胃食管反流引起的反流性食管炎（RE）是食管腺癌的危险因素。约40%胃食管反流病抑酸治疗迁延不愈，挑战传统酸损伤机制。最新研究提出细胞因子介导的炎性损伤是RE的发病机制，食管微生物群释放的脂多糖（LPS)促进促炎因子表达。我们前期实验发现：LPS可刺激RE患者上皮细胞分泌炎症因子并引起细胞焦亡；LPS还可激活TLR4/NF-κb通路上调炎症因子前体，并激活炎症体切割炎症因子前体致炎症因子分泌；且caspase-1抑制剂可抑制LPS所致炎症因子释放保护食管上皮细胞。因此提出：难治性RE患者中LPS激活TLR4/NF-κb通路与炎症体并释放炎症因子，导致食管上皮细胞焦亡，最终引起食管损伤。在本项目中，我们将收集并检测临床RE患者活检标本、构建RE细胞与动物模型，采取QPCR、WB、慢病毒干扰与过表达等技术手段，进一步阐明假设，为治愈RE、预防其炎性增生和癌变提供新思路。

Reflux esophagitis (RE) caused by gastroesophageal reflux (GER) is a risk factor for esophageal adenocarcinoma. About 40% GERD patients failed to show response to acid suppressors, which challenges the conventional pathogenesis of acid-mediated mechanism. Recent studies have raised an alternative concept that chemokines mediate inflammatory damage of esophageal tissue and that lipopolysaccharides(LPS) released by Gram-negative microbiomes in distal esophagus causes expression of inflammatory cytokines. Our preliminary study recently found that LPS can induce cytokine production and pyroptosis. We further discovered that LPS induced production of pro-inflammatory cytokines via TLR4/NF-κb signaling and at the same time activated inflammasome, resulting in incision of pro-inflammatory cytokines and cytokines secretion. Furtherly, we found that caspase-1 inhibitor could suppress inflammatory cytokine secretion and protected esophageal epithelial cells. Therefore we hypothesize that LPS activates TLR4/NF-κb signaling and inflammasome, releasing inflammatory cytokines and inducing pyroptosis, finally resulting in inflammatory damage of esophageal tissue. Inhibition of caspase-1 might by a new target for RE therapy. In this present study, we will collect and detect the biopsy samples from RE paitients, perform experiments in vivo and in vitro using qPCR, western-blot, interference and over-expression, etc. Once our hypothesis gets proved, we are going to contribute to the treatment of RE and the prevention of dysplasia and carcinogenesis.