Biomedical subjects

Saman Arbabi

Publications and source records attributed to Saman Arbabi.

At least 19 recordsLinked to original sources

PubMed2005

Lipopolysaccharide-binding protein modulates acetaminophen-induced liver injury in mice.

Acetaminophen toxicity is the most common cause of acute liver failure in the United States and Europe. Although much is known about the metabolism of acetaminophen, many questions remain regarding the pathogenesis of liver injury. In this study, we examined the role of lipopolysaccharide-binding protein (LBP), a protein important in mediating cellular response to lipopolysaccharides, by using LBP wild-type and knockout (KO) mice. We found that LBP KO mice were protected from acetaminophen-induced hepatotoxicity. At 350 mg/kg of acetaminophen, LBP KO mice had significantly less liver injury and necrosis than wild-type mice. Repletion studies in LBP KO mice using an LBP-adenoviral construct resulted in significantly more hepatic injury and necrosis after acetaminophen exposure compared with mice receiving the control adenoviral construct. In conclusion, LBP KO mice are protected from toxicity with a decrease in hepatic necrosis following acetaminophen challenge. This suggests a novel role for LBP in modulating acetaminophen-induced liver injury. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/O270-9139/suppmat/index.html).

Acetaminophen↗

PubMed2005

Improved survival in mice given systemic gene therapy in a gram negative pneumonia model.

BACKGROUND: We previously demonstrated an essential role for lipopolysaccharide binding protein (LBP) in the pulmonary immune response to Gram-negative bacterial infection. LBP knockout mice had significantly higher mortality, greater rates of bacteremia, and higher counts of viable bacteria in their lungs at sacrifice compared with wild-type controls. We postulate that systemic LBP gene therapy will reconstitute a protective innate immune response in LBP knockout mice and that overexpression of LBP in wild-type mice may offer a survival advantage. METHODS: 12-16 week old female C57BL/6 wild-type mice and age matched LBP knockout mice were given 5 x 10(9) PFU of recombinant adenovirus containing either the gene for LBP or the irrelevant control protein beta-galactosidase by tail vein injection. 72 hours later each mouse was administered 1 x 10(3) CFU of Klebsiella pneumoniae by intratracheal injection. RESULTS: Administration of LBP by systemic gene therapy to LBP knockout mice improved survival from Klebsiella pneumonia to a level equivalent or better than wild-type mice exposed to the same dose of bacteria (36 versus 25%). Wild-type mice given the LBP gene therapy demonstrated increased 7 day survival from Klebsiella pneumonia when compared with controls treated with beta-galactosidase (68 versus 30%, p = 0.03). CONCLUSIONS: Systemic gene therapy with intravenous adenoviral vector transfer of LBP significantly improves survival in LBP knockout mice. Overexpression of LBP in wild-type mice improves survival from Klebsiella pneumonia. Raising levels of LBP in the setting of Gram-negative pneumonia may be of therapeutic benefit.

Acute-Phase Proteins↗

PubMed2004

Blunt splenic injury: operation versus angiographic embolization.

BACKGROUND: Splenic injuries, like other blunt traumatic injuries, are increasingly treated with non-operative management. Angiographic embolization (AE) has emerged as an alternative modality for treatment of splenic injuries. We hypothesized that splenic embolization would lead to equivalent, if not improved, outcomes in terms of mortality, total costs, complications, and duration of stay. METHODS: A retrospective review of a prospective data set was performed for all adult splenic injuries admitted to our level I trauma center from 2000 through 2003. Demographics, number of red cell units, emergency department hemodynamics, costs, and outcomes were examined. The operative group included those who underwent computed tomography (CT) first then went to the operating room (OR) (CT+OR) or those who went directly to the OR. RESULTS: There were 25 CT+OR and 24 AE patients of 164 blunt splenic injuries. After univariate analysis, higher injury severity score (ISS), lower systolic blood pressure, lower pH, and higher packed red blood cell transfusions were associated with increased mortality and duration of stay. The splenic Abbreviated Injury Scale (AIS; mean +/- SD) was the same for AE compared to CT+OR patients (3.8 +/- 0.4 vs 3.5 +/- 0.9). Although the AE group was older (50 +/- 20 vs 36 +/- 13 years, P < .01), Glasgow Comma Score (13 +/- 4 vs 11 +/- 5), age, highest heart rate (109 +/- 24 vs 120 +/- 43), and splenic AIS were not predictive of the need for an operation. Abdominal complications were lower in the AE group compared to the CT+OR (13% vs 29%), but mortality was not different (8% vs 4%). Total costs were similar for both groups after adjustment for ISS, GCS, pH, pretreatment transfusions, and spleen AIS (AE, $49,300 +/- $40,460 vs CT+OR, $54,590 +/- $34,760). The non-operative failure rate in this study was 2%. CONCLUSIONS: AE of splenic injuries is safe and associated with fewer complications. The spleen AIS, heart rate, age, and GCS did not correlate with the need for an operation. Higher ISS, lower blood pressure, lower pH, and increased number of packed red blood cell transfusions were better indicators of the need for an operation versus embolization.

