Effects of sivelestat sodium hydrate on the reduction of radiation pneumonitis

Shimbo, Taiju; Inomata, Taisuke; Takahashi, Masatsugu; Tatsumi, Toshiaki; Uesugi, Yasuo; Narabayashi, Isamu; Sonobe, Hiroshi

doi:10.3892/ijmm.20.6.817

Cited by 4 publications

(7 citation statements)

References 28 publications

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“…Moreover, toxic effects of ozone caused by excessive doses of inhaled ozone in the airways, as well as toxicity to the endocrine, reproductive, and central nervous systems, have been described ( 21 , 22 ). Although it has been demonstrated that an intrarectal or ip ozone/oxygen mixture reduced ROS by stimulation and/or preservation of the endogenous antioxidant systems in experimental models of liver and renal ischemia-reperfusion and radiation-induced organ injury, respectively ( 7 , 9 , 17 , 23 , 24 ), little is known about its side effects that are specifically related to free radical formation and irritation of the respiratory system.…”

Section: Discussionmentioning

confidence: 99%

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Effect of ozone oxidative preconditioning in preventing early radiation-induced lung injury in rats

Bakkal

Gültekin

Güven

et al. 2013

Braz J Med Biol Res

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Ionizing radiation causes its biological effects mainly through oxidative damage induced by reactive oxygen species. Previous studies showed that ozone oxidative preconditioning attenuated pathophysiological events mediated by reactive oxygen species. As inhalation of ozone induces lung injury, the aim of this study was to examine whether ozone oxidative preconditioning potentiates or attenuates the effects of irradiation on the lung. Rats were subjected to total body irradiation, with or without treatment with ozone oxidative preconditioning (0.72 mg/kg). Serum proinflammatory cytokine levels, oxidative damage markers, and histopathological analysis were compared at 6 and 72 h after total body irradiation. Irradiation significantly increased lung malondialdehyde levels as an end-product of lipoperoxidation. Irradiation also significantly decreased lung superoxide dismutase activity, which is an indicator of the generation of oxidative stress and an early protective response to oxidative damage. Ozone oxidative preconditioning plus irradiation significantly decreased malondialdehyde levels and increased the activity of superoxide dismutase, which might indicate protection of the lung from radiation-induced lung injury. Serum tumor necrosis factor alpha and interleukin-1 beta levels, which increased significantly following total body irradiation, were decreased with ozone oxidative preconditioning. Moreover, ozone oxidative preconditioning was able to ameliorate radiation-induced lung injury assessed by histopathological evaluation. In conclusion, ozone oxidative preconditioning, repeated low-dose intraperitoneal administration of ozone, did not exacerbate radiation-induced lung injury, and, on the contrary, it provided protection against radiation-induced lung damage.

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Section: Discussionmentioning

confidence: 99%

“…Experimental studies have shown that, in the case of RILI, the immediate release of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 after IR is closely related to lung toxicity ( 24 ). In our study, OOP reduced the release of radiation-induced TNF-α and IL-1β.…”

Section: Discussionmentioning

confidence: 99%

Effect of ozone oxidative preconditioning in preventing early radiation-induced lung injury in rats

Bakkal

Gültekin

Güven

et al. 2013

Braz J Med Biol Res

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“…Pharmacologic inhibition of NE has been shown to successfully reduce the inflammatory response and disease severity in different pathologies mediated by acute inflammation. [9][10][11][12][13][14][15][16][17] As we and others demonstrated a pronounced acute inflammatory response in AILI, and given the increased production of NE, we hypothesized that NE inhibition may be protective against AILI. A first group of APAP-intoxicated mice were treated with the NE inhibitor sivelestat.…”

Section: Combination Therapy Of the Ne Inhibitor Sivelestat And Nac Amentioning

confidence: 98%

“…7,8 The therapeutic potential of sivelestat, a highly specific NE inhibitor, 6 has been studied in different pathologies mediated by acute inflammation, mainly in the field of pulmonology. 6,[9][10][11][12][13][14][15][16][17] Both preclinical and clinical studies indicate beneficial effects in acute lung injury, with less severe lung damage and improved clinical outcome. 6,18 This has resulted in the approval of sivelestat for the treatment of acute lung injury in Japan and South Korea.…”

