Sivelestat (Selective Neutrophil Elastase Inhibitor) Improves the Mortality Rate of Sepsis Associated With Both Acute Respiratory Distress Syndrome and Disseminated Intravascular Coagulation Patients

Hayakawa, Mineji; Katabami, Kenichi; Wada, Takeshi; Shinoda, Masahiro; Hoshino, Hirokatsu; Sawamura, Atsushi; Gando, Satoshi

doi:10.1097/shk.0b013e3181aa95c4

Cited by 84 publications

(64 citation statements)

References 28 publications

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“…In preclinical models, SIV reduces markers of tissue injury and systemic inflammation, including ischemia reperfusion injury (44), sepsis (45), and acute lung injury (46,47). In our set of experiments, treatment of animals with SIV dose-dependently reduced neutrophil accumulation into the pleural cavity, an effect associated to reduced resolution indices and R i .…”

Section: Discussionmentioning

confidence: 73%

Proresolving Actions of Synthetic and Natural Protease Inhibitors Are Mediated by Annexin A1

Vago

Tavares

Sugimoto

et al. 2016

The Journal of Immunology

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Annexin A1 (AnxA1) is a glucocorticoid-regulated protein endowed with anti-inflammatory and proresolving properties. Intact AnxA1 is a 37-kDa protein that may be cleaved in vivo at the N-terminal region by neutrophil proteases including elastase and proteinase-3, generating the 33-kDa isoform that is largely inactive. In this study, we investigated the dynamics of AnxA1 expression and the effects of synthetic (sivelestat [SIV]; Eglin) and natural (secretory leukocyte protease inhibitor [SLPI]; Elafin) protease inhibitors on the resolution of LPS-induced inflammation. During the settings of LPS inflammation AnxA1 cleavage associated closely with the peak of neutrophil and elastase expression and activity. SLPI expression increased during resolving phase of the pleurisy. Therapeutic treatment of LPS-challenge mice with recombinant human SLPI or Elafin accelerated resolution, an effect associated with increased numbers of apoptotic neutrophils in the pleural exudates, inhibition of elastase, and modulation of the survival-controlling proteins NF-κB and Mcl-1. Similar effects were observed with SIV, which dose-dependently inhibited neutrophil elastase and shortened resolution intervals. Mechanistically, SIV-induced resolution was caspase-dependent, associated to increased levels of intact AnxA1 and decreased expression of NF-κB and Mcl-1. The proresolving effect of antiproteases was also observed in a model of monosodium urate crystals–induced inflammation. SIV skewed macrophages toward resolving phenotypes and enhanced efferocytosis of apoptotic neutrophils. A neutralizing antiserum against AnxA1 and a nonselective antagonist of AnxA1 receptor abolished the accelerated resolution promoted by SIV. Collectively, these results show that elastase inhibition not only inhibits inflammation but actually promotes resolution, and this response is mediated by protection of endogenous intact AnxA1 with ensuing augmentation of neutrophil apoptosis.

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Section: Discussionmentioning

confidence: 73%

Proresolving Actions of Synthetic and Natural Protease Inhibitors Are Mediated by Annexin A1

Vago

Tavares

Sugimoto

et al. 2016

The Journal of Immunology

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“…5,6 Sivelestat is one of the agents which can specifically inhibit NE, 7 and it is used for the treatment of acute lung injury patients or acute respiratory distress syndrome patients. 8,9 Although a few reports showed the possibility that sivelestat might reduce cerebral ischemic damage, 10,11 the detailed protective mechanism of sivelestat in brain tissue has not yet been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil elastase inhibitor prevents ischemic brain damage via reduction of vasogenic edema

