Effect Of Neutrophil Elastase Inhibitor Research Articles

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

Background: Activated neutrophils are reported to be closely involved in ischemia-reperfusion injury after lung transplantation. We investigated the beneficial effects of a new recombinant specific neutrophil elastase inhibitor, ONO-5046 · Na, and an extracorporeal-type granulotrap (G-1) column on ischemia-reperfusion lung injury, by using an in situ warm lung ischemia model in dogs. Methods Warm ischemia was induced for 3 hours by clamping the pulmonary arteries and veins. The left main bronchus was bisected and reanastomosed prior to reperfusion. The left lung was collapsed for 3 hours. A total of 27 adult mongrel dogs were divided into three groups: the control group ( n = 9) treated with a saline vehicle; the ONO group ( n = 9), in which ONO-5046 · Na was continuously administrated from before induced ischemia and to ending 2 hours after reperfusion; and the G-1 group ( n = 9), in which a G-1 column was applied for 90 minutes starting 30 minutes before reperfusion under passive bypass support. Results Circulating neutrophils in the G-1 group decreased significantly ( p < .05) compared to preischemia, and significantly decreased compared with the other groups after reperfusion. Oxygenation was improved actually and pulmonary vascular resistance was kept lower level after the administration of ONO-5046 · Na. The increase of lung weight was significantly ameliorated in both the G-1 and ONO groups. In the histopathological study, lungs from the control group demonstrated diffuse alveolar edema, neutrophil infiltration, massive alveolar exudate and hemorrhage, and thickening of the interstitium. Lungs from the G-1 group showed mild swelling of the alveolar wall and neutrophil infiltration. Lungs from the ONO group showed virtually no abnormalities. Conclusion This study demonstrated that a neutrophil elastase inhibitor and neutrophil depletion prevented lung reperfusion injury. These treatments may prevent ischemia and reperfusion injury in lung transplantation.

The Effect of Neutrophil Elastase Inhibitor in Hepatectomy with Ischemia in Dogs

Activated neutrophils play an important role in reperfusion injury following hepatic ischemia. Neutrophil elastase is a powerful proteolytic enzyme. We investigated the possibility that ONO-5046 · Na, which is a new recombinant-specific neutrophil elastase inhibitor, can reduce ischemia and reperfusion injury in the canine liver. Adult mongrel dogs (n= 19) were used in this experimental study. Seventy-five percent of the liver was resected after 60 min of vascular occlusion. The animals were divided into two groups. The ONO group (n= 8) was given ONO-5046 · Na dissolved in saline starting 30 min prior to clamping the hepatic inflow and continuing for 4 h after reperfusion at a rate of 10 mg/kg/h. The nontreatment group (n= 11) received a saline solution for the same period. ALT and LDH levels were significantly lower (P< 0.05) in the ONO group than in the nontreatment group after reperfusion. Purine nucleoside phosphorylase and hyaluronic acid levels, which are markers of endothelial damage, were significantly lower (P< 0.05) in the ONO group than in the nontreatment group after reperfusion. Histologically, widely spread hepatocyte necrosis was found in dogs in the nontreatment group that died prematurely. Neutrophil infiltration of the sinusoids was less evident in the ONO group than in the nontreatment group. Neutrophil elastase inhibitor may prevent injuries of both endothelial and parenchymal cells in extended hepatectomy with vascular occlusion.

Effects of neutrophil elastase inhibitor on bleomycin-induced pulmonary fibrosis in mice.

Neutrophils play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). To elucidate the possible involvement of neutrophil elastase (NE) in pulmonary fibrosis, we investigated the efficacy of a new specific NE inhibitor (ONO-5046 Na) in a murine model of human IPF, bleomycin-induced pulmonary fibrosis. Bronchoalveolar lavage (BAL) and histopathological analysis were performed on bleomycin-treated mice (group A), bleomycin and ONO-5046 Na-treated mice (group B), and saline control groups at 1, 15, and 29 d after the end of bleomycin treatment. At 29 d, multifocal fibrosis was observed in group A, whereas no fibrotic regions were observed in group B. Interleukin-1 beta and macrophage inflammatory protein-2 mRNA levels in BAL cells on day 1, and platelet-derived growth factor-A and insulin-like growth factor-1 mRNA levels on days 1 and 15, were significantly lower in group B than in group A. Thus, we demonstrated an inhibitory effect of ONO-5046. Na on pulmonary fibrosis in mice, indicating the involvement of NE in the pathogenesis of pulmonary fibrosis. We propose that this effect might be related to suppressed expression of particular cytokines in alveolar macrophages and that this specific NE inhibitor could be a novel therapeutic agent for IPF.

Effect of neutrophil elastase inhibitor (ONO5046) on acute lung injury: Endotoxin and PAF-induced rabbit model : Manabu Kinoshita, Satoshi Ono, Suefumi Aosasa, Hidetaka Mochizuki, and Shoetu Tamakuma From the First Department of Surgery, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359, Japan

Effect of neutrophil elastase inhibitor (ONO5046) on acute lung injury: Endotoxin and PAF-induced rabbit model : Manabu Kinoshita, Satoshi Ono, Suefumi Aosasa, Hidetaka Mochizuki, and Shoetu Tamakuma From the First Department of Surgery, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359, Japan