A Neutrophil Elastase Inhibitor, Sivelestat, Improves Leukocyte Deformability in Patients With Acute Lung Injury

Inoue, Yoshiaki; Tanaka, Hiroshi; Ogura, Hiroshi; Ukai, Isao; Fujita, Kazuyuki; Hosotsubo, Hideo; Shimazu, Takeshi; Sugimoto, Hisashi

doi:10.1097/01.ta.0000217271.25809.a0

Cited by 32 publications

(27 citation statements)

References 41 publications

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“…13,14 A specific NE inhibitor, sivelestat sodium hydrate (ONO-5046), is now approved for clinical use on ALI complicated with systemic inflammatory response syndrome in Japan. Although several clinical reports describe the protective effects of ONO-5046 on human ALI associated with systemic inflammatory response syndrome, [15][16][17][18][19] the literature includes no report of a clinical study evaluating the effect of ONO-5046 on ALI complicated with AKI. The present study is designed to elucidate the possible therapeutic effects of a specific NE inhibitor ONO-5046 on ALI induced by AKI using mouse BNx model.…”

mentioning

confidence: 99%

Neutrophil Elastase Contributes to Acute Lung Injury Induced by Bilateral Nephrectomy

Ishii

Doi

Okamoto

et al. 2010

The American Journal of Pathology

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Acute kidney injury (AKI) is a serious problem in critically ill patients of intensive care units. It has been reported previously that AKI can induce acute lung injury (ALI), as well as cause injuries to other remote organs , including the lungs. Patients with AKI complicated by ALI show remarkably high mortality. ALI is characterized by neutrophil infiltration into the lung. Neutrophil elastase (NE) is a key enzyme for tissue injury caused by activated neutrophils , such as occurs in ALI. Therefore , this study investigated the role of NE in AKI-induced ALI using a specific NE inhibitor , sivelestat sodium hydrate (ONO-5046), in a mouse bilateral nephrectomy model. Bilateral nephrectomy showed not only a remarkable increase in blood urea nitrogen levels, but also demonstrated neutrophil infiltration into the lung, increased pulmonary inflammatory cytokine expression [interleukin-6, neutrophil chemokine keratinocyte-derived chemokine, and tumor necrosis factor-␣], and protein leakage with early increases in both systemic and pulmonary NE activity. ONO-5046 treatment reduced NE activity and improved these pulmonary inflammatory responses. Additionally, ONO-5046-treated animals had longer survival times. These data demonstrate that increasing NE activity induces pulmonary inflammatory damage in a bilateral nephrectomy model. Blockade of NE activity will be a useful therapeutic strategy for ALI complications in AKI patients. Acute lung injury (ALI) is a life-threatening condition that is frequently complicated with acute kidney injury (AKI), which is a serious condition in intensive care units. The ALI mortality is higher than 50% and increases with the development of other organ failure including AKI.1 One report described a mortality rate higher than 80% for patients with AKI complicated with ALI.2 Current prevention and treatment strategies for AKI cannot sufficiently improve the mortality of these severely ill patients. Although many basic and clinical researchers are investigating novel therapies for AKI, 3 targeting of other organ damages caused by AKI is also necessary for improving AKI outcomes.Recently, it has been suggested that AKI influences other remote organs including the lungs.4 -6 Experimental evidence indicates that AKI-induced ALI occurs not only by volume overload, but also through deleterious kidneylung interactions. Mechanisms of AKI-induced ALI include dysregulation of inflammatory reaction, innate immune response, oxidative stress, apoptosis, and soluble mediator metabolism.7 Rodent models of bilateral nephrectomy (BNx) and renal ischemia reperfusion have been used to investigate the role of AKI in the pathogenesis of ALI. 8 -11 Ischemic AKI engenders increased pulmonary vascular permeability by down-regulating pulmonary epithelial sodium channel, Na,K-ATPase, and aquaporin-5. 10 Ischemic AKI induced leukocyte accumulation and activation of inflammatory transcription factors such as nuclear factor-B and p38 mitogen-activated protein kinase in the lung, which was attenuated by an anti-infla...

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confidence: 99%

Neutrophil Elastase Contributes to Acute Lung Injury Induced by Bilateral Nephrectomy

Ishii

Doi

Okamoto

et al. 2010

The American Journal of Pathology

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“…Varied methods to measure PMN deformability have been reported, 17,18 but we used the method described by Tanaka et al, 8,9,13 which is able to measure PMN deformability at the bedside easily and quickly in a serial fashion and in realtime. Therefore, this strategy might lead to earlier diagnosis of DIC, quick institution of treatment, and the effective monitoring of the response to treatment.…”

Section: Discussionmentioning

confidence: 99%

“…To determine the relationship between PMN activity and PMN deformability, the abundance of CD11b on the cell Acute Medicine & Surgery 2015; 2: [13][14][15][16][17][18][19][20] Leukocyte deformability in sepsis-induced DIC 17 surface was measured in 11 sepsis-induced DIC patients and five sepsis patients without DIC in this study. Nine healthy volunteers were used as controls.…”

