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      Functional α4-integrin: A newly identified pathway of neutrophil recruitment in critically ill septic patients

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          Abstract

          Using a novel flow chamber assay system and whole blood, we show that leukocytes from septic individuals have a four-fold elevation of adhesion, but not rolling, on a P-selectin/beta2-integrin substrate. Most leukocytes from septic patients (but not healthy controls) that bound vascular cell adhesion molecule 1 (VCAM-1) were neutrophils. All adhesion was inhibited with an antibody specific for the VCAM-1 ligand alpha4-integrin. The alpha4-integrin was present on neutrophils from septic patients but not on neutrophils from patients with localized bacterial infections. The plasma milieu of septic patients was sufficient to induce neutrophils from healthy subjects to bind VCAM-1 under flow conditions. This is the first description of alpha4-integrin/VCAM-1 pathway of neutrophil recruitment in human disease. This pathway may provide a new therapeutic target to reduce inappropriate neutrophil adhesion without altering the normal yet critical beta2-integrin-mediated adhesive function of neutrophils.

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          Most cited references33

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          American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference

          (1992)
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            Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm.

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              Incidence of and risk factors for ventilator-associated pneumonia in critically ill patients.

              Understanding the risk factors for ventilator-associated pneumonia can help to assess prognosis and devise and test preventive strategies. To examine the baseline and time-dependent risk factors for ventilator-associated pneumonia and to determine the conditional probability and cumulative risk over the duration of stay in the intensive care unit. Prospective cohort study. 16 intensive care units in Canada. 1014 mechanically ventilated patients. Demographic and time-dependent variables reflecting illness severity, ventilation, nutrition, and drug exposure. Pneumonia was classified by using five methods: adjudication committee, bedside clinician's diagnosis, Centers for Disease Control and Prevention definition, Clinical Pulmonary Infection score, and positive culture from bronchoalveolar lavage or protected specimen brush. 177 of 1014 patients (17.5%) developed ventilator-associated pneumonia 9.0 +/- 5.9 days (median, 7 days [interquartile range, 5 to 10 days]) after admission to the intensive care unit. Although the cumulative risk increased over time, the daily hazard rate decreased after day 5 (3.3% at day 5, 2.3% at day 10, and 1.3% at day 15). Independent predictors of ventilator-associated pneumonia in multivariable analysis were a primary admitting diagnosis of burns (risk ratio, 5.09 [95% CI, 1.52 to 17.03]), trauma (risk ratio, 5.00 [CI, 1.91 to 13.11]), central nervous system disease (risk ratio, 3.40 [CI, 1.31 to 8.81]), respiratory disease (risk ratio, 2.79 [CI, 1.04 to 7.51]), cardiac disease (risk ratio, 2.72 [CI, 1.05 to 7.01]), mechanical ventilation in the previous 24 hours (risk ratio, 2.28 [CI, 1.11 to 4.68]), witnessed aspiration (risk ratio, 3.25 [CI, 1.62 to 6.50]), and paralytic agents (risk ratio, 1.57 [CI, 1.03 to 2.39]). Exposure to antibiotics conferred protection (risk ratio, 0.37 [CI, 0.27 to 0.51]). Independent risk factors were the same regardless of the pneumonia definition used. The daily risk for pneumonia decreases with increasing duration of stay in the intensive care unit. Witnessed aspiration and exposure to paralytic agents are potentially modifiable independent risk factors. Exposure to antibiotics was associated with low rates of early ventilator-associated pneumonia, but this effect attenuates over time.
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                Author and article information

                Journal
                Nature Medicine
                Nat Med
                Springer Science and Business Media LLC
                1078-8956
                1546-170X
                April 2001
                April 2001
                : 7
                : 4
                : 465-470
                Article
                10.1038/86539
                11283674
                66c6b03f-66f8-452a-8aa3-188859c30c23
                © 2001

                Free to read

                http://www.springer.com/tdm

                http://www.springer.com/tdm

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