Adult↗

PubMed2004

Extracorporeal life support for severe acute respiratory distress syndrome in adults.

OBJECTIVE: Severe acute respiratory distress syndrome (ARDS) is associated with a high level of mortality. Extracorporeal life support (ECLS) during severe ARDS maintains oxygen and carbon dioxide gas exchange while providing an optimal environment for recovery of pulmonary function. Since 1989, we have used a protocol-driven algorithm for treatment of severe ARDS, which includes the use of ECLS when standard therapy fails. The objective of this study was to evaluate our experience with ECLS in adult patients with severe ARDS with respect to mortality and morbidity. METHODS: We reviewed our complete experience with ELCS in adults from January 1, 1989, through December 31, 2003. Severe ARDS was defined as acute onset pulmonary failure, with bilateral infiltrates on chest x-ray, and PaO2/fraction of inspired oxygen (FiO2) ratio < or =100 or A-aDO2 >600 mm Hg despite maximal ventilator settings. The indication for ECLS was acute severe ARDS unresponsive to optimal conventional treatment. The technique of ECLS included veno-venous or veno-arterial vascular access, lung "rest" at low FiO2 and inspiratory pressure, minimal anticoagulation, and optimization of systemic oxygen delivery. RESULTS: During the study period, ECLS was used for 405 adult patients age 17 or older. Of these 405 patients, 255 were placed on ECLS for severe ARDS refractory to all other treatment. Sixty-seven percent were weaned off ECLS, and 52% survived to hospital discharge. Multivariate logistic regression analysis identified the following pre-ELCS variables as significant independent predictors of survival: (1) age (P = 0.01); (2) gender (P = 0.048); (3) pH < or =7.10 (P = 0.01); (4) PaO2/FiO2 ratio (P = 0.03); and (5) days of mechanical ventilation (P < 0.001). None of the patients who survived required permanent mechanical ventilation or supplemental oxygen therapy. CONCLUSION: Extracorporeal life support for severe ARDS in adults is a successful therapeutic option in those patients who do not respond to conventional mechanical ventilator strategies.

Adolescent↗

PubMed2004

Delayed repair for blunt thoracic aortic injury: is it really equivalent to early repair?

BACKGROUND: Blunt thoracic aortic injury (BTAI) is a severe injury that traditionally has mandated immediate surgical repair. Delaying operative intervention for BTAI can allow other life-threatening injuries to be managed first, but potentially increases the risk of aortic rupture and death. The objective of this study was to evaluate the outcome of delayed repair (DR) compared with early repair (ER) for BTAI and to assess the effectiveness of a protocol for medical control of systolic blood pressure and heart rate in those patients whose repairs were delayed. METHODS: This study is a retrospective review of University of Michigan Health System (UMHS) data from January 1, 1992, through March 1, 2003. ER was defined as operative repair within 16 hours from the time of injury. A similar analysis was conducted for patients with BTAI selected from the National Trauma Data Bank. RESULTS: For the UMHS data, there were 45 patients in the DR group and 33 patients in the ER group. Mortality in the ER group versus the DR group was 9% versus 20%. Multivariate analysis adjusting for age, Injury Severity Score, abdominal Abbreviated Injury Scale score, Glasgow Coma Scale score, and intubation status demonstrated an odds ratio for death from ER compared with DR of 1.72 (p = 0.57). Patients undergoing DR had an absolute increase in hospital length of stay (33.1 vs. 20.9 days) and complication rate (2.1 vs. 1.5 incidents per patient). A similar result was obtained for multivariate analysis of the National Trauma Data Bank data, with an odds ratio of 1.40 (p = 0.51) for death from ER versus DR. UMHS patients whose repairs were delayed achieved target systolic blood pressure and heart rate for 76% and 74% of the hourly measurements recorded, respectively. CONCLUSION: Patients with BTAI can safely undergo delayed aortic repair if other injuries warrant a higher treatment priority without increasing their overall risk of mortality. Delayed repair is, however, associated with a higher complication rate.

