Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Toxicol Appl Pharmacol. 2011 Jun 1;253(2):153-60. doi: 10.1016/j.taap.2011.03.023. Epub 2011 Apr 5.
The present study aimed to investigate the effect of the new tyrosine kinase inhibitor, nilotinib on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and explore its possible mechanisms. Male Sprague-Dawley rats were given nilotinib (10mg/kg) by oral gavage twice daily for 1week prior to exposure to aerosolized LPS. At 24h after LPS exposure, bronchoalveolar lavage fluid (BALF) samples and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathological changes in lungs. Malondialdehyde (MDA) content, superoxidase dismutase (SOD) and reduced glutathione (GSH) activities as well as nitrite/nitrate (NO(2)(-)/NO(3)(-)) levels were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-α (TNF-α), transforming growth factor-β(1) (TGF-β(1)) and inducible nitric oxide synthase (iNOS) were determined in lung tissues. Treatment with nilotinib prior to LPS exposure significantly attenuated the LPS-induced pulmonary edema, as it significantly decreased lung W/D ratio, protein concentration and the accumulation of the inflammatory cells in the BALF. This was supported by the histopathological examination which revealed marked attenuation of LPS-induced ALI in nilotinib treated rats. In addition, nilotinib significantly increased SOD and GSH activities with significant decrease in MDA content in the lung. Nilotinib also reduced LPS mediated overproduction of pulmonary NO(2)(-)/NO(3)(-) levels. Importantly, nilotinib caused down-regulation of the inflammatory cytokines TNF-α, TGF-β(1) and iNOS levels in the lung. Taken together, these results demonstrate the protective effects of nilotinib against the LPS-induced ALI. This effect can be attributed to nilotinib ability to counteract the inflammatory cells infiltration and hence ROS generation and regulate cytokine effects.
本研究旨在探讨新型酪氨酸激酶抑制剂尼洛替尼对脂多糖（LPS）诱导的大鼠急性肺损伤（ALI）的影响，并探讨其可能的机制。雄性 Sprague-Dawley 大鼠在暴露于雾化 LPS 前，每日两次通过口服灌胃给予尼洛替尼（10mg/kg），连续 1 周。在 LPS 暴露后 24h 时，收集支气管肺泡灌洗液（BALF）样本和肺组织。测定肺湿/干重（W/D）比、BALF 中蛋白水平和炎症细胞数。行光学显微镜检查以观察肺的病理变化。测定肺组织中丙二醛（MDA）含量、超氧化物歧化酶（SOD）和还原型谷胱甘肽（GSH）活性以及亚硝酸盐/硝酸盐（NO 2 (-)/NO 3 (-)）水平。测定肺组织中炎症细胞因子肿瘤坏死因子-α（TNF-α）、转化生长因子-β1（TGF-β1）和诱导型一氧化氮合酶（iNOS）的表达。尼洛替尼在 LPS 暴露前治疗显著减轻 LPS 诱导的肺水肿，因为它显著降低肺 W/D 比、蛋白浓度和 BALF 中炎症细胞的积累。组织病理学检查也证实了尼洛替尼治疗大鼠 LPS 诱导的 ALI 显著减轻。此外，尼洛替尼显著增加 SOD 和 GSH 活性，降低肺 MDA 含量。尼洛替尼还降低 LPS 介导的肺 NO 2 (-)/NO 3 (-)水平的过度产生。重要的是，尼洛替尼导致肺中炎症细胞因子 TNF-α、TGF-β1 和 iNOS 水平下调。总之，这些结果表明尼洛替尼对 LPS 诱导的 ALI 具有保护作用。这种作用可归因于尼洛替尼能够抵抗炎症细胞浸润，从而抑制 ROS 的产生并调节细胞因子的作用。
