Inosine exerts a broad range of antiinflammatory effects in a murine model of acute lung injury
Inosine exerts a broad range of antiinflammatory effects in a murine model of acute lung injury
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DOI：
10.1097/00000658-200204000-00016
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发表时间：
2002-04-01
影响因子：
9
通讯作者：
Szabó, C
中科院分区：
文献类型：
--
作者：
Liaudet, L;Mabley, JG;Szabó, C
目的探讨肌苷对体内脂多糖（LPS）诱导的急性肺炎症的影响及促炎细胞因子对体外人肺上皮细胞（A549）的活化和细胞毒性的影响。摘要背景资料肌苷是一种内源性嘌呤，最近被证明具有免疫调节和抗炎作用。方法经气管内注射lip小鼠（50杯），分别于1、6、12 h后给予肌苷（200 mg/kg腹腔注射）或载药。24小时后，取支气管肺泡灌洗液，测定促炎（肿瘤坏死因子- α [tnf - α]、白细胞介素[IL]-1 β、IL-6）和抗炎（IL-10、IL-4）细胞因子、趋化因子（mip -1 α和MIP-2）、髓过氧化物酶活性、总细胞计数、一氧化氮生成和蛋白质。在充气固定肺中进行肺组织学和亚硝化应激标志物3-硝基酪氨酸的免疫组织化学检测。在体外，在肌苷存在或不存在的情况下，用细胞因子混合物刺激A549细胞，评估细胞活力和趋化因子IL-8的产生。结果肌苷可下调lps诱导的tnf - α、il -1 β、IL-6和MIP-2的表达，并有降低mip -1 α的趋势，而肌苷可提高IL-4的产生，肌苷可显著降低白细胞总数、髓过氧化物酶、一氧化氮的产生和蛋白质含量。嘌呤还能改善肺形态，抑制LPS后肺3-硝基酪氨酸染色。肌苷能降低A549细胞的细胞毒性，降低促炎细胞因子诱导的IL-8的表达。结论肌苷在体内可明显抑制lps诱导的肺部炎症，在体外可降低细胞因子对肺细胞的毒性。这些数据支持肌苷可能是急性呼吸窘迫综合征治疗中一种有用的辅助药物的建议。
Objective To investigate the effects of inosine on the acute lung inflammation induced by lipopolysaccharide (LPS) in vivo and on the activation and cytotoxicity elicited by proinflammatory cytokines on human lung epithelial (A549) cells in vitro.Summary Background Data Inosine is an endogenous purine recently shown to exert immunomodulatory and antiinflammatory effects.Methods Mice challenged with intratracheal LIPS (50 mug) were treated after 1, 6, and 12 hours with inosine (200 mg/kg intraperitoneal) or vehicle. After 24 hours, bronchoalveolar lavage fluid was obtained to measure proinflammatory (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1beta, IL-6), and antiinflammatory (IL-10, IL-4) cytokines, chemokines (MIP-1alpha and MIP-2), myeloperoxidase activity and total cell counts, nitric oxide production, and proteins. Lung histology and immunohistochemical detection of 3-nitrotyrosine, a marker of nitrosative stress, were performed in inflated-fixed lungs. In vitro, cell viability and production of the chemokine IL-8 were evaluated in A549 cells stimulated with a mixture of cytokines in the presence or absence of inosine.Results Inosine downregulated the LPS-induced expression of TNF-alpha, IL-1beta, IL-6 and MIP-2 and tended to reduce MIP-1alpha, whereas it enhanced the production of IL-4, Total leukocyte counts, myeloperoxidase, nitric oxide production, and proteins were all significantly decreased by inosine. The purine also improved lung morphology and suppressed 3-nitrotyrosine staining in the lungs after LPS. Inosine attenuated the cytotoxicity and the expression of IL-8 induced by proinflammatory cytokines in A549 cells.Conclusions Inosine largely suppressed LPS-induced lung inflammation in vivo and reduced the toxicity of cytokines in lung cells in vitro. These data support the proposal that inosine might represent a useful adjunct in the therapy of acute respiratory distress syndrome.