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Biomedical subjects

E E Moore

Publications and source records attributed to E E Moore.

At least 55 records · Page 3Linked to original sources
PubMed2000

The devastating potential of blunt vertebral arterial injuries.

OBJECTIVE: To formulate management guidelines for blunt vertebral arterial injury (BVI). SUMMARY BACKGROUND DATA: Compared with carotid arterial injuries, BVIs have been considered innocuous. Although screening for BVI has been advocated, particularly in patients with cervical spine injuries, the appropriate therapy of lesions is controversial. METHODS: In 1996 an aggressive arteriographic screening protocol for blunt cerebrovascular injuries was initiated. A prospective database of all screened patients has been maintained. Analysis of injury mechanisms and patterns, BVI grades, treatment, and outcomes was performed. RESULTS: Thirty-eight patients (0.53% of blunt trauma admissions) were diagnosed with 47 BVIs during a 3.5-year period. Motor vehicle crash was the most common mechanism, and associated injuries were common. Cervical spine injuries were present in 71% of patients, but there was no predilection for cervical vertebral level or fracture pattern. The incidence of posterior circulation stroke was 24%, and the BVI-attributable death rate was 8%. Stroke incidence and neurologic outcome were independent of BVI injury grade. In patients treated with systemic heparin, fewer overall had a poor neurologic outcome, and fewer had a poor outcome after stroke. Trends associated with heparin therapy included fewer injuries progressing to a higher injury grade, fewer patients in whom stroke developed, and fewer patients deteriorating neurologically from diagnosis to discharge. CONCLUSIONS: Blunt vertebral arterial injuries are more common than previously reported. Screening patients based on injury mechanisms and patterns will diagnose asymptomatic injuries, allowing the institution of therapy before stroke. Systemic anticoagulation appears to be effective therapy: it is associated with improved neurologic outcome in patients with and without stroke, and it appears to prevent progression to a higher injury grade, stroke, and deterioration in neurologic status.

Adult↗
PubMed2000

Single-layer continuous versus two-layer interrupted intestinal anastomosis: a prospective randomized trial.

OBJECTIVE: To determine the suitability of a single-layer continuous technique for intestinal anastomosis in a surgical training program. SUMMARY BACKGROUND DATA: Several recent reports have advocated the use of a continuous single-layer technique for intestinal anastomosis. Purported advantages include shorter time for construction, lower cost, and perhaps a lower rate of anastomotic leakage. The authors hypothesized that the single-layer continuous anastomosis could be safely introduced into a surgical training program and that it could be performed in less time and at a lower cost than the two-layer interrupted anastomosis. METHODS: The study was conducted during a 3-year period ending September 1999. All adult patients requiring intestinal anastomosis were considered eligible. Patients who required anastomosis to the stomach, duodenum, and rectum were excluded. Patients were also excluded if the surgeon did not believe either technique could be used. Patients were randomly assigned to one- or two-layer techniques. Single-layer anastomoses were performed with a continuous 3-0 polypropylene suture. Two-layer anastomoses were constructed using interrupted 3-0 silk Lembert sutures for the outer layer and a continuous 3-0 polyglycolic acid suture for the inner layer. The time for anastomosis began with the placement of the first stitch and ended when the last stitch was cut. Anastomotic leak was defined as radiographic demonstration of a fistula or nonabsorbable material draining from a wound after oral administration, or visible disruption of the suture line during reexploration. RESULTS: Sixty-five single-layer and 67 two-layer anastomoses were performed. The groups were evenly matched according to age, sex, diagnosis, and location of the anastomosis. Two leaks (3.1%) occurred in the single-layer group and one (1.5%) in the two-layer group. Two abscesses (3.0%) occurred in each group. A mean of 20.8 minutes was required to construct a single-layer anastomosis versus 30.7 minutes for the two-layer technique. Mean length of stay was 7.9 days for single-layer patients and 9.9 days for two-layer patients; this difference did not quite reach statistical significance. Cost of materials was $4.61 for the single-layer technique and $35.38 for the two-layer method. CONCLUSIONS: A single-layer continuous anastomosis can be constructed in significantly less time and with a similar rate of complications compared with the two-layer technique. It also costs less than any other method and can be incorporated into a surgical training program without a significant increase in complications.

