Role of neutrophil elastase in development of pulmonary vascular injury and septic shock in rats.

Abstract

Prostacyclin prevents pulmonary vascular injury and shock by inhibiting increases in lung tissue levels of TNF in rats administered endotoxin. We previously reported that NO derived from eNOS increases endothelial production of prostacyclin. Because neutrophil elastase has been shown to decrease endothelial production of prostacyclin by inhibiting NOS activity, we examined whether neutrophil elastase inhibitors reduce pulmonary vascular injury and hypotension by inhibiting the decrease in pulmonary endothelial production of prostacyclin in rats administered endotoxin. Animals were pretreated with sivelestat or L-658,758, neutrophil elastase inhibitors, before endotoxin administration. Lung tissue levels of 6-keto-prostaglandin F1alpha were markedly increased after endotoxin administration, followed by a rapid decrease to baseline levels. Sivelestat and L-658,758 inhibited these decreases as well as inhibiting increases in lung tissue levels of TNF and lung wet-to-dry weight ratios in animals administered endotoxin. These inhibitors also reduced hypotension and inhibited increases in lung tissue levels of mRNA of the inducible form of NOS in animals administered endotoxin. The effects of neutrophil elastase inhibitors were completely reversed by pretreatment with nitro-L-arginine methyl ester, an inhibitor of NOS, or indomethacin, a nonspecific cyclooxygenase inhibitor. These observations suggested that neutrophil elastase might decrease the pulmonary endothelial production of prostacyclin by inhibiting endothelial NO production, thereby contributing to the development of pulmonary vascular injury and shock through increases in lung tissue levels of TNF in rats administered endotoxin.

• Authors: Naoaki Harada, Kenji Okajima, Hirotaka Isobe
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 30 Issue 4 Pg. 379-87 (Oct 2008) ISSN: 1540-0514 [Electronic] United States
• PMID: 18323746 (Publication Type: Journal Article)

Chemical References

• Cephalosporins
• Endotoxins
• Enzyme Inhibitors
• Tumor Necrosis Factor-alpha
• L 658758
• Nitric Oxide
• 6-Ketoprostaglandin F1 alpha
• Leukocyte Elastase

Topics

• 6-Ketoprostaglandin F1 alpha (metabolism)
• Animals
• Cephalosporins (pharmacology)
• Endotoxins (metabolism)
• Enzyme Inhibitors (pharmacology)
• Leukocyte Elastase (chemistry, metabolism, physiology)
• Lung (enzymology)
• Lung Diseases (blood, enzymology)
• Male
• Nitric Oxide (metabolism)
• Rats
• Shock, Septic (blood, enzymology)
• Tumor Necrosis Factor-alpha (metabolism)
• Vascular Diseases (blood, enzymology)