to the development of hepatocellular injury. Sprague-Dawley rats treated intraperitoneally with lipopolysaccharide (LPS) (200 microg/kg) plus D-galactosamine (GalN) (600 mg/kg) developed hepatocellular necrosis, as evidenced by liver enzyme release and morphological changes. Pretreatment with DEM abrogated this injury in a dose-dependent fashion. Histology revealed reduced neutrophil accumulation in both the parenchyma and sinusoids, consistent with reduced neutrophil sequestration and transendothelial migration. This effect appeared to be related to the ability of DEM to prevent LPS-induced up-regulation of both vascular cell adhesion molecule-1 (VCAM-1) mRNA and intercellular adhesion molecule-1 (ICAM-1) mRNA in the liver, as well as reducing tumor necrosis factor (TNF) mRNA expression. In addition, DEM prevented hepatocyte apoptosis following LPS treatment. The effect was reproduced when TNF was used as an inflammatory stimulus, suggesting a direct protective effect on the hepatocyte. Taken together, these studies show that redox manipulation through thiol oxidation may represent a novel approach to preventing liver necrosis and apoptosis in inflammatory conditions.

Alanine Transaminase↗
PubMed1998

Thiol-mediated regulation of ICAM-1 expression in endotoxin-induced acute lung injury.

The intracellular redox state regulates several aspects of cell function, suggesting that strategies directed toward altering the cellular redox state may modulate cell activation in inflammatory states. As the most abundant intracellular thiol, glutathione plays a critical role as an intracellular redox buffer. Using diethylmaleate (DEM) as a glutathione-depleting agent, we evaluated the effects of GSH depletion in a rodent model of polymorphonuclear neutrophil (PMN)-dependent acute lung injury. Rats received 500 microg of LPS by intratracheal challenge, inducing a 5.5-fold increase in lung permeability and sixfold increase in lung PMN content. Pretreatment with DEM prevented the LPS-induced increase in lung PMN influx and lung permeability. Northern analysis and immunohistochemical studies suggest that this effect may be mediated by preventing up-regulation of lung ICAM-1 mRNA and protein expression. This effect is specific to ICAM-1, because lung cytokine-induced neutrophil chemoattractant and TNF-alpha mRNA levels are unaffected. This finding is not unique to the lung, because a similar effect on PMN influx was recapitulated in a rodent model of chemical peritonitis. Further, in vitro studies demonstrated that pretreatment of HUVEC monolayers with DEM prevented both ICAM-1 up-regulation and PMN transendothelial migration. These data indicate the presence of a thiol-sensitive mechanism for modulating ICAM-1 gene expression and suggest a potential novel therapeutic strategy for diseases characterized by PMN-mediated tissue injury.

Animals↗
PubMed1998

The glutathione depleting agent diethylmaleate prolongs renal allograft survival.

INTRODUCTION: Intercellular adhesion molecule 1 (ICAM-1) plays an important role in mediating allograft rejection through its role in cellular trafficking and as an important costimulatory signal mediating T cell activation. We have previously reported that systemic administration of the glutathione (GSH) depleting agent diethylmaleate (DEM) prevents upregulation of ICAM-1 in various inflammatory models, suggesting that this agent may offer benefit in preventing allograft rejection. Thus we evaluated the effects of DEM in a murine model of renal transplantation. METHODS: Kidneys from C57BL/6 mice were transplanted into MHC incompatible C3H mice. Donors were treated with DEM 1 h prior to sacrifice, whereas recipients received DEM 1 h following transplantation. Animals were followed until the time of death. In separate studies, renal ICAM-1 mRNA expression was evaluated by polymerase chain reaction and the CD4(+) T cell cytokine profile evaluated in a mixed lymphocyte reaction using C3H responder splenocytes and C57BL/6 stimulator cells. RESULTS: Pretreatment with DEM increased survival from 18.9 +/- 3.6 to 30.6 +/- 10 days (P < 0.05). This increase in survival was associated with a reduction in renal ICAM-1 mRNA expression. Mixed lymphocyte cultures derived from animals pretreated with DEM demonstrated a reduction in the Th1 cytokines IFN-gamma and IL-2 and an increase in the Th2 cytokines IL-4 and IL-10. CONCLUSION: Administration of DEM with consequent systemic GSH depletion significantly reduces allograft ICAM-1 expression and prolongs graft survival. Although speculative, a shift from a Th1 to a Th2 cytokine response raises the possibility that tolerance induction plays a role in prolonged allograft survival.

Animals↗
PubMed1998

Tertiary peritonitis: clinical features of a complex nosocomial infection.

The objective of this study was to define risk factors for and the clinical course of recurrent or tertiary peritonitis. Intensive supportive care of patients with life-threatening intraabdominal infections has led to the emergence of a new clinical syndrome, tertiary peritonitis, defined as the persistence or recurrence of intraabdominal infection following apparently adequate therapy of primary or secondary peritonitis. We undertook a retrospective study of 59 patients admitted with intraabdominal infection to a surgical intensive care unit (ICU). Tertiary peritonitis developed in 74% (44/59) of patients. Despite comparable premorbid health status, source of peritonitis, and admission APACHE II scores, patients with tertiary peritonitis had a significantly longer ICU stay (21.8 +/- 14.9 vs. 8.5 +/- 7.9 days), more advanced organ dysfunction reflected in higher organ dysfunction scores (13.3 +/- 5.1 vs. 7.7 +/- 3.3), and higher ICU mortality (64% vs. 33%) than patients with uncomplicated secondary peritonitis. The most common infecting organisms in patients with tertiary peritonitis were Enterococcus, Candida, Staphylococcus epidermidis, and Enterobacter. Infectious foci were rarely amenable to percutaneous drainage and were found to be poorly localized at laparotomy. Recurrent, or tertiary, peritonitis is a common complication of intraabdominal infection in patients admitted to an ICU. It differs from uncomplicated secondary peritonitis in its microbial flora and lack of response to appropriate surgical and antibiotic therapy. Like nosocomial pneumonia in the critically ill patient, the syndrome appears to be more a reflection than a cause of adverse outcome.

