Reevaluation of the efficacy and safety of the neutrophil elastase inhibitor, Sivelestat, for the treatment of acute lung injury associated with systemic inflammatory response syndrome; a phase IV study

Aikawa, Naoki; Ishizaka, Akitoshi; Hirasawa, Hiroyuki; Shimazaki, Shuji; Yamamoto, Yasuhiro; Sugimoto, Hisashi; Shinozaki, Masaru; Taenaka, Nobuyuki; Endo, Shunsuke; Ikeda, Toshiaki; Kawasaki, Yasushi

doi:10.1016/j.pupt.2011.03.001

Cited by 107 publications

(126 citation statements)

References 26 publications

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“…Neutrophil elastase is a strong mediator of adult respiratory distress syndrome (ARDS), because neutrophil elastase is elevated in the sera and lung tissue of patients with ARDS [28][29][30][31]. There has been some evidence that a neutrophil elastase inhibitor is effective for the treatment of ARDS [32,33]. Since none of the present patients showed evidence of ARDS, the elevated levels of neutrophil elastase might reflect the pathological process of IE itself.…”

Section: Discussionmentioning

confidence: 87%

Elevated serum levels of neutrophil elastase in patients with influenza virus-associated encephalopathy

Sun

Ota

Kitaoka

et al. 2015

Journal of the Neurological Sciences

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Section: Discussionmentioning

confidence: 87%

Elevated serum levels of neutrophil elastase in patients with influenza virus-associated encephalopathy

Sun

Ota

Kitaoka

et al. 2015

Journal of the Neurological Sciences

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“…oxygenation, multiple organ dysfunction score, and ventilator-weaning rate. [30][31][32][33] However, the STRIVE study, a clinical trial in ALI patients requiring mechanical ventilation, failed to demonstrate the efficacy of sivelestat. 34 The discrepancy might be due to differences in the severity of lung injury in the patients.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil elastase inhibitor reduces ventilation-induced lung injury via nuclear factor-κB and NF-κB repressing factor in mice

Lai

Chang

et al. 2014

Exp Biol Med (Maywood)

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Mechanical ventilation used in patients with acute lung injury can damage pulmonary epithelial cells through production of inflammatory cytokines, oxygen radicals, and neutrophil infiltration, termed ventilator-induced lung injury. Neutrophil elastase, nuclear factor-κB (NF-κB), and NF-κB repressing factor (NRF) have previously been shown to participate in the regulation of macrophage inflammatory protein-2 (MIP-2) during airway inflammation. However, the mechanisms regulating interactions among mechanical ventilation, neutrophil influx, and NF-κB/NRF remain unclear. Thus, we hypothesized that neutrophil elastase inhibitor attenuated ventilation-induced neutrophil recruitment and MIP-2 production through inhibition of the NF-κB/NRF pathway. Male C57BL/6 mice were exposed to low-tidal-volume (6 mL/kg) or high-tidal-volume (30 mL/kg) mechanical ventilation using room air with or without 2 µg/g NF-κB inhibitor SN50 or 6 µg/g NRF short interfering RNA or 100 µg/g neutrophil elastase inhibitor administration. Nonventilated mice served as a control group. Evan blue dye, lung wet-to-dry weight ratio, free radicals, myeloperoxidase, histopathologic grading of lung tissue, inflammatory cytokines, Western blot of NF-κB and NRF, and gene expression of NRF were measured to establish the extent of lung injury. Neutrophil elastase inhibitor ameliorated high-tidal-volume ventilation-induced lung injury, neutrophil influx, production of MIP-2 and malondialdehyde, activation of NF-κB and NRF, apoptotic epithelial cell death, and disruption of bronchial microstructure in mice. Mechanical stretch-augmented acute lung injury was also attenuated through pharmacological inhibition of NF-κB activity by SN50 and NRF expression by NRF short interfering RNA. Our data suggest that neutrophil elastase inhibitor attenuates high-tidal-volume mechanical ventilation-induced neutrophil influx, oxidative stress, and production of MIP-2, at least partly, through inhibition of NF-κB/NRF pathway. Understanding the protective effects of neutrophil elastase inhibitor associated with the reduction of MIP-2 allow clarification of the pathophysiological mechanisms regulating severe lung inflammation and development of possible therapeutic strategies involved in acute lung injury.

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“…Sivelestat is a selective NE inhibitor and has been shown to be effective clinically in mitigating the effect of systemic inflammatory response in patients with acute lung injury. 25 PDT-treated tumors that received Sivelestat via intratumor injection were assayed for NE680 fluorescence, and the levels were compared to those obtained from unirradiated and irradiated tumors in the absence of Sivelestat. Figure 5 Sivelestat groups for both SCC VII and EMT6 tumors were not different at the P ¼ 0.1 significance level.…”

Section: Resultsmentioning

confidence: 99%

Enzyme-activatable imaging probe reveals enhanced neutrophil elastase activity in tumors following photodynamic therapy

2013

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Abstract. We demonstrate the use of an enzyme-activatable fluorogenic probe, Neutrophil Elastase 680 FAST (NE680), for in vivo imaging of neutrophil elastase (NE) activity in tumors subjected to photodynamic therapy (PDT). NE protease activity was assayed in SCC VII and EMT6 tumors established in C3H and BALB/c mice, respectively. Four nanomoles of NE680 was injected intravenously immediately following PDT irradiation. 5 h following administration of NE680, whole-mouse fluorescence imaging was performed. At this time point, levels of NE680 fluorescence were at least threefold greater in irradiated versus unirradiated SCC VII and EMT6 tumors sensitized with Photofrin. To compare possible photosensitizer-specific differences in therapy-induced elastase activity, EMT6 tumors were also subjected to 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH)-PDT. NE levels measured in HPPH-PDT-treated tumors were twofold higher than in unirradiated controls. Ex vivo labeling of host cells using fluorophore-conjugated antibodies and confocal imaging were used to visualize Gr1 þ cells in Photofrin-PDT-treated EMT6 tumors. These data were compared with recently reported analysis of Gr1 þ cell accumulation in EMT6 tumors subjected to HPPH-PDT. The population density of infiltrating Gr1 þ cells in treated versus unirradiated drug-only control tumors suggests that the differential in NE680 fold enhancement observed in Photofrin versus HPPH treatment may be attributed to the significantly increased inflammatory response induced by Photofrin-PDT. The in vivo imaging of NE680, which is a fluorescent reporter of NE extracellular release caused by neutrophil activation, demonstrates that PDT results in increased NE levels in treated tumors, and the accumulation of the cleaved probe tracks qualitatively with the intratumor Gr1 þ cell population. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

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Reevaluation of the efficacy and safety of the neutrophil elastase inhibitor, Sivelestat, for the treatment of acute lung injury associated with systemic inflammatory response syndrome; a phase IV study

Cited by 107 publications

References 26 publications

Elevated serum levels of neutrophil elastase in patients with influenza virus-associated encephalopathy

Elevated serum levels of neutrophil elastase in patients with influenza virus-associated encephalopathy

Neutrophil elastase inhibitor reduces ventilation-induced lung injury via nuclear factor-κB and NF-κB repressing factor in mice

Enzyme-activatable imaging probe reveals enhanced neutrophil elastase activity in tumors following photodynamic therapy

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