Modulation of endotoxin-induced cardiopulmonary dysfunction by S-nitroso-albumin.
Nitric oxide (NO) is an endogenous vasodilator and modulator of inflammation. During endotoxemia, the beneficial effects of NO are overwhelmed by the inflammatory cascade, resulting in a functional depletion of NO. S-nitroso-albumin (S-NO-alb) exists as a novel and highly stable NO thiol complex that slowly releases NO into the vascular micro-environment. Using a porcine model, we examined the ability of intravenous S-NO-alb to modulate cardiopulmonary dysfunction characteristic of endotoxemia. Pigs were anesthetized, instrumented for standard cardiopulmonary function measurements, and randomly assigned to receive: (i) albumin + saline; (ii) albumin + LPS; or (iii) S-NO-alb + LPS. Cardiopulmonary parameters were evaluated every 30 min and ex vivo phorbol myristate acetate (PMA)-stimulated superoxide release was serially determined as a marker of in vivo neutrophil priming. Lung myeloperoxidase (MPO) activity was measured as a marker of neutrophil migration into the lung. LPS-induced cardiopulmonary dysfunction was characterized by a sustained elevation in mean pulmonary arterial pressure, pulmonary vascular resistance, and peak intratracheal pressure, as well as a reduction in cardiac index, stroke volume index and PaO(2) over 6 h. Pretreatment with S-NO-alb attenuated LPS-induced cardiopulmonary dysfunction without adversely affecting systemic hemodynamics. Moreover, S-NO-alb blunted the LPS-induced hypoxemic response and reduced neutrophil activation. S-NO-alb did not, however, attenuate LPS-induced increases in lung MPO. Our results suggest that S-NO-alb can selectively modulate endotoxin-induced pulmonary dysfunction, attenuate neutrophil priming and block the early mortality (40%) in this model.
Gluckman
Tracy L
TL
Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive West, Madison, WI 53706, USA.
Grossman
Jeffrey E
JE
Folts
John D
JD
Kruse-Elliott
Kris T
KT
D000818:Animals; D004195:Disease Models, Animal; D004338:Drug Combinations; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D004926:Escherichia coli; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006331:Heart Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D008171:Lung Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology; D009603:Nitroso Compounds; D009919:Orchiectomy; D009195:Peroxidase / Q000378:metabolism; D011897:Random Allocation; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000627:therapeutic use*; D013552:Swine
D004338:Drug Combinations; D008070:Lipopolysaccharides; D009603:Nitroso Compounds; C091665:S-nitrosoalbumin; D012710:Serum Albumin, Bovine; D009195:Peroxidase