Aerosolized linear polyethylenimine-nitric oxide/nucleophile adduct attenuates endotoxin-induced lung injury in sheep.
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.
Kirov
Mikhail Y
MY
Department of Anesthesiology, Faculty of Medicine, University of Tromsø, Norway.
Evgenov
Oleg V
OV
Kuklin
Vladimir N
VN
Virag
Laszlo
L
Pacher
Pal
P
Southan
Garry J
GJ
Salzman
Andrew L
AL
Szabo
Csaba
C
Bjertnaes
Lars J
LJ
D000208:Acute Disease; D000336:Aerosols; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D019446:Endotoxemia / Q000503:physiopathology; D004731:Endotoxins; D004847:Epithelial Cells / Q000187:drug effects; D004926:Escherichia coli; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008171:Lung Diseases / Q000139:chemically induced / Q000503:physiopathology*; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000494:pharmacology; D009603:Nitroso Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D011094:Polyethyleneimine / Q000008:administration & dosage* / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011654:Pulmonary Edema / Q000503:physiopathology; D051381:Rats; D012756:Sheep; D014664:Vasodilation
D000336:Aerosols; D004731:Endotoxins; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C470091:linear polyethylenimine-NONOate; D011094:Polyethyleneimine