Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, USA; Linda Crnic Institute for Down Syndrome, Aurora, Colorado, USA.
Skaggs School of Pharmacy, University of Arizona, Tucson, Arizona, USA.
Prostaglandins Other Lipid Mediat. 2021 Apr;153:106524. doi: 10.1016/j.prostaglandins.2020.106524. Epub 2021 Jan 5.
The triplication of human chromosome 21 results in Down syndrome (DS), the most common genetic form of intellectual disability. This aneuploid condition also results in an enhanced risk of a spectrum of comorbid conditions, such as leukemia, early onset Alzheimer's disease, and diabetes. Individuals with DS also display an increased incidence of wound healing complications and resistance to solid tumor development. Due to this unique phenotype and the involvement of eicosanoids in key comorbidities like poor healing and tumor development, we hypothesized that cells from DS individuals would display altered eicosanoid production. Using age- and sex-matched dermal fibroblasts we interrogated this hypothesis. Briefly, assessment of over 90 metabolites derived from cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome p450 systems revealed a possible deficiency in the COX system. Basal gene expression and Western blotting experiments showed significantly decreased gene expression of COX1 and 2, and COX2 protein abundance in DS fibroblasts compared to euploid controls. Further, using two different stressors, scratch wound or LPS, we found that DS fibroblasts could not upregulate COX2 abundance and prostaglandin E2 production. Together, these findings show that dermal fibroblasts from DS individuals have a deficient COX2 response, which may contribute to wound healing complications and tumor resistance in DS.
人类 21 号染色体的三倍体导致唐氏综合征（DS），这是最常见的智力残疾的遗传形式。这种非整倍体状况也会导致一系列合并症的风险增加，如白血病、早发性阿尔茨海默病和糖尿病。DS 患者还表现出伤口愈合并发症和抵抗实体瘤发展的发生率增加。由于这种独特的表型和类二十烷酸在合并症如愈合不良和肿瘤发展中的作用，我们假设 DS 个体的细胞会显示出类二十烷酸产生的改变。我们使用年龄和性别匹配的真皮成纤维细胞来验证这一假设。简而言之，对来自环加氧酶（COX）、脂加氧酶（LOX）和细胞色素 p450 系统的 90 多种代谢物的评估表明 COX 系统可能存在缺陷。DS 成纤维细胞中 COX1 和 COX2 的基础基因表达和 Western blot 实验显示，与正常二倍体对照相比，COX1 和 COX2 的基因表达显著降低。此外，使用两种不同的应激源，划痕或 LPS，我们发现 DS 成纤维细胞不能上调 COX2 丰度和前列腺素 E2 的产生。这些发现表明，DS 个体的真皮成纤维细胞 COX2 反应不足，这可能导致 DS 中的伤口愈合并发症和肿瘤耐药性。