Section: Polymorphonuclear Leukocyte Activity In Patients With Sepsismentioning

confidence: 99%

“…The system allows microscopic observation of the flow behavior of blood cells using an in vitro model of a capillary. 8,9,13 A blood sample (200 μL) was vacuumed automatically and was passed through a silicon tip in which 8,736 parallel channels of equal diameter (7 μm) were carved. The PMN flow in the channels was monitored and recorded with an inverted microscope and a video camera system.…”

Section: Polymorphonuclear Leukocyte Deformability and Blood Rheologymentioning

confidence: 99%

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Leukocyte deformability is a novel biomarker to reflect sepsis‐induced disseminated intravascular coagulation

Morikawa

Inoue

Sumi

et al. 2014

Acute Medicine & Surgery

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Aim: Sepsis-induced disseminated intravascular coagulopathy is associated with a high mortality rate. The function and deformability of polymorphonuclear leukocytes change in patients with sepsis. The goal of this study was to characterize the changes in polymorphonuclear leukocyte deformability in patients with sepsis-induced disseminated intravascular coagulopathy and to evaluate the relationship between the severity of disseminated intravascular coagulopathy and the deformability of polymorphonuclear leukocytes.Methods: Thirty-five patients with sepsis-induced disseminated intravascular coagulopathy at our department were enrolled in this study. These patients were diagnosed with severe sepsis and an acute disseminated intravascular coagulopathy score ≥ 4. Blood samples were obtained from these patients on days 1, 3, and 7. Polymorphonuclear leukocyte deformability was measured with a microchannel flow analyzer, and polymorphonuclear leukocyte activity, represented as CD11b, was measured by flow cytometry. In contrast, 14 patients who fulfilled with sepsis criteria but without complicated disseminated intravascular coagulopathy were also entered in this study. Results:In patients with sepsis-induced disseminated intravascular coagulopathy, there was a significant correlation between their Japanese Association for Acute Medicine disseminated intravascular coagulopathy score and polymorphonuclear leukocyte deformability, and CD11b expression. Polymorphonuclear leukocytes became more stiffened and CD11b expression was higher in patients with sepsis-induced disseminated intravascular coagulopathy compared to patients without the condition. Conclusion:Polymorphonuclear leukocyte deformability correlated with the severity of sepsis-induced disseminated intravascular coagulopathy and the response to treatment.

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“…Moreover, experiments have shown its efficacy in animal models of lung injuries caused by endotoxin (6), cobra toxin (7) (which is a complement activator), bleomycin (8), and hydrochloric acid (9,10). Today it is widely used in clinics to improve acute lung injury accompanying systemic inflammatory response syndrome caused by aspiration pneumonia, surgery, injury, and infection (11)(12)(13)(14). Experimental studies have shown that, in the case of radiation-induced lung injury, the immediate release of proinflammatory cytokines such as TNF-α, IL-1 and IL-6 after lung irradiation is closely related with lung toxicity.…”

Section: Introductionmentioning

confidence: 99%

Effects of sivelestat sodium hydrate on the reduction of radiation pneumonitis

Shimbo

Inomata²,

Takahashi³

et al. 2007

Int J Mol Med

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Abstract. In this study, we irradiated the murine lung and analyzed the inhibitory effects of sivelestat sodium hydrate, a neutrophil elastase (NE) inhibitor, on lung injury in mice. Sivelestat sodium hydrate (3 mg/kg) was administered by intraperitoneal injection immediately, 3, 6, and 12 h after irradiation in groups RE-0, RE-3, RE-6, and RE-12, respectively. A control group and a group receiving radiation without sivelestat (group R) were also used. NE activity was measured 24 and 48 h after irradiation. The lungs were simultaneously extirpated and stained with hematoxylin and eosin and a naphthol AS-D chloroacetate esterase stain (N-ASDCLA). NE activity increased in the groups in which the murine lungs were irradiated. There was no increase in NE activity in the control group. Among the sivelestatadministered groups, NE activity was slightly elevated in group RE-0 and was suppressed, compared to group R, in groups RE-3, RE-6, and RE-12 at 24 h after irradiation. In the irradiated groups, intra-alveolar neutrophil infiltration, perivascular edema, and alveolar wall thickness were observed, but these changes were mild in the sivelestat-administered groups. The number of N-ASDCLA-positive cells increased in the sivelestat-administered groups, while group R had low values. This indicated that sivelestat sodium hydrate blocked the release of NE from the neutrophils in the irradiated lungs. NE plays an important role in the development of radiationinduced lung injury. Sivelestat is thus expected to decrease radiation-induced lung toxicity by suppressing NE release from neutrophils.

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A Neutrophil Elastase Inhibitor, Sivelestat, Improves Leukocyte Deformability in Patients With Acute Lung Injury

Abstract: NE concentration and neutrophil rigidity are significantly increased in SIRS patients with ALI. Sivelestat appears to reduce NE concentration and neutrophil stiffness and improve pulmonary oxygenation in patients with ALI.

Cited by 32 publications

References 41 publications

Neutrophil Elastase Contributes to Acute Lung Injury Induced by Bilateral Nephrectomy

Neutrophil Elastase Contributes to Acute Lung Injury Induced by Bilateral Nephrectomy

Leukocyte deformability is a novel biomarker to reflect sepsis‐induced disseminated intravascular coagulation

Effects of sivelestat sodium hydrate on the reduction of radiation pneumonitis

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