Nebulized Hyaluronan Ameliorates Lung Inflammation in Cystic Fibrosis Mice
Nebulized Hyaluronan Ameliorates Lung Inflammation in Cystic Fibrosis Mice
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DOI：
10.1002/ppul.22637
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发表时间：
2013-08-01
影响因子：
3.1
通讯作者：
Raia, Valeria
中科院分区：
文献类型：
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作者：
Gavina, Manuela;Luciani, Alessandro;Raia, Valeria
理论基础：慢性肺部炎症和对细菌感染的易感性增加导致囊性纤维化患者的大部分发病率和死亡率，囊性纤维化是高加索人群中最常见的严重常染色体隐性遗传性疾病。外源性吸入透明质酸(HA)对损伤有保护作用，并在慢性呼吸系统疾病的实验模型中显示了有益的作用。我们的目的是检查外源性雾化吸入HA是否可能干扰CF的肺部炎症。研究设计/方法：F508del纯合子小鼠(F508del)和高表达ENaC通道β亚基的转基因小鼠(Scnn1b-TG)雾化吸入HA(0.5 mg/只/d，连续7d)。检测肺组织肿瘤坏死因子-α(TNF-α)、巨噬细胞炎性蛋白-2(MIP-2)、髓过氧化物酶(MPO)水平及巨噬细胞浸润情况。将IB3-1和CFBE410细胞与HA(24小时，100µg/ml)共同培养，用二氯二氢荧光素比色法、荧光共振能量转移(FRET)显微镜或免疫印迹法检测细胞内活性氧(ROS)、组织转谷氨酰胺酶(TG2)超氧化物歧化和过氧化物酶体增殖物激活受体γ(PPAR-γ)及磷酸化p42/p44水平。结果：雾化吸入HA可降低CFTRF508del和Scn1bTg小鼠肺组织中肿瘤坏死因子α的表达(P<；0.005)，降低肺组织中髓过氧化物酶活性(P<；0.05)和CD68+细胞计数(P<；0.005)。HA降低IB3-1和CFBE41o细胞的ROS、TG2 SUMO化、TG2活性、磷酸化P42-44和增加PPARγ蛋白(P<；0.05)。结论：雾化吸入透明质酸可有效控制小鼠气管内炎症和体外人呼吸道上皮细胞炎症。我们为吸入性透明质酸作为一种潜在的抗炎药物在CF治疗中的应用提供了概念上的证据。(C)2012年威利期刊公司。
Rationale: Chronic lung inflammation with increased susceptibility to bacterial infections cause much of the morbidity and mortality in patients with cystic fibrosis (CF), the most common severe, autosomal recessively inherited disease in the Caucasian population. Exogenous inhaled hyaluronan (HA) can exert a protective effect against injury and beneficial effects of HA have been shown in experimental models of chronic respiratory diseases. Our objective was to examine whether exogenous administration of nebulized HA might interfere with lung inflammation in CF. Study design/methods: F508del homozygous mice (Cftr(F508del)) and transgenic mice overexpressing the ENaC channel beta-subunit (Scnn1b-Tg) were treated with nebulized HA (0.5 mg/mouse/day for 7 days). Tumor necrosis factor-alpha (TNF alpha), macrophage inflammatory protein-2 (MIP-2), myeloperoxidase (MPO) levels, and macrophage infiltration were assessed on lung tissues. IB3-1 and CFBE41o-epithelial cell lines were cultured with HA (24 hr, 100 mu g/ml) and Reactive Oxygen Species (ROS), Tissue Transglutaminase (TG2) SUMOylation and Peroxisome Proliferator Activated Receptor gamma (PPAR gamma) and phospho-p42/p44 levels were measured by dichlorodihydrofluorescein assay, or fluorescence resonance energy transfer (FRET) microscopy or immunoblots. Results: Nebulized HA reduced TNF alpha expression (P < 0.005); TNF alpha, MIP-2, and MPO protein levels (P < 0.05); MPO activity (P < 0.05); and CD68+ cells counts (P < 0.005) in lung tissues of Cftr(F508del) and Scnn1b-Tg mice, compared with saline-treated mice. HA reduced ROS, TG2 SUMOylation, TG2 activity, phospho-p42-44, and increased PPAR gamma protein in both IB3-1 and CFBE41o cells (P < 0.05). Conclusions: Nebulized HA is effective in controlling inflammation in vivo in mice CF airways and in vitro in human airway epithelial cells. We provide the proof of concept for the use of inhaled HA as a potential anti-inflammatory drug in CF therapy. (C) 2012 Wiley Periodicals, Inc.