Adult↗

PubMed2004

Beta-blocker use is associated with improved outcomes in adult burn patients.

BACKGROUND: There is no direct evidence that beta-blockers improve mortality in burn victims. Beta-blockers attenuate hypermetabolic states in burned children, and perioperative use in elective adult cases has beneficial effects, which suggests that beta-blockers may also improve burn outcomes. However, beta-blockers decrease cardiac output and may decrease oxygen delivery, and theoretically may increase mortality. What is the effect of beta-blockers on healing time and mortality in burn patients? METHODS: This was a retrospective cohort study. We identified three cohorts of adult burn patients between 1996 and 2001: all who were on beta-blockers (BB) before their injury (PMH BB); all who were initiated on BB during their hospitalization for management of hypertension or tachyarrhythmia (HOSP BB); and control, who were never treated with beta-blockers. For each patient in the PMH BB and HOSP BB groups, two patients were placed in the control cohort by matching age and total body surface area burn. Premorbid conditions such as diabetes, hypertension, cardiac disease, renal insufficiency, and diuretic and calcium channel blocker use were analyzed. Multivariate regression models were used to identify independent modifiers. RESULTS: There were 21 PMH BB, 22 HOSP BB, and 86 control patients. All PMH BB patients remained on their BB regimen in the hospital. HOSP BB patients were initiated on beta-blockers at a mean of 8.8 days postinjury. There were no differences in age (mean, 58 +/- 17 years), total body surface area burned (mean, 14 +/- 12%), or mechanism of injury among the cohorts. The mortality rate was 5% for the PMH BB cohort, 27% for the HOSP BB cohort, and 13% for controls. The mean healing times were 51 +/- 29 days for PMH BB patients, 79 +/- 54 days for HOSP BB patients, and 60 +/- 39 for controls. In multivariate analyses, PMH BB was associated with a significant decrease in fatal outcome and healing time (p < or = 0.05 compared with control). CONCLUSION: Beta-blockers have the potential to improve adult burn outcomes. Postinjury treatment should be studied in a randomized, clinical trial.

Adrenergic beta-Antagonists↗

PubMed2004

A comparison of prehospital and hospital data in trauma patients.

OBJECTIVE: The use of prehospital data as an indicator for trauma team activation has been established. The relationship between field (Fd) and emergency department (ED) systolic blood pressure (SBP), Glasgow Coma Scale (GCS) score, and airway control as it relates to outcomes is unclear. We hypothesized that ED and Fd physiologic parameters are equally valid predictors of outcomes. In addition, we hypothesized that early field intubation will improve survival compared with later ED intubation. METHODS: Trauma registry data from two academic Level I centers from 1994 to 2001, excluding all transfers and burn patients, were analyzed using Wilcoxon signed-rank test and multivariate logistic regression with appropriate adjustments. RESULTS: There were 19,409 patients, 16,277 blunt and 3,132 penetrating trauma. There were 3,571 Fd and 746 ED intubations. ED intubation was associated with increased risk of fatal outcome compared with nonintubated patient (adjusted odds ratio, 3.1; p < 0.0001) and field intubations (adjusted odds ratio, 3.0; p < 0.0001). ED-GCS score was not significantly different from Fd-GCS score, with 82% having the same GCS category. This was not the case for SBP, and only in 60% of the cases were ED-SBP and Fd-SBP in the same category. In 31% of the patients, the ED-SBP increased, and in 9% of cases, the ED-SBP decreased compared with Fd-SBP. This was true for both blunt and penetrating trauma. Both Fd-SBP and ED-SBP were independent predicators of fatal outcome, and mortality rate significantly increased if ED-SBP category decreased compared with Fd-SBP. CONCLUSION: Early field intubation was associated with a decreased risk of fatal outcome compared with ED intubation. ED-GCS score was not significantly different from Fd-GCS score, and either one can be used to predict fatal outcome. However, ED-SBP was different from Fd-SBP in 40% of the patients, with the majority of cases having higher ED-SBP. Although ED-SBP was a better predictor of outcome, the best model is achieved when both ED and field SBP are used.

