Sivelestat Attenuates Lung Injury in Surgery for Congenital Heart Disease With Pulmonary Hypertension

Nomura, Norikazu; Asano, Masahisa; Saito, Takayuki; Nakayama, Takuya; Mishima, Akira

doi:10.1016/j.athoracsur.2013.07.017

Cited by 15 publications

(20 citation statements)

References 15 publications

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“…In all models, a dramatic suppression of tissue infiltration of neutrophils was noted, with some indications of concomitant inhibition of acute tissue injury. Similar results were obtained using an NE inhibitor, observations that are in agreement with previously published works using different models of I/R injury and confirming the efficacy of sivelestat in the treatment of perioperative acute inflammatory responses in the clinic . In sharp contrast, the use of NE‐deficient mice has led to conflicting and varied results regarding the functions of this protease in neutrophil infiltration, questioning the efficacy and specificity of existing NE inhibitors.…”

Section: Discussionsupporting

confidence: 89%

“…sivelestat) inhibitors of NE . The use of sivelestat, in particular, confirmed the potential of targeting NE for the treatment of disorders such as acute lung injury , complications arising from myocardial surgery , organ transplantation and several model of I/R injury . However, at present the specific role(s) of NE in I/R injury remains poorly understood.…”

Section: Discussionmentioning

confidence: 91%

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Neutrophil elastase plays a non‐redundant role in remodeling the venular basement membrane and neutrophil diapedesis post‐ischemia/reperfusion injury

Voisin

Leoni

Woodfin

et al. 2019

The Journal of Pathology

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Ischemia/reperfusion (I/R) injury is a severe inflammatory insult associated with numerous pathologies, such as myocardial infarction, stroke and acute kidney injury. I/R injury is characterized by a rapid influx of activated neutrophils secreting toxic free radical species and degrading enzymes that can irreversibly damage the tissue, thus impairing organ functions. Significant efforts have been invested in identifying therapeutic targets to suppress neutrophil recruitment and activation post‐I/R injury. In this context, pharmacological targeting of neutrophil elastase (NE) has shown promising anti‐inflammatory efficacy in a number of experimental and clinical settings of I/R injury and is considered a plausible clinical strategy for organ care. However, the mechanisms of action of NE, and hence its inhibitors, in this process are not fully understood. Here we conducted a comprehensive analysis of the impact of NE genetic deletion on neutrophil infiltration in four murine models of I/R injury as induced in the heart, kidneys, intestine and cremaster muscle. In all models, neutrophil migration into ischemic regions was significantly suppressed in NE−/− mice as compared with wild‐type controls. Analysis of inflamed cremaster muscle and mesenteric microvessels by intravital and confocal microscopy revealed a selective entrapment of neutrophils within venular walls, most notably at the level of the venular basement membrane (BM) following NE deletion/pharmacological blockade. This effect was associated with the suppression of NE‐mediated remodeling of the low matrix protein expressing regions within the venular BM used by transmigrating neutrophils as exit portals. Furthermore, whilst NE deficiency led to reduced neutrophil activation and vascular leakage, levels of monocytes and prohealing M2 macrophages were reduced in tissues of NE−/− mice subjected to I/R. Collectively our results identify a vital and non‐redundant role for NE in supporting neutrophil breaching of the venular BM post‐I/R injury but also suggest a protective role for NE in promoting tissue repair. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 91%

Neutrophil elastase plays a non‐redundant role in remodeling the venular basement membrane and neutrophil diapedesis post‐ischemia/reperfusion injury

Voisin

Leoni

Woodfin

et al. 2019

The Journal of Pathology

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“…In our murine studies in which transplanted cells were exposed to sivelestat or sivelestat was administered in vivo, sivelestat treatment resulted in increased percentage of murine cells compared with DMSO-treated mice, indicating there was no detected adverse impact on murine hematopoiesis. Consistent with these findings, sivelestat has been well tolerated in clinical trials and following postmarket studies without increased toxicity to hematopoietic systems compared with control groups (35,36). When used in combination with azacitidine and decitabine, sivelestat was additive to promote MDS cell death in a dose-dependent manner.…”

