A neutrophil elastase inhibitor, sivelestat, ameliorates lung injury after hemorrhagic shock in rats

Yuichiro Toda, Toru Takahashi, Kyoichiro Maeshima, Hiroko Shimizu, Kazuyoshi Inoue, Hiroshi Morimatsu, Emiko Omori, Mamoru Takeuchi, Reiko Akagi, Kiyoshi Morita

Research output: Contribution to journalArticle

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Abstract

Hemorrhagic shock followed by resuscitation (HSR) causes neutrophil sequestration in the lung which leads to acute lung injury (ALI). Neutrophil elastase (NE) is thought to play a pivotal role in the pathogenesis of ALI. This study investigated whether sivelestat, a specific NE inhibitor, can attenuate ALI induced by HSR in rats. Male Sprague-Dawley rats were subjected to hemorrhagic shock by withdrawing blood so as to maintain a mean arterial blood pressure of 30±5 mm Hg for 60 min followed by resuscitation with the shed blood. HSR-treated animals received a bolus injection of sivelestat (10 mg/kg) intravenously at the start of resuscitation followed by continuous infusion for 60 min (10 mg/kg/h) during the resuscitation phase, or the vehicle. Lung injury was assessed by pulmonary histology, lung wet-weight to dry-weight (W/D) ratio, myeloperoxidase (MPO) activity, gene expression of tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS), DNA binding activity of nuclear factor (NF)-κB, and immunohistochemical analysis of intercellular adhesion molecule (ICAM)-1. HSR treatment induced lung injury, as demonstrated by pulmonary edema with infiltration of neutrophils, the increase in lung W/D ratio, MPO activity, gene expression of TNF-α and iNOS, and DNA-binding activity of NF-κB, and enhanced expression of ICAM-1. In contrast, sivelestat treatment significantly ameliorated the HSR-induced lung injury, as judged by the marked improvement in all these indices. These results indicate that sivelestat attenuated HSR-induced lung injury at least in part through an inhibition of the inflammatory signaling pathway, in addition to the direct inhibitory effect on NE.

Original languageEnglish
Pages (from-to)237-243
Number of pages7
JournalInternational Journal of Molecular Medicine
Volume19
Issue number2
Publication statusPublished - Feb 2007

Fingerprint

Secretory Proteinase Inhibitory Proteins
Hemorrhagic Shock
Lung Injury
Resuscitation
Acute Lung Injury
Leukocyte Elastase
Nitric Oxide Synthase Type II
Pulmonary Edema
Intercellular Adhesion Molecule-1
Lung
Peroxidase
Arterial Pressure
Tumor Necrosis Factor-alpha
Gene Expression
Weights and Measures
Neutrophil Infiltration
DNA
Sprague Dawley Rats
Histology
Neutrophils

Keywords

  • Acute lung injury
  • Elastase inhibitor
  • Hemorrhagic shock
  • Inflammation
  • Neutrophil

ASJC Scopus subject areas

  • Genetics

Cite this

Toda, Y., Takahashi, T., Maeshima, K., Shimizu, H., Inoue, K., Morimatsu, H., ... Morita, K. (2007). A neutrophil elastase inhibitor, sivelestat, ameliorates lung injury after hemorrhagic shock in rats. International Journal of Molecular Medicine, 19(2), 237-243.

A neutrophil elastase inhibitor, sivelestat, ameliorates lung injury after hemorrhagic shock in rats. / Toda, Yuichiro; Takahashi, Toru; Maeshima, Kyoichiro; Shimizu, Hiroko; Inoue, Kazuyoshi; Morimatsu, Hiroshi; Omori, Emiko; Takeuchi, Mamoru; Akagi, Reiko; Morita, Kiyoshi.

In: International Journal of Molecular Medicine, Vol. 19, No. 2, 02.2007, p. 237-243.

Research output: Contribution to journalArticle

Toda, Y, Takahashi, T, Maeshima, K, Shimizu, H, Inoue, K, Morimatsu, H, Omori, E, Takeuchi, M, Akagi, R & Morita, K 2007, 'A neutrophil elastase inhibitor, sivelestat, ameliorates lung injury after hemorrhagic shock in rats', International Journal of Molecular Medicine, vol. 19, no. 2, pp. 237-243.
Toda, Yuichiro ; Takahashi, Toru ; Maeshima, Kyoichiro ; Shimizu, Hiroko ; Inoue, Kazuyoshi ; Morimatsu, Hiroshi ; Omori, Emiko ; Takeuchi, Mamoru ; Akagi, Reiko ; Morita, Kiyoshi. / A neutrophil elastase inhibitor, sivelestat, ameliorates lung injury after hemorrhagic shock in rats. In: International Journal of Molecular Medicine. 2007 ; Vol. 19, No. 2. pp. 237-243.
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abstract = "Hemorrhagic shock followed by resuscitation (HSR) causes neutrophil sequestration in the lung which leads to acute lung injury (ALI). Neutrophil elastase (NE) is thought to play a pivotal role in the pathogenesis of ALI. This study investigated whether sivelestat, a specific NE inhibitor, can attenuate ALI induced by HSR in rats. Male Sprague-Dawley rats were subjected to hemorrhagic shock by withdrawing blood so as to maintain a mean arterial blood pressure of 30±5 mm Hg for 60 min followed by resuscitation with the shed blood. HSR-treated animals received a bolus injection of sivelestat (10 mg/kg) intravenously at the start of resuscitation followed by continuous infusion for 60 min (10 mg/kg/h) during the resuscitation phase, or the vehicle. Lung injury was assessed by pulmonary histology, lung wet-weight to dry-weight (W/D) ratio, myeloperoxidase (MPO) activity, gene expression of tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS), DNA binding activity of nuclear factor (NF)-κB, and immunohistochemical analysis of intercellular adhesion molecule (ICAM)-1. HSR treatment induced lung injury, as demonstrated by pulmonary edema with infiltration of neutrophils, the increase in lung W/D ratio, MPO activity, gene expression of TNF-α and iNOS, and DNA-binding activity of NF-κB, and enhanced expression of ICAM-1. In contrast, sivelestat treatment significantly ameliorated the HSR-induced lung injury, as judged by the marked improvement in all these indices. These results indicate that sivelestat attenuated HSR-induced lung injury at least in part through an inhibition of the inflammatory signaling pathway, in addition to the direct inhibitory effect on NE.",
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