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 号染色体三倍体导致唐氏综合症 (DS)，这是智力障碍最常见的遗传形式。这种非整倍体疾病还会导致一系列合并症的风险增加，例如白血病、早发性阿尔茨海默病和糖尿病。患有 DS 的个体还表现出伤口愈合并发症的发生率增加以及对实体瘤发展的抵抗力。由于这种独特的表型以及类二十烷酸参与关键合并症（如愈合不良和肿瘤发展），我们假设来自 DS 个体的细胞会表现出类二十烷酸产生的改变。使用年龄和性别匹配的真皮成纤维细胞，我们质疑了这一假设。简而言之，对来自环氧合酶 (COX)、脂氧合酶 (LOX) 和细胞色素 p450 系统的 90 多种代谢物的评估揭示了 COX 系统可能存在缺陷。基础基因表达和蛋白质印迹实验表明，与整倍体对照相比，DS 成纤维细胞中 COX1 和 2 的基因表达以及 COX2 蛋白丰度显着降低。此外，使用两种不同的应激源（划伤或 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。总之，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 的伤口愈合并发症和肿瘤抵抗。