Adult↗

PubMed2003

Patient outcomes in academic medical centers: influence of fellowship programs and in-house on-call attending surgeon.

BACKGROUND: There are very few data on characteristics or policies that improve patient outcomes in academic medical institutions. We were interested in 2 such policies or characteristics that are commonly implemented in academic centers: an in-house on-call attending physician policy and the existence of postgraduate medical education. HYPOTHESIS: An in-house attending surgeon on-call policy and the presence of trauma and critical care fellowship programs improve outcomes of critically injured patients. DESIGN: Multicenter cohort study. Two cohorts were analyzed: blunt trauma (n = 601; mortality, 16.0%) and penetrating abdominal trauma (n = 503; mortality, 7.5%). SETTING: Thirty-one academic level I trauma centers, 10 (32.3%) with in-house on-call policy and 11 (35.5%) with fellowship programs. MAIN OUTCOME MEASURES: Mortality, hospital length of stay, and intensive care unit length of stay. RESULTS: In-house on-call surgeon policy had no impact on mortality or length of hospital or intensive care unit stay for either the blunt or penetrating trauma cohort. However, the presence of fellowship programs was associated with a significant decrease in blunt trauma mortality (odds ratio, 0.4; 95% confidence interval [CI], 0.1-0.8) and a decrease in length of intensive care unit stay (mean difference, 4.7 days; 95% CI, 0.6-8.8 days) and hospital stay (mean difference, 3.2 days; 95% CI, 0.6-5.9 days). There were no significant effects of fellowship programs on penetrating trauma outcomes. CONCLUSIONS: An in-house on-call attending surgeon policy is not associated with improved outcomes. In contrast, presence of a trauma and surgical critical care fellowship program, a potential surrogate marker for an institution that is committed to this specialty interest, is associated with improved outcomes for critically injured patients. An investment in advanced postgraduate medical education has potential benefits in patient care and outcomes.

Academic Medical Centers↗

PubMed2003

Normal D-dimer levels do not exclude thrombotic complications in trauma patients.

BACKGROUND: Deep venous thrombosis (DVT) and pulmonary embolism (PE) are common complications in trauma patients. These diagnoses can be difficult and expensive to make. Recent studies report that a negative D-dimer test excludes thrombotic complications. We questioned the predictive value of a D-dimer test to exclude DVT and PE. METHODS: Adult trauma patients admitted March 1999 to March 2001, with an Injury Severity Score > or =9 and expected length of stay >3 days, were approached for enrollment. Bilateral lower extremity duplex ultrasounds and d-dimer levels were performed within 36 hours of admission, day 3-4, day 7, and weekly until discharge. RESULTS: Twenty-three patients were diagnosed with DVTs, with 18 DVTs detected within the first week of admission. Five DVT patients had normal D-dimer levels. One of three PE patients tested had a normal D-dimer level. The false negative rate for DVT by d-dimer assay was 24%, and the sensitivity was 76%. The negative predictive value for D-dimers was 92%. All false negative d-dimer tests occurred in patients diagnosed with DVT or PE within the 4 days after admission. CONCLUSION: In the early postinjury phase, a negative d-dimer test does not exclude DVT or PE. However, the negative predictive value of a D-dimer test after the first 4 days from admission rose to 100%. Patients with clinical signs and symptoms of DVT or PE in the immediate postinjury phase should undergo further screening to exclude thromboembolic complications.

False Negative Reactions↗

PubMed2003

Mitogen-activated protein kinases in the intensive care unit: prognostic potential.