Anastomosis, Surgical↗
PubMed2000

Hypertonic saline resuscitation abrogates neutrophil priming by mesenteric lymph.

OBJECTIVE: Neutrophil (PMN) priming after hemorrhagic shock is predictive of the subsequent development of multiple organ failure, but the mechanism remains unknown. Recently, we and others have demonstrated that mesenteric lymph from shock animals resuscitated with lactated Ringer's solution (LR) is not only a potent PMN priming agent but also causes lung injury. Work by others has shown that resuscitation with hypertonic saline (HTS) protects animals from lung injury after hemorrhagic shock. Therefore, we hypothesize that resuscitation with HTS will abolish PMN priming by postshock mesenteric lymph. METHODS: After mesenteric lymph duct catheterization, male rats underwent hemorrhagic shock (mean arterial pressure of 40 mm Hg for 90 minutes) and resuscitation with shed blood plus either LR (2x volume of shed blood) or 4 mL/kg of 7% HTS (isonatremic). Priming for superoxide by PMN was measured after fMLP (1 microM) activation. RESULTS: Shock significantly decreased mesenteric lymph flow from preshock levels in both groups. LR resuscitation produced significantly more mesenteric lymph than HTS resuscitation. Mesenteric lymph from LR animals primed PMN for superoxide production, whereas, HTS eliminated this priming. CONCLUSION: HTS not only decreases postshock mesenteric lymph production, it eliminates PMN priming by mesenteric lymph, suggesting a mechanism for the beneficial effects of HTS resuscitation.

Animals↗
PubMed2000

Complications of prone ventilation in patients with multisystem trauma with fulminant acute respiratory distress syndrome.

INTRODUCTION: Prone ventilation improves oxygenation in selected patients with acute respiratory distress syndrome (ARDS). However, prone positioning of critically ill patients with multiple invasive lines and tubes is potentially dangerous. Trauma patients, in particular, may require special consideration because of skeletal fixation devices or prior operative procedures. Our objective was to critically evaluate our experience with prone positioning in patients with severe postinjury ARDS. METHODS: Injured patients admitted to our Level I trauma center who developed ARDS were prospectively identified. Serial lung injury severity and pulmonary mechanical data, as well as complications of prone ventilation were recorded. RESULTS: During the 12-month period ending August of 1998, nine patients with postinjury ARDS were treated with prone ventilation because of hypoxemia refractory to other ventilatory strategies. All patients suffered blunt trauma. Their mean age was 29 +/- 4.5 years; seven patients were men. The average Injury Severity Score was 26 +/- 5; and, at the time of prone positioning, the mean Lung Injury Score was 3.5. The mean PaO2/FIO2 ratio increased from 75 +/- 7 to 147 +/- 27 with prone ventilation (p < 0.05, paired t test); and in six patients, the FIO2 could be decreased. Four major complications occurred (44%). One patient experienced a midline abdominal wound dehiscence. Severe facial or upper chest wall pressure necrosis developed in two patients, despite extensive padding and careful attention to skin care. The fourth patient sustained a cardiac arrest immediately after prone positioning. CONCLUSION: Prone ventilation in postinjury patients with ARDS may improve oxygenation but has the potential for significant complications. Careful consideration is required before prone positioning in this subset of patients.

Adult↗
PubMed2000

Hypertonic saline attenuation of polymorphonuclear neutrophil cytotoxicity: timing is everything.

