S-nitroso human serum albumin given after LPS challenge reduces acute lung injury and prolongs survival in a rat model of endotoxemia.
Endotoxemia leads to the induction of inducible nitric oxide synthase (NOS-2) and increased expression of numerous inflammatory mediators contributing to endotoxin-induced acute lung injury. We tested the hypothesis that supplementation of nitric oxide (NO) by the novel NO donor S-nitroso human serum albumin (S-NO-HSA) given after lipopolysaccharide (LPS) challenge may reduce NOS-2 expression, lung inflammation and acute lung injury. Rats were divided into four groups: sham-operated (no treatment), LPS, LPS+HSA (human serum albumin), and LPS+S-NO-HSA. LPS was administered intravenously (20 mg kg(-1)) resulting in acute lung injury and a high mortality rate within 6 h (>90%). LPS-induced lung injury was characterized by an increased lung edema (lung wet/dry weight ratio), pulmonary neutrophil infiltration (myeloperoxidase activity, MPO) as well as a robust inflammatory response [increased expression of intercellular adhesion molecule-1 (ICAM-1), NOS-2, and cyclooxygenase-2 (COX-2)]. Infusion of S-NO-HSA or HSA was started 2 h after LPS and continued for 4 h (total dose of 72 mg kg(-1)) at a rate of 300 microg kg(-1) min(-1). S-NO-HSA but not HSA prolonged survival of endotoxemic rats, reduced the hypotensive response to LPS, minimized LPS-induced lung edema and injury, normalized MPO activity as well as diminished lung expression of pro-inflammatory molecules such as ICAM-1, NOS-2, and COX-2. Continuous supplementation of NO by S-NO-HSA after LPS challenge prevents induction of NOS-2, provides significant protection of endotoxin-induced acute lung injury, and prevents early mortality in endotoxic shock in rats. Our results suggest a potential therapeutic role for S-NO-HSA in endotoxemia.
Jakubowski
A
A
Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, ul. Grzegórzecka 16, 31-531, Kraków, Poland.
Maksimovich
N
N
Olszanecki
R
R
Gebska
A
A
Gasser
H
H
Podesser
B K
BK
Hallström
S
S
Chlopicki
S
S
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D019446:Endotoxemia / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D053208:Kaplan-Meier Estimate; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009603:Nitroso Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D011654:Pulmonary Edema / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000008:administration & dosage / Q000627:therapeutic use*; D000075462:Serum Albumin, Human
D008070:Lipopolysaccharides; D009603:Nitroso Compounds; C511514:S-nitrosoalbumin, human; D012709:Serum Albumin; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D000075462:Serum Albumin, Human