Aerosolized linear polyethylenimine-nitric oxide/nucleophile adduct attenuates endotoxin-induced lung injury in sheep

Mikhail Y. Kirov, Oleg V. Evgenov, Vladimir N. Kuklin, László Virág, Pál Pacher, Garry J. Southan, Andrew L. Salzman, Csaba Szabó, Lars J. Bjertnaes

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    6 Scopus citations

    Abstract

    Pulmonary hypertension and edema are mainstays of acute lung injury (ALI). We synthesized linear polyethylenimine-nitric oxide/nucleophile adduct (DS-1), a water-soluble nitric oxide donor, and demonstrated that it is a potent relaxant of precontracted rat aortic rings without inducing desensitization. Moreover, DS-1 does not suppress the viability of human pulmonary epithelial cells in vitro. We also tested whether DS-1 counteracts ALI in endotoxemic sheep. Animals were instrumented for a chronic study. In 16 awake, spontaneously breathing sheep, Escherichia coil endotoxin (10 ng/kg/minute) was infused for 8 hours. From 2 hours of endotoxemia, sheep received either nebulized DS-1 (1 mg/kg/hour) or isotonic saline. DS-1 reduced endotoxin-induced rises in pulmonary arterial and microwedge pressures and vascular resistance index by 40-70%. In parallel, DS-1 decreased the accumulation of extravascular lung water by 60-70% and reduced the increment in right ventricle stroke work index and the falls in right ventricle ejection fraction, stroke volume, and left ventricle stroke work indices. Furthermore, DS-1 reduced venous admixture and improved arterial oxygen saturation. In four healthy animals, DS-1 alone slightly increased arterial oxygenation but had no other effects. Thus, aerosolized DS-1 attenuates endotoxin-induced ALI in sheep by reducing pulmonary hypertension and edema and improving myocardial function and gas exchange.

    Original languageEnglish (US)
    Pages (from-to)1436-1442
    Number of pages7
    JournalAmerican Journal of Respiratory and Critical Care Medicine
    Volume166
    Issue number11
    DOIs
    StatePublished - Dec 1 2002

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    Keywords

    • Acute lung injury
    • Endotoxin
    • Extravascular lung water
    • Nitric oxide donor
    • Pulmonary circulation

    ASJC Scopus subject areas

    • Pulmonary and Respiratory Medicine
    • Critical Care and Intensive Care Medicine

    Cite this

    Kirov, M. Y., Evgenov, O. V., Kuklin, V. N., Virág, L., Pacher, P., Southan, G. J., Salzman, A. L., Szabó, C., & Bjertnaes, L. J. (2002). Aerosolized linear polyethylenimine-nitric oxide/nucleophile adduct attenuates endotoxin-induced lung injury in sheep. American Journal of Respiratory and Critical Care Medicine, 166(11), 1436-1442. https://doi.org/10.1164/rccm.2202021