BACKGROUND: The potential to modulate the inflammatory response has renewed interest in hypertonic saline (HTS) resuscitation of injured patients. However, the effect of the timing of HTS treatment with respect to polymorphonuclear neutrophil (PMN) priming and activation remains unexplored. We hypothesized that HTS attenuation of PMN functions requires HTS exposure before priming and activation. METHODS: Isolated PMN were incubated in HTS (180 mM Na+) before L-alpha-phosphatidylcholine, beta-acetyl-gamma-O-alkyl (PAF)/N-formylmethionyl-leucyl-phenylalanine (fMLP) priming/activation, after priming, or after priming/activation. Superoxide production was measured by the reduction cytochrome c, elastase release by cleavage of AAPV-pNA, and beta2-integrin expression by flow cytometry. RESULTS: HTS before priming or activation decreased beta2-integrin expression, superoxide production, and elastase release. In contrast, HTS after priming/activation augmented superoxide production and elastase release. CONCLUSION: The timing of HTS is a key variable in the attenuation of PMN cytotoxic functions. Maximal attenuation of cytotoxicity is achieved before priming, whereas HTS exposure after activation augments cytotoxicity.

CD18 Antigens↗
PubMed2000

Treatment of posttraumatic internal carotid arterial pseudoaneurysms with endovascular stents.

BACKGROUND: The sequelae of blunt injury to the carotid arteries are unusual, but pseudoaneurysms causing subsequent strokes are devastating. The utility of treatment of these pseudoaneurysms was examined. METHODS: All patients at a Level I trauma center with previously documented traumatic risk factors were assessed for blunt injury to the carotid arteries and, when a pseudoaneurysm was present, a self-expanding metallic stent was placed across the lesion and the patient placed on anticoagulation. Follow-up arteriograms were obtained in 2 months and every 6 months thereafter. RESULTS: Fourteen patients (7 men, 7 women) with an average age of 27 years, an Injury Severity Score of 38, had formed pseudoaneurysms in 16 extracranial internal carotid arteries. These were stented with metallic endoprostheses. No strokes occurred after the placement of the stents. Mean follow-up period has been 2.5 years. CONCLUSIONS: Use of metallic endoprostheses is an effective method to treat this potentially devastating injury. However, longer follow-up and more patients studied are needed to further examine this promising treatment.

Adolescent↗
PubMed2000

NISS predicts postinjury multiple organ failure better than the ISS.

BACKGROUND: The Injury Severity Score (ISS) has been observed consistently to be a robust predictor of postinjury multiple organ failure (MOF). However, the ISS fails to account for multiple injuries to the same body region. Recently, the "new" ISS (NISS) has been proposed to address this shortcoming. Preliminary studies suggest the NISS is superior to the ISS in predicting trauma mortality. Our purpose was to determine whether the NISS is a better predictor of postinjury MOF than the ISS. METHODS: A total of 558 patients admitted to our Level I trauma center with ISS > 15, age > 15 years, and survival > 48 hours were prospectively identified; 101 (18%) developed postinjury MOF. Data characterizing postinjury MOF were collected, and the NISS was calculated retrospectively. The ISS and NISS were compared as univariate predictors of MOF. Multivariate analysis was used to determine whether substitution of NISS for ISS resulted in a superior predictive model. RESULTS: In 295 patients (53%), the NISS was greater than the ISS. This subgroup of patients experienced a greater frequency of MOF (26.7% vs. 8.3%, p < 0.0001), a higher mortality (12.8% vs. 4.9%, p < 0.001), and a higher early transfusion requirement (6.7 U vs. 3.6 U, p < 0.0001) compared with the group in which NISS equaled ISS. Moreover, the NISS yielded better separation between patients with and without MOF reflected by the greater difference in median NISS scores compared with ISS scores. The multivariate predictive model, including NISS, showed a better goodness of fit compared with the same model that included ISS. CONCLUSIONS: The NISS is superior to the ISS in the prediction of postinjury MOF. This measure of tissue injury severity should replace the ISS in trauma research.