OBJECTIVE: To evaluate the prognostic significance of the activational status of p38, specifically progression to multiple organ dysfunction syndrome (MODS), in a group of severely injured trauma patients. SUMMARY BACKGROUND DATA: To date, therapeutic manipulation of the host immunoinflammatory response has not affected the outcome of patients with MODS. A major concern is the inability to identify the patient most at risk so as to enable early intervention. METHODS: Nineteen trauma patients underwent bronchoalveolar lavage (BAL). Cells obtained were plated, stimulated with lipopolysaccharide (LPS), and then harvested at varying time points after stimulation. p38 was evaluated by Western blot. RESULTS: Nineteen patients were categorized into two groups according to baseline and LPS-stimulated p38 activation in cells obtained by BAL. Group 1 demonstrated a 10-fold increase in p38 activation with LPS treatment over unstimulated controls. Group 2 had high baseline levels of p38 that were unresponsive to subsequent LPS stimulation. Both groups were similar with respect to age, gender, shock (systolic blood pressure < 90), Injury Severity Score, APACHE II, lactate levels, base deficit, blood transfusions, and the cell differential of BAL fluid. However, patients in group 2 had a greater incidence of progression to MODS as defined by the Marshall MOD score, a longer duration of mechanical ventilation, a longer stay in the intensive care unit, and a longer overall hospital stay than group 1. CONCLUSIONS: These results demonstrate the prognostic significance of p38 activation in predicting outcome in critically ill trauma patients. Furthermore, these results demonstrate that trauma populations identical by current scoring systems contain a mixture of patients with markedly different outcomes as identified by p38 activation. Measurement of p38 may enable early identification of a subgroup of patients at increased risk for MODS to permit effective therapeutic intervention.

APACHE↗

PubMed2003

Does bronchoalveolar lavage enhance our ability to treat ventilator-associated pneumonia in a trauma-burn intensive care unit?

BACKGROUND: Recent literature supports the notion that bronchoalveolar lavage (BAL) in ventilated trauma patients may improve our ability to diagnose and treat ventilator-associated pneumonia (VAP). We hypothesized that BAL would decrease the number of cases of VAP diagnosed and impact our antibiotic use and ventilator days. METHODS: Prospective data on all infectious complications were collected for patients admitted to the trauma-burn service for the year 2001. All VAPs between January 1, 2001, through June 30, 2001, were diagnosed without BAL (No BAL group) using clinical signs of fever, sputum production, leukocytosis, chest radiographs, and sputum culture. After July 1, 2001, VAP was diagnosed with the use of BAL. RESULTS: There were 37 cases of VAP in the No BAL group (11%) and 29 cases of VAP (8%) in the BAL group. There were no statistical differences in Injury Severity Score, hospital length of stay, ventilator days, or mortality between the two groups. The time to initial treatment of VAP was shorter for the BAL group, but did not reach significance. The number of patients who had their VAP pathogens correctly treated with empiric antibiotics was also the same between the two groups. There was no difference in the rate of recurrent pneumonias. The antibiotic costs and respiratory therapy/ventilator costs were not statistically different between the groups for trauma patients, although antibiotic costs were higher for burn patients. CONCLUSION: The routine use of BAL to diagnose VAP in our mixed trauma-burn population did not impact on clinical outcomes or antibiotic use. Our results do not justify the additional costs and potential risks of BAL for all patients. The means of VAP diagnosis may not be as important as choosing the appropriate antibiotics for common VAP organisms in any given intensive care unit.

Adult↗

PubMed2003

The cushion effect.

BACKGROUND: The pattern and severity of crash injury depends on a complex interaction of biomechanical factors such as deceleration velocity at impact (delta-V), seat-belt and airbag use, and type of impact. Human body characteristics such as height and weight may play an important role. We hypothesized that body mass index (BMI) will influence crash injury patterns. METHODS: The University of Michigan Program for Injury Research and Education database was queried. Three cohorts were analyzed, lean (BMI </= 25 kg/m2), overweight (BMI 25-30 kg/m2), and obese (BMI > 30 kg/m2) RESULTS: There were 189 detailed crash cases, with 22 fatalities. There was an increased risk of fatal outcome associated with the obese cohort (adjusted odds ratio, 4.2 compared with lean; p = 0.04). Age, delta-V, seat-belt use, and type of impact were independent predictors of Injury Severity Score (ISS). After adjusting for other modifiers, being overweight was associated with decreased ISS (p = 0.03) and abdominal maximal Abbreviated Injury Scale (mAIS) score (p = 0.008) when compared with the lean cohort. However, the lower extremity mAIS score increased when overweight (p = 0.03) and obese cohorts (p = 0.001) were compared with the lean cohort. CONCLUSION: Although no difference in ISS was identified between the lean and obese cohorts, there was an increase in mortality with the obese cohort. The severity of lower extremity injuries increased with increasing BMI. The overweight cohort was associated with lower ISS and abdominal mAIS score compared with the lean cohort. This protection may be attributable to an increase in insulating tissue, or a "cushion effect," without a significant increase in mass and momentum.

