Cystic fibrosis (CF) is the most common genetic disorder in the Caucasian population. Despite remarkable improvements in morbidity and mortality during the last decades, the disease still limits survival and reduces quality of life of affected patients. Moreover, CF still represents substantial economic burden for healthcare systems. Inflammation and infection already start in early life and play important roles in pulmonary impairment. The aim of this study is to analyze the potential role of DMBT1, a protein with functions in inflammation, angiogenesis, and epithelial differentiation, in CF. Immunohistochemically DMBT1 protein expression was upregulated in lung tissues of CF patients compared to healthy controls. Additionally, pulmonary expression of Dmbt1 was approximately 6-fold increased in an established transgenic mouse model of CF-like lung disease (ENaC tg) compared to wild-type mice as detected by qRT-PCR. Since acetylcysteine (ACC) has been shown to reduce inflammatory markers in the airways, its potential influence on DMBT1 expression was analyzed. A549 cells stably transfected with an expression plasmid encoding the largest (8kb) DMBT1 variant (DMBT1+ cells) or an empty vector control (DMBT1- cells) and incubated with ACC both showed significantly reduced DMBT1 concentrations in the culture medium (p = 0.0001). To further elucidate the function of DMBT1 in pulmonary airways, respiratory epithelial cells were examined by phase contrast microscopy. Addition of human recombinant DMBT1 resulted in altered cilia motility and irregular beat waves (p < 0.0001) suggesting a potential effect of DMBT1 on airway clearance. DMBT1 is part of inflammatory processes in CF and may be used as a potential biomarker for CF lung disease and a potential tool to monitor CF progression. Furthermore, DMBT1 has a negative effect on ciliary motility thereby possibly compromising airway clearance. Application of ACC, leading to reduced DMBT1 concentrations, could be a potential therapeutic option for CF patients.

中文翻译：

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DMBT1 在囊性纤维化中上调，影响纤毛运动，并被乙酰半胱氨酸降低

囊性纤维化 (CF) 是高加索人群中最常见的遗传疾病。尽管在过去几十年中发病率和死亡率显着改善，但该疾病仍然限制了生存并降低了受影响患者的生活质量。此外，CF 仍然代表医疗保健系统的巨大经济负担。炎症和感染在生命早期就已经开始，并在肺损伤中起重要作用。本研究的目的是分析 DMBT1（一种在炎症、血管生成和上皮分化中具有功能的蛋白质）在 CF 中的潜在作用。与健康对照相比，CF 患者肺组织中的免疫组织化学 DMBT1 蛋白表达上调。此外，与通过 qRT-PCR 检测的野生型小鼠相比，已建立的 CF 样肺病 (ENaC tg) 转基因小鼠模型中 Dmbt1 的肺表达增加约 6 倍。由于乙酰半胱氨酸 (ACC) 已被证明可减少气道中的炎症标志物，因此分析了其对 DMBT1 表达的潜在影响。用编码最大 (8kb) DMBT1 变体（DMBT1+ 细胞）或空载体对照（DMBT1- 细胞）的表达质粒稳定转染并与 ACC 一起孵育的 A549 细胞均显示培养基中 DMBT1 浓度显着降低（p = 0.0001）。为了进一步阐明 DMBT1 在肺气道中的功能，通过相差显微镜检查了呼吸道上皮细胞。添加人重组 DMBT1 导致纤毛运动改变和不规则拍波 (p < 0. 0001）表明 DMBT1 对气道清除的潜在影响。DMBT1 是 CF 炎症过程的一部分，可用作 CF 肺病的潜在生物标志物和监测 CF 进展的潜在工具。此外，DMBT1 对纤毛运动有负面影响，从而可能影响气道清除。应用 ACC 可降低 DMBT1 浓度，可能是 CF 患者的潜在治疗选择。