胃食管反流病炎症-氧化应激信号网络及分层药物干预研究进展

Research progress in the inflammation-oxidative stress signaling network and stratified therapeutic interventions for gastroesophageal reflux disease

摘要:

胃食管反流病（GERD）是一种常见的慢性消化系统疾病，其发病机制不仅涉及胃酸及胆汁反流导致的黏膜损伤，还与炎症反应和氧化应激的持续激活密切相关。近年来研究发现，反流刺激可诱导食管上皮屏障破坏及活性氧（ROS）过度生成，并通过TLR4/MyD88、NF-κB、MAPK、Nrf2及IL-6/JAK/STAT3等信号通路形成炎症与氧化应激相互促进的病理网络，推动疾病持续进展及Barrett食管形成。本文系统综述GERD炎症反应与氧化应激相关信号通路的研究进展，并结合疾病演变过程，构建“炎症启动-信号放大-氧化应激失衡-慢性重塑”的分层调控模式，对各阶段关键分子事件及其相互作用进行梳理。同时，本文结合质子泵抑制剂、钾离子竞争性酸阻滞剂、黏膜保护剂，以及针对炎症和氧化应激相关靶点的新型干预策略，阐述其作用机制及研究现状。该分层调控模式有助于深化对GERD发病机制的认识，并为机制导向的精准治疗和新药研发提供理论依据。

Abstract:

Gastroesophageal reflux disease (GERD) is a common chronic digestive disorder whose pathogenesis involves not only reflux-induced mucosal injury caused by gastric acid and bile acids but also persistent activation of inflammatory and oxidative stress responses. Emerging evidence indicates that reflux stimulation disrupts the esophageal epithelial barrier and promotes excessive generation of reactive oxygen species (ROS), leading to the activation of multiple signaling pathways, including TLR4/MyD88, NF-κB, MAPK, Nrf2, and IL-6/JAK/STAT3. These pathways interact to form an inflammation-oxidative stress network that drives disease progression and Barrett's esophagus development. This review summarizes recent advances in inflammation- and oxidative stress-related signaling pathways in GERD and proposes a stage-specific regulatory model consisting of inflammation initiation, signal amplification, oxidative stress imbalance, and chronic remodeling. Key molecular events and their interactions during disease progression are discussed. In addition, current and emerging therapeutic strategies, including proton pump inhibitors, potassium-competitive acid blockers, mucosal protective agents, and pathway-targeted interventions, are reviewed with respect to their mechanisms of action and research status. This stage-specific regulatory framework may provide new insights into the pathogenesis of GERD and offer a theoretical basis for mechanism-based precision therapy and future drug development.