Adult↗
PubMed2000

Thoracic aortic injury: how predictive is mechanism and is chest computed tomography a reliable screening tool? A prospective study of 1,561 patients.

BACKGROUND: Thoracic aortic injury (TAI) is a devastating condition in which prompt recognition can obviate morbidity and mortality. It is a long-held belief that TAI is more likely when there is a "major mechanism of injury." The purposes of this prospective study were to determine mechanism characteristics that are predictive of TAI and to evaluate chest computed tomography (CT) as a screening tool for TAI. METHODS: Over a 5 1/2 year period, blunt chest trauma patients at two Level I trauma centers were evaluated for potential TAI. Patients were assigned mechanism and radiograph scores from 1 (low suspicion for TAI) to 5 (very high suspicion for TAI). Immediate aortography was obtained when suspicion for TAI was very high. The remaining patients were evaluated with contrast-enhanced chest CT. Confirmatory aortography was obtained on all positive chest CT scans and on all patients with mechanism scores of 4 or 5 even if the CT was negative. Mechanism and radiographic data were correlated with the results of aortic imaging. RESULTS: Of the 1,561 patients evaluated for TAI, 30 aortic injuries were found. The assessment of mechanism was imperfect with a reliance on often incomplete and subjective data. The subjective mechanism score proved to be the most useful predictor of TAI. Radiographic scores were useful but insensitive for intimal injuries. Computed tomography was found to have 100% and 100% NPV for TAI. CONCLUSION: Considering the inherent difficulties in identifying patients at risk for TAI and the effectiveness of chest CT as a screening tool for aortic injury, we recommend liberal use of chest CT in blunt chest trauma. Guidelines for determining the need for aortic imaging are outlined.

Accidental Falls↗
PubMed2000

Operative management of injured children at an adult level I trauma center.

BACKGROUND: The geographic distribution of trauma centers results in a significant number of children being treated in adult centers. The emphasis on nonoperative management of pediatric blunt trauma has heightened concern that in adult trauma centers, an aggressive operative approach will continue to be used. We hypothesized that pediatric commitment at a Level I trauma center results in appropriate nonoperative care of injured children as established by regional pediatric trauma centers. METHODS: The records of 1,792 consecutively treated children admitted to the trauma service during a 6-year period (January of 1990 to December of 1995) were reviewed. Patients were stratified into one of three age groups: 0 to 5, 6 to 11, and 12 to 17 years of age. RESULTS: Mean age of the study patients was 10.0 +/- 0.1 years, 1,147 were boys (64%), and their mean Injury Severity Score was 7.3 +/- 0.3. The injury mechanism was blunt in 1,550 (87%) and 132 (7%) required laparotomy. In the 0- to 5-year-old blunt mechanism group, 6% underwent laparotomy or thoracotomy from 1990 to 1992. In comparison, only 1% of this age group had a laparotomy from 1993 to 1995 (p < 0.05, Fisher's exact test). A similar trend was found in the 6- to 11-year-old children after blunt injury (4% laparotomy rate from 1990 to 1992; 2% from 1993-1995). CONCLUSION: There has been a declining trend in the operative management of blunt pediatric trauma, especially in children less than 6 years old, whereas the operative management of penetrating injuries has remained stable. These data confirm that pediatric commitment in a Level I trauma center results in nonoperative treatment of injured children commensurate with that established in regional pediatric trauma centers.

Adolescent↗
PubMed2000

Stored red blood cells selectively activate human neutrophils to release IL-8 and secretory PLA2.