Accidents, Traffic↗

PubMed2003

Increased depth of subcutaneous fat is protective against abdominal injuries in motor vehicle collisions.

The objective of this study was to determine the effect of differences in subcutaneous fat depth on adult injury patterns in motor vehicle collisions. Sixty-seven consecutive adult crash subjects aged 19-65 who received computed tomography of their chest, abdomen and pelvis as part of their medical evaluation and who consented to inclusion in the Crash Injury Research Engineering Network (CIREN) study were included. Subcutaneous fat was measured just lateral to the rectus abdominus muscle in a transverse section taken through the subject at the level of L4. Women had significantly greater subcutaneous fat depth than men. Increased subcutaneous fat depth was associated with significantly decreased injury severity to the abdominal region of females. A similar trend was noted in males although it did not reach statistical significance. Our findings suggest that increased subcutaneous fat may be protective against injuries by cushioning the abdominal region against injurious forces in motor vehicle collisions.

Abbreviated Injury Scale↗

PubMed2002

Decreased juvenile arson and firesetting recidivism after implementation of a multidisciplinary prevention program.

OBJECTIVES: In 1999, we developed the multidisciplinary Trauma Burn Outreach Prevention Program (TBOPP), which focuses on the medical and societal consequences of firesetting behavior. The basis for this program development was a 17% increase in pediatric burn admissions. The purpose of this study was to determine the value of this trauma burn center prevention program from a financial, clinical, and recidivism perspective. METHODS: Juveniles (ages 4-17 years) were enrolled into our 1-day program on the basis of referrals from the county court system, fire departments, schools, and parents. The program's interactive content focuses on the medical, financial, legal, and societal impact of firesetting behavior, with emphasis on individual accountability and responsibility. The court system and fire departments tracked all episodes of firesetting behavior within their respective communities. Arson is defined as behavior with the intent to produce damage, whereas firesetting is defined as having no ill intent. The recidivism rate was determined using fire department and court follow-up records. Follow-up was from 8 months to 2.5 years. A random control group that did not receive TBOPP education (noTBOPP group) with identical entry criteria was used for comparison. Institutional review board approval was obtained. RESULTS: There were 132 juveniles in the TBOPP group (66 arsonists and 66 firesetters) and 102 juveniles in the noTBOPP group (33 arsonists and 66 firesetters). Fifty-nine TBOPP participants had a medical history of behavioral disorders. Property damage for arson averaged $4,040, with additional court costs of $1,135 per incident. Family environment was an independent predictor for risk of repeat offense. The odds ratio for risk of repeat offense in foster care was 17.9 (p < 0.05) as compared with two-parent homes. The recidivism rate was 1 of 32 (<1%) for the TBOPP group and 37 of 102 (36%) for the noTBOPP group (adjusted odds ratio, 0.02; p < 0.001). CONCLUSION: When compared with the noTBOPP group, TBOPP participants had essentially no recidivism. The financial impact of arson behavior was over $6,000 per incident. The implementation of a juvenile firesetting prevention program has demonstrable benefits to the participants and to society.

Adolescent↗

PubMed2002

The actin cytoskeleton: an essential component for enhanced TNFalpha production by adherent monocytes.

Monocyte adherence induces the formation of focal adhesions, the interaction sites of intracellular signaling molecules and cytoskeletal proteins such as actin. We previously demonstrated that adherence potentiates human monocyte LPS-induced TNFalpha production. Hence, we hypothesized that the actin cytoskeleton is integral to adherence-induced priming for enhanced LPS-induced TNFalpha production. In contrast to nonadherent cells, LPS induced significant transcription of TNFalpha mRNA and production of TNFalpha in adherent monocytes. Disrupting the actin cytoskeleton with cytochalasin D (CD) in adherent monocytes inhibited LPS-induced TNFalpha production by 55%, thereby abrogating adherence-induced priming. Moreover, CD pretreatment abrogated adherence-induced activation of Pyk2, a major focal adhesion kinase, and ERK 1/2, a component of the mitogen-activated protein kinase (MAPK) signaling pathway, and it completely inhibited LPS-induced ERK 1/2 activation. However, CD treatment of nonadherent monocytes failed to inhibit cytokine production. In conclusion, the actin cytoskeleton is integral in the reprogramming of the monocyte for enhanced cytokine production and in maintaining this "primed" state.

