Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Mellowes Center for Genomic Science and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Int J Mol Sci. 2024 Oct 5;25(19):10714. doi: 10.3390/ijms251910714.
Breakthrough symptoms are thought to occur in roughly half of all gastroesophageal reflux disease (GERD) patients despite maximal acid suppression (proton pump inhibitor, PPI) therapy. Topical alginates have recently been shown to enhance mucosal defense against acid-pepsin insult during GERD. We aimed to examine potential alginate protection of transcriptomic changes in a cell culture model of PPI-recalcitrant GERD. Immortalized normal-derived human esophageal epithelial cells underwent pretreatment with commercial alginate-based anti-reflux medications (Gaviscon Advance or Gaviscon Double Action), a matched-viscosity placebo control, or pH 7.4 buffer (sham) alone for 1 min, followed by exposure to pH 6.0 + pepsin or buffer alone for 3 min. RNA sequencing was conducted, and Ingenuity Pathway Analysis was performed with a false discovery rate of ≤0.01 and absolute fold-change of ≥1.3. Pepsin-acid exposure disrupted gene expressions associated with epithelial barrier function, chromatin structure, carcinogenesis, and inflammation. Alginate formulations demonstrated protection by mitigating these changes and promoting extracellular matrix repair, downregulating proto-oncogenes, and enhancing tumor suppressor expression. These data suggest molecular mechanisms by which alginates provide topical protection against injury during weakly acidic reflux and support a potential role for alginates in the prevention of GERD-related carcinogenesis.
突破性症状被认为发生在大约一半的胃食管反流病（GERD）患者中，尽管进行了最大酸抑制（质子泵抑制剂，PPI）治疗。最近已经证明，局部藻酸盐在 GERD 期间增强了对酸 - 胃蛋白酶损伤的粘膜防御。我们旨在检查细胞培养模型中 PPI 难治性 GERD 中藻酸盐潜在保护转录组变化的能力。永生化的正常衍生的人食管上皮细胞经过商业藻酸盐抗反流药物（Gaviscon Advance 或 Gaviscon Double Action）、匹配粘度安慰剂对照或单独 pH 7.4 缓冲液（假处理）预处理 1 分钟，然后暴露于 pH 6.0 + 胃蛋白酶或单独缓冲液 3 分钟。进行 RNA 测序，并使用错误发现率≤0.01 和绝对倍数变化≥1.3 进行了 Ingenuity 通路分析。胃蛋白酶 - 酸暴露破坏了与上皮屏障功能、染色质结构、癌变和炎症相关的基因表达。藻酸盐制剂通过减轻这些变化并促进细胞外基质修复、下调原癌基因和增强肿瘤抑制基因表达来提供保护。这些数据表明藻酸盐在弱酸性反流期间提供局部保护免受损伤的分子机制，并支持藻酸盐在预防 GERD 相关癌变中的潜在作用。