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confidence: 99%

Combination of sivelestat and N-acetylcysteine alleviates the inflammatory response and exceeds standard treatment for acetaminophen-induced liver injury

Raevens

Campenhout

Debacker

et al. 2019

Journal of Leukocyte Biology

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Hepatocyte death during acetaminophen (APAP) intoxication elicits a reactive inflammatory response, with hepatic recruitment of neutrophils and monocytes, which further aggravates liver injury. Neutrophil elastase (NE), secreted by activated neutrophils, carries degradative and cytotoxic functions and maintains a proinflammatory state. We investigated NE as a therapeutic target in acetaminophen-induced liver injury (AILI). C57BL/6 mice were administered a toxic dose of APAP, 2 h prior to receiving the NE inhibitor sivelestat, N-acetylcysteine (NAC), or a combination therapy, and were euthanized after 24 and 48 h. Upon APAP overdose, neutrophils and monocytes infiltrate the injured liver, accompanied by increased levels of NE. Combination therapy of NAC and sivelestat significantly limits liver damage, as evidenced by lower serum transaminase levels and less hepatic necrosis compared to mice that received APAP only, and this to a greater extent than NAC monotherapy. Lower hepatic expression of proinflammatory markers was observed in the combination treatment group, and flow cytometry revealed significantly less monocyte influx in livers from mice treated with the combination therapy, compared to untreated mice and mice treated with NAC only. The potential of NE to induce leukocyte migration was confirmed in vitro. Importantly, sivelestat did not impair hepatic repair. In conclusion, combination of NE inhibition with sivelestat and NAC dampens the inflammatory response and reduces liver damage following APAP overdose. This strategy exceeds the standard of care and might represent a novel therapeutic option for AILI. K E Y W O R D S acute liver failure, acute liver injury, hepatotoxicity, paracetamol 1 INTRODUCTION Drug-induced liver injury, and more specifically acetaminophen (APAP) overdose, is the leading cause of acute liver failure (ALF) in the United States and Europe. 1 APAP is a widely used analgesic and antipyretic drug that is considered safe in therapeutic doses, but may cause severe liver damage, ALF, and death at supratherapeutic doses. 2 The Abbreviations: AILI, acetaminophen-induced liver injury; ALF, acute liver failure; APAP, acetaminophen; DAMPs, damage-associated molecular patterns; NAC, N-acetylcysteine; NAPQI, N-acetyl-p-benzoquinone imine; NE, neutrophil elastase. antioxidant N-acetylcysteine (NAC) represents the only antidote; however, treatment should be started in time, as the benefit of NAC decreases with the time passed between the moment of overdose and treatment. 1,3 If NAC and supportive therapy fail to allow spontaneous recovery, liver transplantation may be the only curative option. 1 As such, there is a need to develop novel medical therapies that restrict liver damage and prevent the progression to liver failure, which may reduce the necessity of transplants and APAP-related deaths. Over the last few years, research focused on understanding the immunologic mechanisms underlying acetaminophen-induced liver injury (AILI) and the potential to modulate the inflammatory

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“…В результате внутрибрюшинного введения мы шам после облучения легких специфического инги битора эластазы нейтрофилов (Sivelestat, Elaspol) на 18 % увеличилась выживаемость за счет уменьшения лучевых повреждений легких (пневмонита) [58,59].…”

Section: обзорыunclassified

Drug therapy to prevent and diminish radiation injury of the lungs

Сычева¹,

Грушина²

2013

Pulʹmonologiâ (Mosk.)

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Effects of sivelestat sodium hydrate on the reduction of radiation pneumonitis

Cited by 4 publications

References 28 publications

Effect of ozone oxidative preconditioning in preventing early radiation-induced lung injury in rats

Effect of ozone oxidative preconditioning in preventing early radiation-induced lung injury in rats

Combination of sivelestat and N-acetylcysteine alleviates the inflammatory response and exceeds standard treatment for acetaminophen-induced liver injury

Drug therapy to prevent and diminish radiation injury of the lungs

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