The aim of the work was to study a dose-dependent effect of inhaled carnosine (10, 50 or 100 mg/kg/day) in mice exposed to cigarette smoke as a model of chronic obstructive pulmonary disease (COPD). A dose-dependent loading of the dipeptide in lung tissue and bronchoalveolar lavage (BAL) was firstly demonstrated by LC-ESI-MS analysis. Cigarette smoke exposure induced a significant lung inflammation and oxidative stress in mice which was dose-dependently reduced by carnosine. Inflammation was firstly evaluated by measuring the cytokines content in the BAL. All the measured cytokines were found significantly higher in the smoke group in respect to control, although the data are affected by a significant variability. Carnosine was found effective only at the highest dose tested and significantly only for keratinocyte-derived cytokine (KC). Due to the high variability of cytokines, a quantitative proteomic approach to better understand the functional effect of carnosine and its molecular mechanisms was used. Proteomic data clearly indicate that smoke exposure had a great impact on lung tissue with 692 proteins differentially expressed above a threshold of 1.5-fold. Protein network analysis identified the activation of some pathways characteristic of COPD, including inflammatory response, fibrosis, induction of immune system by infiltration and migration of leukocyte pathways, altered pathway of calcium metabolism and oxidative stress. Carnosine at the tested dose of 100 mg/kg was found effective in reverting all the pathways evoked by smoke. Only a partial reverse of the dysregulated proteins was evident at low- and mid-tested doses, although, for some specific proteins, indicating an overall dose-dependent effect. Regarding the molecular mechanisms involved, we found that carnosine upregulated some key enzymes related to Nrf2 activation and in particular glutathione peroxidase, reductase, transferase, SOD, thioredoxins, and carbonyl reductase. Such mechanism would explain the antioxidant and anti-inflammatory effects of the dipeptide.

中文翻译：

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一种定量蛋白质组学方法，用于评估肌肽在慢性阻塞性肺病 （COPD） 小鼠模型中的疗效


这项工作的目的是研究吸入肌肽（10、50 或 100 mg/kg/天）对暴露于香烟烟雾的小鼠的剂量依赖性效应，作为慢性阻塞性肺病 （COPD） 的模型。首先通过 LC-ESI-MS 分析证明了肺组织和支气管肺泡灌洗液 （BAL） 中二肽的剂量依赖性负载。香烟烟雾暴露在小鼠中诱导了显着的肺部炎症和氧化应激，肌肽呈剂量依赖性降低。首先通过测量 BAL 中的细胞因子含量来评估炎症。与对照组相比，烟雾组发现所有测量的细胞因子都显着升高，尽管数据受到显着变异性的影响。发现肌肽仅在测试的最高剂量下有效，并且仅对角质形成细胞衍生的细胞因子 （KC） 显着有效。由于细胞因子的高度可变性，使用了定量蛋白质组学方法来更好地了解肌肽的功能效应及其分子机制。蛋白质组学数据清楚地表明，烟雾暴露对肺组织有很大影响，692 种蛋白质的差异表达超过 1.5 倍的阈值。蛋白质网络分析确定了 COPD 的一些特征性通路的激活，包括炎症反应、纤维化、白细胞通路浸润和迁移诱导免疫系统、钙代谢途径改变和氧化应激。发现 100 mg/kg 测试剂量的肌肽可有效逆转烟雾诱发的所有途径。在低剂量和中试剂量下，只有部分相反的失调蛋白，尽管对于某些特定蛋白，表明总体剂量依赖性效应。 关于所涉及的分子机制，我们发现肌肽上调了一些与 Nrf2 激活相关的关键酶，特别是谷胱甘肽过氧化物酶、还原酶、转移酶、SOD、硫氧还蛋白和羰基还原酶。这种机制可以解释二肽的抗氧化和抗炎作用。