Packed red blood cell (PRBC) transfusion has been invoked previously with immunosuppression and increased infections, but it has now been demonstrated that stored PRBCs (>14 days) can prime PMNs and provoke multiple organ failure. Recently, the role of PMNs in the genesis of MOF has been extended to their release of inflammatory cytokines, notably IL-1, IL-8, TNFalpha, and secretory phospholipase A2 (sPLA2). We hypothesize that stored PRBCs can act as a second event via stimulating the release of inflammatory cytokines from PMNs. Isolated human PMNs were incubated for 24 h in RPMI with either 20% fresh plasma or plasma from 42 day old PRBC (day of outdate) and release of IL-8, IL-1beta, TNFalpha, and sPLA2 were measured. Plasma from stored PRBCs contained small amounts of IL-8, sPLA2, and TNFalpha (102.1 +/-5.6 pg/ml, 87.6+/-6.0 pg/ml and 9.7+/-.7 pg/ml). Levels of IL-1beta were below detection (<1 pg/ml). Day 42 PRBC plasma stimulated significant PMN release of both IL-8 and sPLA2 as compared to both control and day 0 plasma (*P < .05), but PRBC plasma did not stimulate PMN release of either IL-1beta or TNFalpha. Transfused blood is emerging as an inflammatory agent that is capable of producing PMN priming. In this study we have demonstrated that PRBC plasma selectively activates PMNs to release both IL-8 and sPLA2. Thus, transfusion of PRBCs may represent a preventable inflammatory insult via modification of both blood banking and transfusion practices.

Blood Preservation↗
PubMed2000

NF-kappaB regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome.

Activation of the nuclear regulatory factor NF-kappaB occurs in the lungs of patients with the acute respiratory distress syndrome (ARDS) and may contribute to the increased expression of immunoregulatory cytokines and other proinflammatory mediators in this setting. Because of the important role that NF-kappaB activation appears to play in the development of acute lung injury, we examined cytoplasmic and nuclear NF-kapppaB counterregulatory mechanisms, involving IkappaB proteins, in alveolar macrophages obtained from 7 control patients without lung injury and 11 patients with established ARDS. Cytoplasmic levels of the NF-kappaB subunits p50, p65, and c-Rel were significantly decreased in alveolar macrophages from patients with ARDS, consistent with enhanced migration of liberated NF-kappaB dimers from the cytoplasm to the nucleus. Cytoplasmic and nuclear levels of IkappaBalpha were not significantly altered in alveolar macrophages from patients with established ARDS, compared with controls. In contrast, nuclear levels of Bcl-3 were significantly decreased in patients with ARDS compared with controls (P = 0.02). No IkappaBgamma, IkappaBbeta, or p105 proteins were detected in the cytoplasm of alveolar macrophages from control patients or patients with ARDS. The presence of activated NF-kappaB in alveolar macrophages from patients with established ARDS implies the presence of an ongoing stimulus for NF-kappaB activation. In this setting, appropriate counterregulatory mechanisms to normalize nuclear levels of NF-kappaB and to suppress NF-kappaB-mediated transcription, such as increased cytoplasmic and nuclear IkappaBalpha levels or decreased Bcl-3 levels, appeared to be induced. Nevertheless, even though counterregulatory mechanisms to NF-kappaB activation are activated in lung macrophages of patients with ARDS, NF-kappaB remains activated. These results suggest that fundamental abnormalities in transcriptional mechanisms involving NF-kappaB and important in the inflammatory response occur in the lungs of patients with ARDS.

B-Cell Lymphoma 3 Protein↗
PubMed2000

Hypertonic saline inhibits neutrophil (PMN) priming via attenuation of p38 MAPK signaling.

