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Aerosolized Linear Polyethylenimine-Nitric Oxide/Nucleophile Adduct Attenuates Endotoxin-induced Lung Injury in Sheep

Department of Anesthesiology, Faculty of Medicine, University of Tromsø, Tromsø, Norway; and Inotek Corporation, Beverly, Massachusetts

Correspondence and requests for reprints should be addressed to Lars J. Bjertnaes, M.D., Ph.D., Department of Anesthesiology, Faculty of Medicine, University of Tromsø, N-9037 Tromsø, Norway. E-mail: lars.bjertnaes{at}unn.no

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 coli 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.

Key Words: acute lung injury • pulmonary circulation • extravascular lung water • nitric oxide donor • endotoxin

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