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

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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 μg 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.

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Abbreviations

ARDS:

acute respiratory distress syndrome

HSA:

human serum albumin

LPS:

lipopolysaccharide

MAP:

mean arterial blood pressure

MPO:

myeloperoxidase

S-NO-GSH:

S-nitroso-glutathione

S-NO-HSA:

S-nitroso human serum albumin

SNAP:

S-nitroso-N-acetyl-penicyllamine

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Acknowledgments

This work was supported by the Austro-Polish exchange programs (MZ/1/L/2005 and MZ/1/L/2006) and by the Polish Ministry of Science and Higher Education (grant No. N N401015135).

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Authors and Affiliations

  1. Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, ul. Grzegórzecka 16, 31-531, Kraków, Poland

    A. Jakubowski & S. Chlopicki

  2. Medical University, Grodno, Belarus

    N. Maksimovich

  3. Department of Pharmacological Analysis, Chair of Pharmacology, Jagiellonian University Medical College, Kraków, Poland

    R. Olszanecki & A. Gebska

  4. Ludwig Boltzmann Cluster for Cardiovascular Research, Medical University of Vienna, Vienna, Austria

    H. Gasser & B. K. Podesser

  5. Institute of Physiological Chemistry, Centre of Physiological Medicine, Medical University Graz, Harrachgasse 21, 8010, Graz, Austria

    S. Hallström

Authors
  1. A. Jakubowski
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  2. N. Maksimovich
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  3. R. Olszanecki
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  4. A. Gebska
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  5. H. Gasser
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  6. B. K. Podesser
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  7. S. Hallström
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  8. S. Chlopicki
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Corresponding authors

Correspondence to S. Hallström or S. Chlopicki.

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A. Jakubowski and N. Maksimovich contributed equally to this work.

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Jakubowski, A., Maksimovich, N., Olszanecki, R. et al. S-nitroso human serum albumin given after LPS challenge reduces acute lung injury and prolongs survival in a rat model of endotoxemia. Naunyn-Schmied Arch Pharmacol 379, 281–290 (2009). https://doi.org/10.1007/s00210-008-0351-2

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