Adult↗
PubMed1998

The indeterminate abdominal sonogram in multisystem blunt trauma.

BACKGROUND: North American trauma centers are beginning to note the limitations of emergent torso sonography. The purpose of this prospective study was to evaluate the frequency, causes, associations, and sequelae of indeterminate (IND) sonograms in blunt trauma. METHODS: Among adult blunt trauma patients assessed with screening torso sonography, clinician sonographers recorded the abdominal sonogram as positive, negative, or IND for free fluid. Patients with IND sonograms were further investigated with repeat sonography, computed tomography, or diagnostic peritoneal lavage. RESULTS: Among 417 patients with blunt trauma (mean Injury Severity Score = 21) managed with sonography, there were 28 (6.7%) IND and 389 (93.3%) non-IND sonograms. Sonograms were IND because of patient factors in 71% (20 of 28) and because of operator factors in 29% (8 of 28). None of the 28 patients were managed with repeat sonography alone. All 4 diagnostic peritoneal lavage examinations gave negative results, whereas 8 of 23 computed tomographic scans were abnormal (6 of 8 patients underwent laparotomy). The mean time required for diagnostic workup was 117 minutes in the IND group and 48 minutes in the non-IND group (p < 0.001 in both cases). CONCLUSION: This prospective study has demonstrated that IND sonograms are not common at our center (6.7%), are usually attributable to patient factors, and are associated with greater diagnostic time. Patients with IND sonograms require further investigation because they often have injuries requiring laparotomy.

Abdominal Injuries↗
PubMed1997

Neutrophil apoptosis is modulated by endothelial transmigration and adhesion molecule engagement.

Termination of a neutrophil-mediated inflammatory response occurs through the activation of the endogenous cell death program, apoptosis. Neutrophil apoptosis is a constitutive process that can be accelerated or delayed by signals from the microenvironment. Since cellular localization at the site of an inflammatory challenge is the critical first step in a neutrophil response, we investigated the effects of neutrophil transendothelial transmigration on the kinetic expression of apoptosis. Neutrophils isolated from rat lung following challenge with LPS demonstrated a significant delay in spontaneous apoptosis. This delay was a consequence of transmigration, since a comparable delay was seen when TNF-alpha, a potent inducer of apoptosis in vitro, was used as the inflammatory stimulus. Human neutrophils demonstrated comparable delays in apoptosis in vitro following migration across an endothelial monolayer in response to FMLP. Delayed apoptosis only occurred in cells that had first been primed by LPS, a stimulus shown to up-regulate beta2 integrins and down-regulate L-selectin. Finally, crosslinking of CD11a or CD11b, but not of CD18, with mAbs and F(ab')2 fragments produced a delay in spontaneous apoptosis, whereas crosslinking of L-selectin with mAb or its natural ligand, sulfatides, accelerated the apoptotic process. Cells in which apoptosis was inhibited demonstrated persistent functional respiratory burst activity. These observations establish a role for endothelial transmigration in the regulation of neutrophil apoptosis, and suggest that adhesion molecules serve a modulatory role in the expression of neutrophil programmed cell death.

Animals↗
PubMed1997

Glutathione depletion prevents lipopolysaccharide-induced local skin inflammation.

BACKGROUND: We have previously shown that the thiol-oxidizing agent diethyl maleate prevents lipopolysaccharide (LPS)-induced up-regulation of endothelial cell intercellular adhesion molecule-1 (ICAM-1) in vitro. OBJECTIVE: To determine the effect of glutathione depletion on the development of local skin inflammation in vivo, a model known to be dependent on ICAM-1. DESIGN: Swiss Webster mice were injected with intradermal LPS (30 micrograms) or isotonic saline solution. INTERVENTION: Mice were pretreated for 1 hour with intraperitoneal diethyl maleate (6 mmol/kg) or corn oil vehicle. MAIN OUTCOME MEASURES: Injection sites were harvested after 12 and 24 hours and evaluated for changes in vascular permeability and histological characteristics. To determine the mechanism underlying our findings, we evaluated skin ICAM-1 immunohistochemistry, levels of ICAM-1 protein and messenger RNA (mRNA), and neutrophil CD11b expression at the 24-hour point. RESULTS: Diethyl maleate significantly decreased the skin permeability index in a dose-dependent fashion at 24 hours but not at 12 hours. Skin histological examination under light microscopy showed a marked LPS-induced neutrophil infiltration at 24 hours, which was inhibited with diethyl maleate pretreatment. Immunohistochemical examination showed that diethyl maleate reduced ICAM-1 expression. In keeping with the hypothesized mechanism, diethyl maleate attenuated the LPS-induced up-regulation of ICAM-1 mRNA by 44%. Diethyl maleate also slightly but insignificantly reduced CD11b expression in vivo. CONCLUSIONS: Diethyl maleate markedly attenuates LPS-induced dermal inflammation, primarily through a reduction in ICAM-1 protein and mRNA expression. These data suggest that manipulation of the intracellular redox state may have a beneficial role in neutrophil-mediated inflammation.

Animals↗