Actins↗

PubMed2002

The macrophage response to endotoxin requires platelet activating factor.

Platelet activating factor (PAF) is a key proinflammatory mediator of septic shock and is metabolized by PAF-acetylhydrolase (PAF-AH). Low circulating levels of PAF-AH have been associated with the development of autodestructive excessive inflammatory responses such as post-injury multiple organ failure, and recombinant PAF-AH is being studied for the prevention of acute respiratory distress syndrome (ARDS). However, the potential role of PAF as an autocrine mediator of macrophage activation is unclear. We wanted to examine the role of PAF in the endotoxin- (LPS) induced macrophage response using PAF-AH. Rabbit alveolar macrophages were stimulated with LPS (10 ng/mL) with or without PAF-AH (0.1-10 microg/mL). Supernatants were collected to measure the production of tumor necrosis factor (TNF), interleukin 8 (Il-8), and prostaglandin E2 (PGE2). Cell monolayers were assessed for procoagulant activity (PCA). TNF mRNA production was determined by Northern blot and RNA stability was assessed. Evaluation of intracellular signaling pathways for LPS included western blots for phosphorylated p38 and ERK kinases and gel shift for nuclear factor-kappaB. There was a dose-response inhibition of TNF, PCA, Il-8, and PGE2 production following pretreatment with PAF-AH. Time course studies revealed effective inhibition of TNF production with administration of PAF-AH up to 2 h after LPS challenge. TNF mRNA production was inhibited, while mRNA stability was not affected. There was no effect on the phosphorylation of p38 or ERK 1 kinases; however, the nuclear translocation of NF-kappaB was inhibited. Macrophage cytokine production in response to endotoxin is PAF dependent. This effect involves the inhibition of TNF gene transcription and concomitant inhibition of NF-kappaB.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2002

Porphyromonas gingivalis lipopolysaccharide is both agonist and antagonist for p38 mitogen-activated protein kinase activation.

Lipopolysaccharide (LPS) is a key inflammatory mediator. It has been proposed to function as an important molecule that alerts the host of potential bacterial infection. Although highly conserved, LPS contains important structural differences among different bacterial species that can significantly alter host responses. For example, LPS obtained from Porphyromonas gingivalis, an etiologic agent for periodontitis, evokes a highly unusual host cell response. Human monocytes respond to this LPS by the secretion of a variety of different inflammatory mediators, while endothelial cells do not. In addition, P. gingivalis LPS inhibits endothelial cell expression of E-selectin and interleukin 8 (IL-8) induced by other bacteria. In this report the ability of P. gingivalis LPS to activate p38 mitogen-activated protein (MAP) kinase was investigated. It was found that p38 MAP kinase activation occurred in response to P. gingivalis LPS in human monocytes. In contrast, no p38 MAP kinase activation was observed in response to P. gingivalis LPS in human endothelial cells or CHO cells transfected with human Toll-like receptor 4 (TLR-4). In addition, P. gingivalis LPS was an effective inhibitor of Escherichia coli-induced p38 MAP kinase phosphorylation in both endothelial cells and CHO cells transfected with human TLR-4. These data demonstrate that P. gingivalis LPS activates the LPS-associated p38 MAP kinase in monocytes and that it can be an antagonist for E. coli LPS activation of p38 MAP kinase in endothelial and CHO cells. These data also suggest that although LPS is generally considered a bacterial component that alerts the host to infection, LPS from P. gingivalis may selectively modify the host response as a means to facilitate colonization.

Animals↗

PubMed2002

Mitogen-activated protein kinases.

The cellular control switches are regulated through an extensive network of interactive intracellular signal transduction pathways, such as the mitogen-activated protein kinase (MAPK) family. The MAPK pathways may play an important role in the inappropriate inflammatory responses that lead to systemic inflammatory response syndrome or multiple organ dysfunction syndrome. Therefore, elucidating the activation status of the MAPK pathways may be a method to identify patients at risk for systemic inflammatory response syndrome/multiple organ dysfunction syndrome. Also, manipulating the proper pathways may improve patients' outcomes. However, the MAPK family is part of a complex interactive network, which may initiate an unpredictable reaction to the indiscriminate inhibition or activation of a single component. A major challenge is to elucidate the principles by which the network is assembled, so a more tissue- and temporal-specific approach can be used.

Critical Care↗