Priming of the neutrophil cytotoxic response is central to the pathogenesis of early postinjury multiple organ failure (MOF). Platelet-activating factor (PAF) has been implicated as a key inflammatory mediator in postinjury neutrophil priming and requires p38 MAPK signaling to produce its biologic effects. Hypertonic saline (HTS) resuscitation decreases the postinjury inflammatory response following shock in animals and decreases receptor-mediated neutrophil (PMN) cytotoxic functions in vitro. We hypothesized that HTS attenuates PAF priming of the PMN cytotoxic response by interfering with PAF-mediated p38 MAPK signal transduction. Isolated PMNs were preincubated in isotonic buffer or HTS (Na+ = 180 mM), then primed with PAF. Neutrophil CD11b/CD18 expression was measured by flow cytometry. Receptor-dependent (fMLP), N-formyl-methionyl-leucyl-phenylalanine, fMLP) and receptor-independent (PMA) O2- production was measured by reduction of cytochrome c in resting and PAF primed PMNs. Total p38 MAPK protein PAF-mediated p38 MAPK activation was assessed by western blot of PMN lysates. Clinically relevant levels of HTS attenuated PAF-mediated beta2-integrin expression. While HTS attenuated receptor-dependent (fMLP and PAF/fMLP) O2- production, receptor-independent (PMA) O2- production was unaffected. Conversely, HTS attenuated PAF priming of PMA-mediated O2- production. PAF and HTS did not alter total cellular p38 MAPK content. Clinically relevant levels of HTS alone did not activate p38 MAPK but inhibited PAF mediated p38 MAPK activation. HTS attenuates PAF priming of the PMN cytotoxic response by altering intracellular signal transduction. Therefore, HTS resuscitation may attenuate postinjury PMN priming and ultimately the risk of developing MOF.

CD18 Antigens↗
PubMed2000

The lipid fraction of post-hemorrhagic shock mesenteric lymph (PHSML) inhibits neutrophil apoptosis and enhances cytotoxic potential.

Dysfunctional neutrophil (PMN) apoptosis facilitates hyperinflammatory tissue injury. Previous work has demonstrated that post-hemorrhagic shock mesenteric lymph (PHSML) provokes PMN-mediated acute lung injury in animal models, but the mechanism remains unclear. We have documented that the lipid fraction of PHSML is responsible for PMN priming of the respiratory burst. In this study, we hypothesized that PHSML lipids delay PMN apoptosis and thereby further enhance PMN cytotoxic potential. Mesenteric lymph was collected from rats (n = 5) before (control), during non-lethal hemorrhagic shock (MAP 40 mmHg, 30 min), and during resuscitation (shed blood + 2x crystalloid). Human PMNs were incubated with control, PHSML, PHSML lipid extracts, and heat-treated PHSML (60 degrees C, 30 min.) at 1-10% (v:v) in RPMI 1640 for 24 h. Apoptosis was assessed using acridine orange/ethidium bromide staining and fluorescence microscopy. Priming of the respiratory burst was evaluated by incubating PMNs with (a) control PHSML or (b) PHSML lipid extracts for 24 h and by activating with fMLP (1 micromol/L). PHSML and PHSML lipid extracts (5-10%) inhibited PMN apoptosis. Heat denaturing the PHSML (to eliminate cytokines and complement) had no effect on the inhibition of PMN apoptosis. Similarly, incubation with polymixin B at a concentration that binds endotoxin had no effect. Both the PHSML and PHSML lipids (5%) following 24-h incubation primed the fMLP-activated oxidase. At physiologic concentrations, both PHSML and the lipid fraction of PHSML delay PMN apoptosis and prime the NADPH oxidase. These data further implicate the lipid components of mesenteric lymph as central in the pathogenesis of hemorrhagic shock induced PMN-mediated acute lung injury.

Animals↗
PubMed2000

An objective analysis of process errors in trauma resuscitations.

