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  • Ward, N.S., Waxman, A.B., Homer, R.J., Einarrson, O., Du, Y.F., and J.A. Elias, IL-6 induced protection in hyperoxic lung injury. American Journal of Respiratory Cell and Molecular Biology.2000. 22(5):535.


    Hyperoxic lung injury is commonly encountered in patients who require treatment with high concentrations of inspired oxygen.To determine whether interleukin (IL)-6 is protective in oxygentoxicity, we compared the effects of 100% O2 in transgenic mice that overexpress IL-6 in the lung and transgene controls.IL-6 markedly enhanced survival, with 100% of transgene animals dying within 72 to 96 h, 100% of transgene (+) animals living for more than 8 d and more than 90% of transgene (+) animals living longer than 12 d. This protection was associated with markedlydiminished alveolar-capillary protein leak, endothelial and epithelialmembrane injury, and lung lipid peroxidation. Hyperoxia also caused cell death with DNA fragmentation in the lungs of transgene animals and IL-6 markedly diminished this cytopathic response.The protective effects of IL-6 were not associated with significant alterations in the activities of copper/ zinc superoxide dismutase (SOD) or manganese SOD. They were, however, associated with the enhanced accumulation of the cell-death inhibitor Bcl-2, but not the cell-death stimulator BAX, and with the heightened accumulation of the cell-death regulator tissue inhibitor of metalloproteinase-1(TIMP-1). These studies demonstrate that IL-6 markedly diminishes hyperoxic lung injury and that this protection is associated witha marked diminution in hyperoxia-induced cell death and DNA fragmentation.They also demonstrate that this protection is not associated with significant alterations in SOD activity, but is associated with the induction of Bcl-2 and TIMP-1.

    Khun, C., Homer, R., Zhou, Ward, N.S., Z., Flavell, R.A., Geba, G., and J.E. Elias, Airways hyperresponsiveness and airways obstruction in transgenic mice: morphologic correlates in mice overexpressing interleukin-11 and interleukin-6 in the lungs. American Journal of Respiratory Cell and Molecular Biology. 2000. 22:289.


    Understanding the sources of variation in airway reactivity and airflow is important for unraveling the pathophysiology of asthma, obstructive lung disease, and other pulmonary disorders.Transgenic expression of two closely related cytokines in the mouse lung produced opposite effects on these parameters. Interleukin(IL)-6 did not alter basal airways resistance and decreased methacholine responsiveness, whereas IL-11 caused airways obstruction and increased airway responses to methacholine. To clarify these differences we examined histologic sections and used morphometry to compare bronchiolar and parenchymal dimensions in 1- to 2-mo-old transgenic mice expressing IL-6 or IL-11 and littermate control mice. Both transgenic strains showed similar emphysema-like airspace enlargement,nodular peribronchiolar collections of mononuclear cells, thickening of airway walls, and subepithelial airway fibrosis. When compared with littermate control mice, the IL-6 mice showed an approximately50% increase in the caliber of their bronchioles and an increasein airway wall thickness that was in proportion to the increasein the size of their airways. In contrast, the remodeling response was more robust in the IL-11 transgenic mice. It was also seen in airways with normal external and luminal diameters and thus was out of proportion to the caliber of their airways. These resultssupport the hypothesis that structural alterations and resulting caliber changes of respiratory airways can have important effectson airway physiology andreactivity.

    Ward, N.S., Lin, D.Y., Nelson, K.L., Houtchens, J., Schwartz, W.A., Klinger, J. R., Hill, N.S., and M.M. Levy, Successful Determination of Lower Inflection Point and Maximal Compliance in a Population of Patients with ARDS, Critical Care Medicine, 2002. 30(5):963.


    Objective: To compare the ease and efficacy of two commonly used methods for choosing optimal positive end-expiratory pressure (PEEP) in patients with acute respiratory distress syndrome: a static pressure-volume curve to determine the lower inflection point (Pflex) and the "best PEEP" (PEEPbest) as determined by the maximal compliance curve.

    Design: Prospective study.

    Setting: Medical and respiratory intensive care units of university-associated tertiary care hospital.

    Patients: Twenty-eight patients on mechanical ventilation with acute respiratory distress syndrome.

    Interventions: A critical care attending physician or fellow and an experienced respiratory therapist attempted to obtain both static pressure-volume curves and maximal compliance curves on 28 patients with acute respiratory distress syndrome by using established methods that were practical to everyday use. The curves then were used to determine both Pflex and PEEPbest, and the results were compared.

    Measurement and Main results: Our results showed at least one value for optimal PEEP was obtained in 26 of 28 patients (93%). Pflex was determined in 19 (68%), a PEEPbest in 24 (86%), and both values in 17 (61%). In patients who had both Pflex and PEEPbest determined, there was a close concordance (+/-3 cm H2O) in 60%. When the values of Pflex and PEEPbest were interpreted by two additional investigators, there was unanimous agreement on the Pflex (+/-3) only 64% of the time. There was agreement on the value of PEEPbest 93% of the time.

    Conclusions: Our data show that optimal PEEP, as determined by a pressure-volume curve and a maximal compliance curve, are sometimes unobtainable by practical means but, when obtained, often correspond. A maximal compliance is more often identified, has less interobserver variability, and poses less risk to the patient. We conclude that determining optimal PEEP by maximal static compliance may be easier to measure and more frequently obtained at the bedside than by using a static pressure-volume curve.