Köksel Oğuz, Yildirim Cağlar, Tiftik Rukiye Nalan, Kubat Havva, Tamer Lülüfer, Cinel Leyla, Kaplan Murat Bayram, Değirmenci Ulaş, Ozdülger Ali, Büyükafşar Kansu
Department of Thoracic Surgery, Medical Faculty Hospital, Mersin University 33179 Mersin, Turkey.
Eur J Pharmacol. 2005 Mar 7;510(1-2):135-42. doi: 10.1016/j.ejphar.2004.12.010.
The possible contribution of Rho/Rho-kinase signalling in oleic acid (100 mg kg-1, i.v., for 4 h)-induced lung injury was investigated in rats. Furthermore, the possible protective effect of the administration of a Rho-kinase inhibitor, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y-27632, 0.5-5 mg kg-1, i.v., 15 min before the administration of oleic acid), was also examined. Western blot analysis as well as histopathological examination revealed that Rho-kinase (ROCK-1 and ROCK-2) was upregulated in lungs obtained from oleic acid-administrated rats. In addition, the markers of oxidative and nitrosative stress, i.e., malondialdehyde, myeloperoxidase, 3-nitro-L-tyrosine and nitrite/nitrate, in serum and lung tissue were also increased in the injury group. Treatment of rats with 5 mg kg-1 Y-27632 reversed the oleic acid-induced lung damage, which was demonstrated by histopathological assessment and confirmed in Western blot experiments: ROCK-blots were more intense in the oleic acid group than in control and Y-27632 treatment reversed ROCK upregulation. In addition, malondialdehyde, myeloperoxidase, 3-nitro-L-tyrosine and nitrite/nitrate were also normalized after the administration of Y-27632 (0.5 mg kg-1 and 5 mg kg-1). These findings suggest that ROCK-1 and ROCK-2 are involved in oleic acid-induced lung damage in rats, and that inhibition of this enzyme by Y-27632 may have a protective effect against such damage. Consequently, Rho kinase inhibitors may be potential therapeutic agents in the treatment of acute respiratory distress syndrome (ARDS).
在大鼠中研究了Rho/Rho激酶信号传导在油酸（100毫克/千克，静脉注射，持续4小时）诱导的肺损伤中的可能作用。此外，还研究了给予Rho激酶抑制剂（+）-（R）-反式-4-（1-氨基乙基）-N-（4-吡啶基）环己烷甲酰胺二盐酸盐一水合物（Y-27632，0.5 - 5毫克/千克，静脉注射，在给予油酸前15分钟）的可能保护作用。蛋白质免疫印迹分析以及组织病理学检查显示，在给予油酸的大鼠的肺中，Rho激酶（ROCK-1和ROCK-2）上调。此外，损伤组血清和肺组织中的氧化应激和亚硝化应激标志物，即丙二醛、髓过氧化物酶、3-硝基-L-酪氨酸和亚硝酸盐/硝酸盐也增加。用5毫克/千克Y-27632处理大鼠可逆转油酸诱导的肺损伤，这通过组织病理学评估得到证实，并在蛋白质免疫印迹实验中得到确认：ROCK印迹在油酸组中比对照组更强烈，而Y-27632处理可逆转ROCK的上调。此外，给予Y-27632（0.5毫克/千克和5毫克/千克）后，丙二醛、髓过氧化物酶、3-硝基-L-酪氨酸和亚硝酸盐/硝酸盐也恢复正常。这些发现表明，ROCK-1和ROCK-2参与了大鼠油酸诱导的肺损伤，并且Y-27632对该酶的抑制可能对这种损伤具有保护作用。因此，Rho激酶抑制剂可能是治疗急性呼吸窘迫综合征（ARDS）的潜在治疗药物。
