Neutrophil Elastase Inhibitor Sivelestat Attenuates Perioperative Inflammatory Response in Pediatric Heart Surgery With Cardiopulmonary Bypass

Inoue, Nobuyuki; Oka, Norihiko; Kitamura, Tadashi; Shibata, Kazuaki; Tomoyasu, Takahiro; Miyaji, Kagami

doi:10.1536/ihj.54.149

Cited by 22 publications

(21 citation statements)

References 23 publications

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“…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%

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: 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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“…Interventions which may prove efficacious in the adult brain can not necessarily be extrapolated to function similarly or safely in the developing brain (Natale et al, 2006). Of note, inhibition of human NE using the compound sivelestat (ONO 5046, Ono Pharmaceuticals Co., Ltd.) has demonstrated safety in a pediatric population for acute respiratory distress syndrome (Kikuchi et al, 2006; Matsumoto et al, 2009), as well as efficacy attenuating the post-operative inflammatory response and improving clinical outcomes after cardiopulmonary surgery in children (Inoue et al, 2013; Kohira et al, 2013). Although acute NE inhibition failed to improve long-term outcomes in the current study, these clinical findings suggest that administration of optimized NE inhibitors to pediatric patients may be a safe and feasible option after pediatric TBI.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil elastase mediates acute pathogenesis and is a determinant of long-term behavioral recovery after traumatic injury to the immature brain

Semple

Trivedi

Gimlin

et al. 2015

Neurobiology of Disease

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While neutrophil elastase (NE), released by activated neutrophils, is a key mediator of secondary pathogenesis in adult models of brain ischemia and spinal cord injury, no studies to date have examined this protease in the context of the injured immature brain, where there is notable vulnerability resulting from inadequate antioxidant reserves and prolonged exposure to infiltrating neutrophils. We thus reasoned that NE may be a key determinant of secondary pathogenesis, and as such, adversely influence long-term neurological recovery. To address this hypothesis, wild-type (WT) and NE knockout (KO) mice were subjected to a controlled cortical impact at post-natal day 21, approximating a toddler-aged child. To determine if NE is required for neutrophil infiltration into the injured brain, and whether this protease contributes to vasogenic edema, we quantified neutrophil numbers and measured water content in the brains of each of these genotypes. While leukocyte trafficking was indistinguishable between genotypes, vasogenic edema was markedly attenuated in the NE KO. To determine if early pathogenesis is dependent on NE, indices of cell death (TUNEL and activated caspase-3) were quantified across genotypes. NE KO mice showed a reduction in these markers of cell death in the injured hippocampus, which corresponded to greater preservation of neuronal integrity as well as reduced expression of heme oxygenase-1, a marker of oxidative stress. WT mice, treated with a competitive inhibitor of NE at 2, 6 and 12 h post-injury, likewise showed a reduction in cell death and oxidative stress compared to vehicle-treated controls. We next examined the long-term behavioral and structural consequences of NE deficiency. NE KO mice showed an improvement in long-term spatial memory retention and amelioration of injury-induced hyperactivity. However, volumetric and stereological analyses found comparable tissue loss in the injured cortex and hippocampus independent of genotype. Further, WT mice treated acutely with the NE inhibitor showed no long-term behavioral or structural improvements. Together, these findings validate the central role of NE in both acute pathogenesis and chronic functional recovery, and support future exploration of the therapeutic window, taking into account the prolonged period of neutrophil trafficking into the injured immature brain.

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“…In patients with ARDS secondary to sepsis, selective neutrophil elastase inhibitor sivelestat has been reported to improve oxygenation, reduce lung injury and shorten the length of ICT stay 160-161 . In the context of postoperative ALI without sepsis, while it improves inflammatory mediator levels, the benefit on prognosis is unclear 162-164 .…”

Section: Conclusion and Way Forwardmentioning

confidence: 99%

Perioperative “remote” acute lung injury: recent update

Jin

Suen

2017

J Biomed Res

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Perioperative acute lung injury (ALI) is a syndrome characterised by hypoxia and chest radiograph changes. It is a serious post-operative complication, associated with considerable mortality and morbidity. In addition to mechanical ventilation, remote organ insult could also trigger systemic responses which induce ALI. Currently, there are limited treatment options available beyond conservative respiratory support. However, increasing understanding of the pathophysiology of ALI and the biochemical pathways involved will aid the development of novel treatments and help to improve patient outcome as well as to reduce cost to the health service. In this review we will discuss the epidemiology of peri-operative ALI; the cellular and molecular mechanisms involved on the pathological process; the clinical considerations in preventing and managing perioperative ALI and the potential future treatment options.

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Neutrophil Elastase Inhibitor Sivelestat Attenuates Perioperative Inflammatory Response in Pediatric Heart Surgery With Cardiopulmonary Bypass

Cited by 22 publications

References 23 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

Neutrophil elastase mediates acute pathogenesis and is a determinant of long-term behavioral recovery after traumatic injury to the immature brain

Perioperative “remote” acute lung injury: recent update

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