et al. 2010

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Release of neutrophil elastase is one of the harmful inflammatory reactions in acute cerebral ischemia. Therefore, inhibition of elastase released from neutrophils could be a useful strategy for the treatment of acute stroke. To evaluate this hypothesis, the effect of sivelestat, a selective neutrophil elastase inhibitor was examined in a mouse model of focal ischemia. The results obtained indicate that sivelestat reduced brain edema and vascular permeability, and subsequently improved the neurological deficit in an acute focal ischemia. The architecture of microvessels was analyzed by identifying vascular endothelial cells, which were prelabeled by injecting fluorescein-labeled Griffonia simplicifolia lectin I-isolectin B4 into a tail vein. Most of the microvessels in the infarcted area were structurally destroyed in the control group. In sharp contrast, microvessels in the boundary zone were well maintained in the sivelestat-treated group. Moreover, the expression of angiopoietin-1 was elevated at the ischemic margin in the sivelestat-treated group. Furthermore, the neutrophil elastase inhibitor rescued human brain microvascular endothelial cells in culture from neutrophil elastase-induced damage. These results suggest that neutrophil elastase inhibition could protect blood-brain barrier function in acute cerebral ischemia by augmentation of angiopoietin-1 expression and survival of endothelial cells.

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“…Because VE-cadherin and CD31 are known substrates of elastase 23 and MMP9, 24 respectively, we assessed whether we could prevent the loss of these junctional proteins and subsequent transendothelial albumin passage by inhibiting the activity of NET-associated elastase and MMP9. Pre-treatment of NETs with sivelestat, a selective inhibitor of elastase, 25 abolished the NET-induced loss of VE-cadherin expression ( Figure 2F and 2G) and reduced transendothelial albumin passage ( Figure 2E). The inhibition of MMP9 with anti-MMP9 antibodies could limit CD31 loss ( Figure IID in the online-only Data Supplement), but this did not alter endothelial monolayer integrity (data not shown).…”

Section: Net-associated Elastase Promotes Transendothelial Albumin Pamentioning

confidence: 99%

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Pieterse

Rother

Garsen

et al. 2017

ATVB

199

150

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Objective— An excessive release and impaired degradation of neutrophil extracellular traps (NETs) leads to the continuous exposure of NETs to the endothelium in a variety of hematologic and autoimmune disorders, including lupus nephritis. This study aims to unravel the mechanisms through which NETs jeopardize vascular integrity. Approach and Results— Microvascular and macrovascular endothelial cells were exposed to NETs, and subsequent effects on endothelial integrity and function were determined in vitro and in vivo. We found that endothelial cells have a limited capacity to internalize NETs via the receptor for advanced glycation endproducts. An overflow of the phagocytic capacity of endothelial cells for NETs resulted in the persistent extracellular presence of NETs, which rapidly altered endothelial cell–cell contacts and induced vascular leakage and transendothelial albumin passage through elastase-mediated proteolysis of the intercellular junction protein VE-cadherin. Furthermore, NET-associated elastase promoted the nuclear translocation of junctional β-catenin and induced endothelial-to-mesenchymal transition in cultured endothelial cells. In vivo, NETs could be identified in kidney samples of diseased MRL/lpr mice and patients with lupus nephritis, in whom the glomerular presence of NETs correlated with the severity of proteinuria and with glomerular endothelial-to-mesenchymal transition. Conclusions— These results indicate that an excess of NETs exceeds the phagocytic capacity of endothelial cells for NETs and promotes vascular leakage and endothelial-to-mesenchymal transition through the degradation of VE-cadherin and the subsequent activation of β-catenin signaling. Our data designate NET-associated elastase as a potential therapeutic target in the prevention of endothelial alterations in diseases characterized by aberrant NET release.

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Sivelestat (Selective Neutrophil Elastase Inhibitor) Improves the Mortality Rate of Sepsis Associated With Both Acute Respiratory Distress Syndrome and Disseminated Intravascular Coagulation Patients

Cited by 84 publications

References 28 publications

Proresolving Actions of Synthetic and Natural Protease Inhibitors Are Mediated by Annexin A1

Proresolving Actions of Synthetic and Natural Protease Inhibitors Are Mediated by Annexin A1

Neutrophil elastase inhibitor prevents ischemic brain damage via reduction of vasogenic edema

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

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