S-nitroso human serum albumin given after LPS challenge reduces acute lung injury and prolongs survival in a rat model of endotoxemia.

Abstract

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.

• Authors: A Jakubowski, N Maksimovich, R Olszanecki, A Gebska, H Gasser, B K Podesser, S Hallström, S Chlopicki
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 379 Issue 3 Pg. 281-90 (Mar 2009) ISSN: 1432-1912 [Electronic] Germany
• PMID: 18854985 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipopolysaccharides
• Nitroso Compounds
• S-nitrosoalbumin, human
• Serum Albumin
• Intercellular Adhesion Molecule-1
• Peroxidase
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• Cyclooxygenase 2
• Ptgs2 protein, rat
• Serum Albumin, Human

Topics

• Animals
• Blood Pressure (drug effects)
• Cyclooxygenase 2 (biosynthesis)
• Disease Models, Animal
• Drug Administration Schedule
• Endotoxemia (complications, drug therapy)
• Humans
• Intercellular Adhesion Molecule-1 (biosynthesis)
• Kaplan-Meier Estimate
• Lipopolysaccharides
• Lung (drug effects, enzymology, metabolism, pathology)
• Nitric Oxide Synthase Type II (biosynthesis)
• Nitroso Compounds (administration & dosage, therapeutic use)
• Peroxidase (metabolism)
• Pulmonary Edema (etiology, prevention & control)
• Rats
• Rats, Wistar
• Serum Albumin (administration & dosage, therapeutic use)
• Serum Albumin, Human