Section: Discussionsupporting

confidence: 56%

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

Kam

Piryani

McCall

et al. 2019

Clinical Cancer Research

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Purpose: Myelodysplastic syndrome (MDS) is associated with a dysregulated innate immune system. The purpose of this study was to determine whether modulation of the innate immune system via high mobility group box-1 (HMGB1) could reduce cell viability in MDS.Experimental Design: We quantified HMGB1 in an MDS cell line MDS-L and in primary MDS cells compared with nonmalignant hematopoietic cells. We performed loss-offunction studies of HMGB1 using pooled siRNAs and a small-molecule inhibitor sivelestat compared with standard chemotherapy. We measured levels of engraftment of MDS-L cells in NOD-scidIL2Rg null (NSG) mice following treatment with sivelestat. Mechanistically, we interrogated cell survival pathways and 45 targets within the NFkB pathway using both protein analysis and a proteome profiler array.Results: We discovered that HMGB1 had increased expression in both MDS-L cells and in primary CD34 þ MDS cells compared with healthy CD34 þ hematopoietic cells. Sivelestat impaired MDS cell expansion, increased cellular death, and spared healthy hematopoietic cells. MDS-L marrow engraftment is reduced significantly at 17 weeks following treatment with sivelestat compared with control mice. Treatment of CD34 þ MDS cells with sivelestat and azacitidine or decitabine was additive to increase apoptotic cell death compared with chemotherapy alone. Sivelestat promoted apoptosis with increased expression of PUMA, activated caspase 3, and increased DNA double-strand breaks. Inhibition of HMGB1 reduced levels of Toll-like receptors (TLR) and suppressed activation of NFkB in MDS-L cells.Conclusions: Inhibition of HMGB1 could promote MDS cell death and alter innate immune responses via suppression of NFkB pathways.

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“…When mice were pretreated with the neutrophil elastase inhibitor sivelestat, the altered leukocyte kinetics and hyperaemia induced by neutrophil elastase were no longer observed. Sivelestat inhibits the enzymic action of neutrophil elastase directly by a reversible ‘acylation‐deacylation’ mechanism (Nakayama et al ., ) and has been shown to reverse inflammatory changes induced by neutrophil elastase (Kakimoto et al ., ; Fukatsu et al ., ; Nomura et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Neutrophil elastase induces inflammation and pain in mouse knee joints via activation of proteinase‐activated receptor‐2

Muley

Reid

Botz

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSENeutrophil elastase plays a crucial role in arthritis. Here, its potential in triggering joint inflammation and pain was assessed, and whether these effects were mediated by proteinase-activated receptor-2 (PAR2). EXPERIMENTAL APPROACHNeutrophil elastase (5 μg) was injected into the knee joints of mice and changes in blood perfusion, leukocyte kinetics and paw withdrawal threshold were assessed. Similar experiments were performed in animals pretreated with the neutrophil elastase inhibitor sivelestat, the PAR2 antagonist GB83, the p44/42 MAPK inhibitor U0126 and in PAR2 receptor knockout (KO) mice. Neutrophil elastase activity was also evaluated in arthritic joints by fluorescent imaging and sivelestat was assessed for anti-inflammatory and analgesic properties. KEY RESULTSIntra-articular injection of neutrophil elastase caused an increase in blood perfusion, leukocyte kinetics and a decrease in paw withdrawal threshold. Sivelestat treatment suppressed this effect. The PAR2 antagonist GB83 reversed neutrophil elastase-induced synovitis and pain and these responses were also attenuated in PAR2 KO mice. The MAPK inhibitor U0126 also blocked neutrophil elastase-induced inflammation and pain. Active neutrophil elastase was increased in acutely inflamed knees as shown by an activatable fluorescent probe. Sivelestat appeared to reduce neutrophil elastase activity, but had only a moderate anti-inflammatory effect in this model. CONCLUSIONS AND IMPLICATIONSNeutrophil elastase induced acute inflammation and pain in knee joints of mice. These changes are PAR2-dependent and appear to involve activation of a p44/42 MAPK pathway. Blocking neutrophil elastase, PAR2 and p44/42 MAPK activity can reduce inflammation and pain, suggesting their utility as therapeutic targets. DOI:10.1111/bph.13237 www.brjpharmacol.org © 2015 The British Pharmacological Society Themed Section: Inflammation: maladies, models, mechanisms and molecules BJP British Journal of Pharmacology LINKED ARTICLESThis article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit http://dx

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Sivelestat Attenuates Lung Injury in Surgery for Congenital Heart Disease With Pulmonary Hypertension

Cited by 15 publications

References 15 publications

Neutrophil elastase plays a non‐redundant role in remodeling the venular basement membrane and neutrophil diapedesis post‐ischemia/reperfusion injury

Neutrophil elastase plays a non‐redundant role in remodeling the venular basement membrane and neutrophil diapedesis post‐ischemia/reperfusion injury

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

Neutrophil elastase induces inflammation and pain in mouse knee joints via activation of proteinase‐activated receptor‐2

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