A specific neutrophil elastase inhibitor (ONO-5046.Na) attenuates LPS-induced acute lung inflammation in the hamster

Yasui, Shuji; Nagai, Atsushi; Aoshiba, Kazutetsu; Ozawa, Yoshihito; Kakuta, Yumi; Konno, K.

doi:10.1183/09031936.95.08081293

Cited by 43 publications

(21 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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“…[35][36][37] In contrast to endogenous protease inhibitors, ONO-5046 assumed to be able to inhibit NE effectively in inflammatory conditions because it is not inactivated by reactive oxygen species. 38,39 The present study is the first report that shows the protective effect of ONO-5046 on AKI-induced ALI.…”

Section: Discussionmentioning

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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“…Therapeutic approaches for AATD include AAT augmentation therapy (Abboud et al 2001), administration of either natural (elafin (Simpson et al 2001) or secretory leukoprotease inhibitor (SLPI) (Gibbons et al 2009)) or synthetic (Sivelestat) anti-proteases (Iba et al 2006;Yasui et al 1995) or inhibition of AAT polymerization (Bjork et al 1992;Chang et al 1996;Fitton et al 1997)) and gene therapy (Liqun Wang et al 2009). Augmentation therapy involves infusion of purified human plasma AAT (60 mg per kilogram of body weight per week) to achieve serum Fig.…”

Section: The Use Of Aat Augmentation Therapy In Treatment Of Lung Dismentioning

confidence: 99%

Alpha-1 Antitrypsin: A Potent Anti-Inflammatory and Potential Novel Therapeutic Agent

Bergin

Hurley

McElvaney

et al. 2012

Arch. Immunol. Ther. Exp.

120

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Alpha-1 antitrypsin (AAT) has long been thought of as an important anti-protease in the lung where it is known to decrease the destructive effects of major proteases such as neutrophil elastase. In recent years, the perception of this protein in this simple one dimensional capacity as an anti-protease has evolved and it is now recognised that AAT has significant anti-inflammatory properties affecting a wide range of inflammatory cells, leading to its potential therapeutic use in a number of important diseases. This present review aims to discuss the described anti-inflammatory actions of AAT in modulating key immune cell functions, delineate known signalling pathways and specifically to identify the models of disease in which AAT has been shown to be effective as a therapy.

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A specific neutrophil elastase inhibitor (ONO-5046.Na) attenuates LPS-induced acute lung inflammation in the hamster

Cited by 43 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 Contributes to Acute Lung Injury Induced by Bilateral Nephrectomy

Alpha-1 Antitrypsin: A Potent Anti-Inflammatory and Potential Novel Therapeutic Agent

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