OBJECTIVE: A computer-based system to apply trauma resuscitation protocols to patients with penetrating thoracoabdominal trauma was previously validated for 97 consecutive patients at a Level 1 trauma center by a panel of the trauma attendings and further refined by a panel of national trauma experts. The purpose of this article is to describe how this system is now used to objectively critique the actual care given to those patients for process errors in reasoning, independent of outcome. METHODS: A chronological narrative of the care of each patient was presented to the computer program. The actual care was compared with the validated computer protocols at each decision point and differences were classified by a predetermined scoring system from 0 to 100, based on the potential impact on outcome, as critical/noncritical/no errors of commission, omission, or procedure selection. RESULTS: Errors in reasoning occurred in 100% of the 97 cases studied, averaging 11.9/case. Errors of omission were more prevalent than errors of commission (2. 4 errors/case vs 1.2) and were of greater severity (19.4/error vs 5. 1). The largest number of errors involved the failure to record, and perhaps observe, beside information relevant to the reasoning process, an average of 7.4 missing items/patient. Only 2 of the 10 adverse outcomes were judged to be potentially related to errors of reasoning. CONCLUSIONS: Process errors in reasoning were ubiquitous, occurring in every case, although they were infrequently judged to be potentially related to an adverse outcome. Errors of omission were assessed to be more severe. The most common error was failure to consider, or document, available relevant information in the selection of appropriate care.

Abdominal Injuries↗
PubMed1999

Posthemorrhagic shock mesenteric lymph primes circulating neutrophils and provokes lung injury.

Mesenteric lymph has recently been invoked as an avenue for gut-derived factors that may result in distant organ injury following hemorrhagic shock. We demonstrate that posthemorrhagic shock mesenteric lymph primes neutrophils (PMNs) and causes lung injury. Methods. Mesenteric lymph was collected from Sprague-Dawley rats from their mesenteric lymph duct prior to, during, and following hemorrhagic shock (MAP 40 for 90 min). The rats were then resuscitated with shed blood plus lactated Ringers (2X shed blood) over 3 h. Lung leak was assessed by transudation of Evan's blue dye into the alveolus as measured by bronchoalveolar lavage. Isolated human PMNs were incubated with 1 and 10% lymph; priming was measured by the fMLP (1 microM)-stimulated production of superoxide and surface expression of CD11b determined by flow cytometry. Results. Mesenteric lymph flow increased significantly during resuscitation: preshock 144.4 microl/h, shock 44.5 microl/h, resuscitation 566.6 microl/h. Furthermore, diversion of this lymph abrogated lung injury as compared to rats without lymph diversion. Finally, mesenteric lymph from postshock animals primed PMNs for superoxide production (nearly three times control cells) as well as increased surface expression of CD11b (2-fold over control). Conclusion. Mesenteric lymph primes PMNs and causes lung injury following hemorrhagic shock. Mesenteric lymph provides a conduit for proinflammatory mediators that may participate in the pathogenesis of MOF.

Animals↗
PubMed1999

Extracellular signal-related kinase 1/2 and p38 mitogen-activated protein kinase pathways serve opposite roles in neutrophil cytotoxicity.

BACKGROUND: Inflammatory stimuli rapidly activate mitogen-activated protein kinases (MAPKs) in neutrophils (PMNs). However, their role in cytotoxic function remains unknown. Elucidating the signals involved in release of cytotoxic agents from PMNs may provide new avenues for therapy in diseases of diminished or excessive PMN function. HYPOTHESIS: The p38 MAPK and extracellular signal-related kinase 1/2 (ERK1/2) modulate superoxide generation and elastase release in activated human PMNs. STUDY DESIGN: Isolated human PMNs were incubated with specific inhibitors of MAPK pathways, or vehicle control solution, before activation with the bacterial peptide f-Met-Leu-Phe. MAIN OUTCOME MEASURES: The rate of superoxide release from activated PMNs was measured by the superoxide dismutase-inhibitable reduction of cytochrome-c. Elastase release from PMNs was determined by cleavage of the substrate Ala-Ala-Pro-Val-pNA. RESULTS: Superoxide release from activated PMNs was inhibited by blockade of p38 MAPK activation but unaffected by blockade of ERK1/2. Conversely, elastase release was unaffected by p38 MAPK inhibition and increased by ERK1/2 inhibition. CONCLUSIONS: Activation of p38 MAPK promotes superoxide release from PMNs activated by f-Met-Leu-Phe. The ERK1/2 pathway may serve as a negative feedback mechanism for granule exocytosis.

Cytotoxicity, Immunologic↗