Improving effect of Sivelestat on lipopolysaccharide-induced lung injury in rats.

Abstract

Sepsis causes neutrophil sequestration in the lung, which leads to acute lung injury (ALI). Neutrophil elastase (NE) is thought to play an important role in the pathogenesis of ALI. This study investigated whether Sivelestat, a specific NE inhibitor, can attenuate ALI induced by lipopolysaccharide (LPS). In vivo, 30 male Wistar rats were divided into three groups (n = 10 each groups) on the basis of the reagent used, which were subjected to LPS injection with or without Sivelestat treatments to induce ALI model. Lung injury was assessed by pulmonary histology, lung wet-weight to dry-weight (W/D) ratio, immunohistochemical analysis of intercellular adhesion molecule-1 (ICAM-1), the number of myeloperoxidase (MPO)-positive cells, and gene expression of ICAM-1. In vitro, pulmonary microvascular endothelial cells (PMVECs) were stimulated with LPS in the presence and absence of Sivelestat; nuclear factor-κB (NF-κB) p65 was measured by immunocytochemistry staining and Western blotting. Infusion of LPS induced lung injury, in vivo, as demonstrated by pulmonary edema with infiltration of neutrophils, the increase in lung W/D ratio, the number of MPO-positive cells and enhanced expression of ICAM-1 and ICAM-1 gene. In vitro, the significant increased release of NF-κB p65 and its subsequent translocation into the nucleus in PMVECs. In contrast, Sivelestat treatment significantly ameliorated the LPS-induced lung injury, as judged by the marked improvement in all these indices. These results indicated that inhibition of NE attenuated LPS-induced lung injury through an inhibition of the inflammatory signaling pathway, besides the direct inhibitory effect on NE.

• Authors: Qing Yuan, Yan-Wen Jiang, Qiu-Hong Fang
• Journal: APMIS : acta pathologica, microbiologica, et immunologica Scandinavica (APMIS) Vol. 122 Issue 9 Pg. 810-7 (Sep 2014) ISSN: 1600-0463 [Electronic] Denmark
• PMID: 24484066 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 APMIS. Published by John Wiley & Sons Ltd.

Chemical References

• Lipopolysaccharides
• Proteinase Inhibitory Proteins, Secretory
• Rela protein, rat
• Serine Proteinase Inhibitors
• Sulfonamides
• Transcription Factor RelA
• Intercellular Adhesion Molecule-1
• sivelestat
• Peroxidase
• Leukocyte Elastase
• Glycine

Topics

• Acute Lung Injury (chemically induced, drug therapy)
• Animals
• Endothelial Cells (cytology, pathology)
• Glycine (analogs & derivatives, therapeutic use)
• Intercellular Adhesion Molecule-1 (biosynthesis)
• Leukocyte Elastase
• Lipopolysaccharides
• Lung (cytology, pathology)
• Male
• Neutrophil Infiltration (immunology)
• Peroxidase (biosynthesis)
• Proteinase Inhibitory Proteins, Secretory (therapeutic use)
• Pulmonary Edema (drug therapy, immunology)
• Rats
• Rats, Wistar
• Sepsis (drug therapy)
• Serine Proteinase Inhibitors (therapeutic use)
• Sulfonamides (therapeutic use)
• Transcription Factor RelA (biosynthesis)