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 Szabo, Lars J. Bjertnaes

Research output: Contribution to journalArticle

6 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Polyethyleneimine
Lung Injury
Endotoxins
Acute Lung Injury
Sheep
Nitric Oxide
Heart Ventricles
Pulmonary Edema
Pulmonary Hypertension
Stroke
Extravascular Lung Water
Escherichia
Lung
Endotoxemia
Nitric Oxide Donors
Vascular Resistance
Stroke Volume
Arterial Pressure
Respiration
Gases

Keywords

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

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Aerosolized linear polyethylenimine-nitric oxide/nucleophile adduct attenuates endotoxin-induced lung injury in sheep. / Kirov, Mikhail Y.; Evgenov, Oleg V.; Kuklin, Vladimir N.; Virág, László; Pacher, Pál; Southan, Garry J.; Salzman, Andrew L.; Szabo, Csaba; Bjertnaes, Lars J.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 166, No. 11, 01.12.2002, p. 1436-1442.

Research output: Contribution to journalArticle

Kirov, Mikhail Y. ; Evgenov, Oleg V. ; Kuklin, Vladimir N. ; Virág, László ; Pacher, Pál ; Southan, Garry J. ; Salzman, Andrew L. ; Szabo, Csaba ; Bjertnaes, Lars J. / Aerosolized linear polyethylenimine-nitric oxide/nucleophile adduct attenuates endotoxin-induced lung injury in sheep. In: American Journal of Respiratory and Critical Care Medicine. 2002 ; Vol. 166, No. 11. pp. 1436-1442.
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