Effect of a neutrophil elastase inhibitor (ONO-5046 Na) on ischemia/reperfusion injury using the left-sided heterotopic canine heart transplantation model

Ueno, Masahiro; Moriyama, Yukinori; Toda, Riichiro; Yotsumoto, Goichi; Yamamoto, Hiroyuki; Fukumoto, Yoshihiro; Sakasegawa, K; Nakamura, Kazuo; Sakata, Ryuzo

doi:10.1016/s1053-2498(01)00281-9

Cited by 25 publications

(24 citation statements)

References 29 publications

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“…Different types of elastase inhibitors have been characterized from human skin (Lammers et al, 1986), parotid secretions, and bronchial mucus (Hochstrasser et al, 1981), as well as from other sources such as soybean (Odani and Ikenaka, 1978), turkey ovomucoid and leech (Seemuller et al, 1980) and suggested that the innate elastase inhibitors may play an important role for the protection of organs and tissues (Ashcroft et al, 2000;O'Blenes et al, 2000;Tonai et al, 2001;Ueno et al, 2001;Waugh et al, 2001). Furthermore, the leukocyte elastase inhibitors were considered as potential therapeutic agents for preventing number of chronic inflammatory diseases.…”

Section: Introductionmentioning

confidence: 99%

Paradoxical effects of elastase inhibitor guamerin on the tissue repair of two different wound models: sealed cutaneous and exposed tongue wounds

Lee

Lee²,

Song³

et al. 2004

Exp Mol Med

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Section: Introductionmentioning

confidence: 99%

Paradoxical effects of elastase inhibitor guamerin on the tissue repair of two different wound models: sealed cutaneous and exposed tongue wounds

Lee

Lee²,

Song³

et al. 2004

Exp Mol Med

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“…Haga et al [29] demonstrated that sivelestat at clinically available concentrations can inhibit proinflammatory cytokine production in isolated human monocytes. Further examination is needed to clarify whether the 18 suppression of IL-6 production could result from inhibition of neutrophil elastase activation or inhibition of proinflammatory cytokine release from monocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Recent animal studies have shown that sivelestat reduces the ischemia-reperfusion injury associated with liver [16], lung [17], or heart [18] transplantation.…”

Section: Introductionmentioning

confidence: 99%

Postischemic infusion of sivelestat sodium hydrate, a selective neutrophil elastase inhibitor, protects against myocardial stunning in swine

et al. 2010

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Purpose. It seems controversial whether or not neutrophil elastase inhibitors are effective in attenuating the myocardial ischemia/reperfusion injury. We thus investigated possible protective effects of sivelestat, a neutrophil elastase inhibitor, against myocardial stunning-i.e., prolonged myocardial dysfunction following a brief episode of ischemia.Methods. Swine were divided into control group (group C), low-dose sivelestat group (group L), and high-dose sivelestat group (group H) (n=7 for each group). All the swine were subjected to myocardial ischemia through ligation of the left anterior descending coronary artery (LAD) for 12-min, followed by 90-min reperfusion. Sivelestat was infused intracoronally at concentrations of 6 and 60 mg/ml throughout the reperfusion period in the group L and H, respectively, while saline in the group C. Heart rate (HR), left ventricular developed pressure (LVdP), maximum rate of LVdP (LVdP/dtmax), LV end-diastolic pressure (LVEDP), percentage of segment shortening (%SS, an index of regional myocardial contractility), and coronary venous interleukin-6 concentration in LAD perfusion area were measured before ischemic induction and during reperfusion. Results. The ischemia-reperfusion insult did not cause any significant changes in the HR, LVdP, LVdP/dtmax, and LVEDP in all groups. However, it significantly decreased %SS in the LAD perfusion area, while increased the interleukin-6 concentration in the group C. Those changes in %SS and the interleukin-6 concentration were both greatly attenuated, but not prevented, in the group L and group H. Conclusion.Sivelestat presumably attenuates myocardial contractile dysfunction due to myocardial stunning by inhibiting neutrophil-derived elastase and thereby suppressing the production of interleukin-6 in activated neutrophils.(250 words) 4

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“…The priority in renal transplantation, and the principal clinical goal of our research team, is the prevention of I/R injury and the reduction of ATN (1). Recent studies have suggested a significant relationship between I/R injury and neutrophils (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Neutrophils release various substances that cause tissue damage, including oxgen-free radicals, neutrophil elastase and arachidonic acid (9).…”

Section: Discussionmentioning

confidence: 99%

The effect of neutrophil elastase inhibitor on acute tubular necrosis after renal ischemia-reperfusion injury

Matsuyama

Hayama²,

Funao³

et al. 2008

Mol Med Report

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Abstract. In renal transplantation, ischemia-reperfusion (I/R) injury is a major cause of renal dysfunction. Activated neutrophils are reported to be closely involved in I/R injury after renal transplantation. Neutrophil elastase, a protease released from activated neutrophils, damages tubular endothelial cells. We investigated the beneficial effect of neutrophil elastase inhibitor (ONO-5046.Na) on renal I/R injury in rats. The study was conducted using 10 male Lewis rats (270-320 g) that were intravenously administered ONO-5046.Na (30 mg/kg before ischemia and after reperfusion) (group A) and control rats (group B) in a 90-min renal warm I/R injury model. Neutrophil elastase expression was analyzed using immunohistochemical staining, and the degree of renal dysfunction was evaluated using H&E staining and blood biochemistry. Neutrophil elastase was detected in tubular endothelial cells. The necrotic area extended to and encompassed nearly all the ischemic kidney within 12 h after reperfusion. The necrotic area and the grade of neutrophil elastase staining were significantly reduced in group A compared to group B. Significant differences in blood urea nitrogen and serum creatinine levels were observed. Survival rates over a 14-day period were examined. No rats survived for more than 4 days in group B. However, 2 of the 10 rats (20%) in group A survived for a 14-day period. To conclude, ONO-5046.Na inhibits neutrophil elastase and reduces acute tubular necrosis. Thus, it is a potent therapeutic agent for the control of renal I/R injury in renal transplantation.

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Effect of a neutrophil elastase inhibitor (ONO-5046 Na) on ischemia/reperfusion injury using the left-sided heterotopic canine heart transplantation model

Cited by 25 publications

References 29 publications

Paradoxical effects of elastase inhibitor guamerin on the tissue repair of two different wound models: sealed cutaneous and exposed tongue wounds

Paradoxical effects of elastase inhibitor guamerin on the tissue repair of two different wound models: sealed cutaneous and exposed tongue wounds

Postischemic infusion of sivelestat sodium hydrate, a selective neutrophil elastase inhibitor, protects against myocardial stunning in swine

The effect of neutrophil elastase inhibitor on acute tubular necrosis after renal ischemia-reperfusion injury

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