ONO-1714, a nitric oxide synthase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits
ONO-1714, a nitric oxide synthase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits
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DOI：
10.1213/01.ane.0000086896.90343.13
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发表时间：
2003-12-01
影响因子：
5.7
通讯作者：
Obara, H
中科院分区：
文献类型：
--
作者：
Mikawa, K;Nishina, K;Obara, H
诱导型一氧化氮合酶（induciblenitricoxidesynthase，iNOS）在肺组织中的过度表达在内毒素诱导的急性肺损伤（acutelunginjury，ALI）的发病机制中起重要作用。在这个两部分的研究中，我们确定ONO-1714，一种新的选择性iNOS抑制剂，是否减轻内毒素诱导的兔ALI。对于研究的第I部分，对照组接受IV盐水，并且在4个组中通过在30分钟内IV输注内毒素5 mg/kg诱导ALI。三组在开始内毒素前10分钟接受0.1、0.03或0.01 mg/kg ONO-1714，第四组接受生理盐水。对于研究的R部分，所有6组均通过内毒素输注诱导ALI。一组用生理盐水处理。其他5组在不同时间（ALI诱导前10 min或ALI诱导后1、2、3或4 h）接受ONO-1714 0.1 mg/kg。诱导ALI后，采用40%氧气机械通气6小时。在部分L中，用0.1 mg/kg ONO-1714预处理减轻了内毒素诱导的ALI。在第11部分中，ONO-1714的早期后处理（损伤后2小时内）在改善氧合、肺力学、肺白细胞隔离、肺水肿和组织学变化方面与预处理一样有效。然而，在接受药物后3或4小时的兔肺损伤没有得到改善。这些数据表明，目前的研究是未来临床试验的基础，以阐明ONO-1714是否可以成为内毒素/脓毒症诱导的急性呼吸窘迫综合征患者的一种有前途的治疗方法。
Overproduction of nitric oxide by inducible nitric oxide synthase (iNOS) expressed in the lung is thought to play a crucial role in the pathogenesis of endotoxin-induced acute lung injury (ALI). In this two-part study, we determined whether ONO-1714, a new selective iNOS inhibitor, attenuates endotoxin-induced ALI in rabbits. For Part I of the study, a control group received IV saline and ALI was induced by IV infusion of endotoxin 5 mg/kg over 30 min in 4 groups. Three groups received either 0.1, 0.03, or 0.01 mg/kg of ONO-1714 10 min before the start of endotoxin and the fourth group received saline. For Part R of the study, ALI was induced by endotoxin infusion in all 6 groups. One group was treated with saline. The other 5 groups received ONO-1714 0.1 mg/kg at various timings (10 min before or 1, 2, 3, or 4 h after ALI induction). The lungs were mechanically ventilated with 40% oxygen for 6 h after induction of ALI. In Part L pretreatment with 0.1 mg/kg ONO-1714 mitigated endotoxin-induced ALI. In Part 11, early posttreatment (within 2 h after the insult) with ONO-1714 was as effective as pretreatment in improving oxygenation, lung mechanics, lung leukosequestration, pulmonary edema, and histological change. However, lung damage was not improved in rabbits receiving the drug 3 or 4 h after endotoxin. These data suggest that the current study is a basis for future clinical trials to elucidate whether ONO-1714 can be a promising therapeutic approach in patients with acute respiratory distress syndrome induced by endotoxin/sepsis.