The effects of a neutrophil elastase inhibitor (ONO-5046 · Na) and neutrophil depletion using a granulotrap (G-1) column on lung reperfusion injury in dogs

Tomizawa, Naoki; Ohwada, Susumu; Ohya, Toshihiro; Takeyoshi, Izumi; Ogawa, Tetsushi; Kawashima, Yasunaru; Adachi, Masakazu; Morishita, Yasuo

doi:10.1016/s1053-2498(99)00030-3

Cited by 24 publications

(23 citation statements)

References 30 publications

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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%

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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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Section: Discussionmentioning

confidence: 99%

“…This inhibitor is clinically used to ameliorate acute respiratory distress syndrome. It is reported to have a positive effect on heart (5), lung (6)(7)(8), liver (9-11) and intestinal (12) I/R injury in experimental models; however, no study has addressed its effect on renal I/R injury.…”

Section: Introductionmentioning

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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“…ONO-5046 Na, sodium N-[2-[4-(2,2-dimethylpropionyloxy)phenyl-sulfonylamino]benzoyl] aminoacetate tetrahydrate (Ono Pharma Co., Ltd, Osaka, Japan), is a new recombinant specifi c neutrophil elastase inhibitor. Cross-reactivity between human elastase inhibitor and canine leukocyte elastase was not tested in this experimental study, but there are reports of the effi cacy of this agent against reperfusion injury of the heart [8] and lungs [9,10] in canine models. However, the experimental studies of lung reperfusion were performed on the warm ischemic model [9] , not the transplantation model [9,10] .…”

Section: Discussionmentioning

confidence: 99%

“…Cross-reactivity between human elastase inhibitor and canine leukocyte elastase was not tested in this experimental study, but there are reports of the effi cacy of this agent against reperfusion injury of the heart [8] and lungs [9,10] in canine models. However, the experimental studies of lung reperfusion were performed on the warm ischemic model [9] , not the transplantation model [9,10] . Thus, the aim of the present study was to investigate the effect of neutrophil elastase inhibitor on lung ischemia-reperfusion injury in a canine model of single lung transplantation after 18 h of cold preservation.…”

Section: Discussionmentioning

confidence: 99%

“…Lung reperfusion injury is thought to increase pulmonary vascular permeability [3][4][5][6] , allowing neutrophil endopeptidases, such as elastase and protease, to directly injure pulmonary endothelial cells [7] . Neutrophil endopeptidase inhibitors have been shown to attenuate reperfusion injury of the heart [8] and lungs [6,9,10] in animal models, but there has been no report of neutrophil elastase inhibitors preventing lung reperfusion injury in situ after cold preservation. Thus, we investigated the effects of neutrophil elastase inhibitor on lung ischemia-reperfusion injury in a canine model of single lung transplantation after cold preservation.…”

Section: Introductionmentioning

confidence: 99%

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Neutrophil Elastase Inhibitor Ameliorates Reperfusion Injury in a Canine Model of Lung Transplantation

Aoki¹,

Tsuchida²,

Takekubo³

et al. 2005

Eur Surg Res

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Background: We investigated the effects of neutrophil elastase inhibitor ONO-5046 Na on lung ischemia-reperfusion injury in a canine model of single lung transplantation. Methods: 24 mongrel dogs, 12 donors and 12 recipients, were used for single lung transplantation. Lung grafts were preserved for 18 h by cold ischemia then transplanted into the left thoracic cavity of recipients. In 6 recipients (ONO group), a bolus of ONO-5046 Na (10 mg/kg) was introduced before reperfusion and followed by continuous infusion (10 mg/kg/h). The remaining 6 recipients (control group) did not receive ONO-5046 Na and thus served as controls. We evaluated lung function and respiratory parameters over 240 min. Results: The total cell number in bronchoalveolar lavage fluid increased significantly in the control group in comparison to that in the ONO group. Histologic scores after 4 h of reperfusion and myeloperoxidase activity were significantly lower in the ONO group than in the control group. Conclusion: Neutrophil elastase inhibitor ONO-5046 Na may be useful in ameliorating lung reperfusion injury after transplantation.

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Protease inhibitors of the sulfonamide type: Anticancer, antiinflammatory, and antiviral agents

Supuran

Casini

Scozzafava

2003

Medicinal Research Reviews

394

153

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The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anticarbonic anhydrase, diuretic, hypoglycemic, and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial protease inhibitory properties. Of particular interest are some metalloprotease inhibitors belonging to this class, which by inhibiting several matrix metalloproteases (MMPs) show interesting antitumor properties. Some of these compounds are currently being evaluated in clinical trials. The large number of sulfonamide MMP inhibitors ultimately reported also lead to the design of effective tumor necrosis factor-alpha converting enzyme (TACE) inhibitors, potentially useful in the treatment of inflammatory states of various types. Since both MMPs and TACE contribute synergistically to the pathophysiology of many diseases, such as arthritis, bacterial meningitis, tumor invasion; the dual inhibition of these enzymes emerged as an interesting target for the drug design of anticancer/antiinflammatory drugs, and many such sulfonamide derivatives were recently reported. Human neutrophyl elastase (HNE) inhibitors of the sulfonamide type may also be useful in the treatment of inflammatory conditions, such as emphysema, cystic fibrosis, chronic bronchitis, ischemia reperfusion injury, and acute respiratory distress syndrome. Inhibition of some cysteine proteases, such as several caspase and cathepsin isozymes, may lead to the development of pharmacological agents effective for the management of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, brain damage, and stroke. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Some clinically used HIV protease inhibitors (such as amprenavir) possess sulfonamide moieties in their molecules, which are critical for the potency of these drugs, as shown by means of X-ray crystallography, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with lower toxicity or augmented activity against viruses resistant to the such first generation drugs. Other viral proteases, such as those isolated from several types of herpes viruses may be inhibited by sulfonamide derivatives, leading thus to more effective classes of antiviral drugs.

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The effects of a neutrophil elastase inhibitor (ONO-5046 · Na) and neutrophil depletion using a granulotrap (G-1) column on lung reperfusion injury in dogs

Cited by 24 publications

References 30 publications

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

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

Neutrophil Elastase Inhibitor Ameliorates Reperfusion Injury in a Canine Model of Lung Transplantation

Protease inhibitors of the sulfonamide type: Anticancer, antiinflammatory, and antiviral agents

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