Souza Rhonda Frances
Center for Esophageal Research, Baylor Scott and White Research Institute, 2 Hoblitzelle, Suite 250, 3500 Gaston Avenue, Dallas, TX, 75246, USA.
J Gastroenterol. 2017 Jul;52(7):767-776. doi: 10.1007/s00535-017-1342-1. Epub 2017 Apr 27.
Reflux esophagitis damages the squamous epithelium that normally lines the esophagus, and promotes replacement of the damaged squamous lining by the intestinal metaplasia of Barrett's esophagus, the precursor of esophageal adenocarcinoma. Therefore, to prevent the development of Barrett's metaplasia and esophageal adenocarcinoma, the pathogenesis of reflux esophagitis must be understood. We have reported that reflux esophagitis, both in a rat model and in humans, develops as a cytokine-mediated inflammatory injury (i.e., cytokine sizzle), not as a caustic chemical injury (i.e., acid burn), as traditionally has been assumed. Moreover, reflux induces activation of hypoxia inducible factor (HIF)-2α, which enhances the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) causing increases in pro-inflammatory cytokines and in migration of T lymphocytes, an underlying molecular mechanism for this cytokine-mediated injury. In some individuals, reflux esophagitis heals with Barrett's metaplasia. A number of possibilities exist for the origin of the progenitor cells that give rise to this intestinal metaplasia including those of the esophagus, the proximal stomach, or the bone marrow. However, intestinal cells are not normally found in the esophagus, the stomach, or the bone marrow. Thus, the development of Barrett's intestinal metaplasia must involve some molecular reprogramming of key developmental transcription factors within the progenitor cell, a process termed transcommitment, which may be initiated by the noxious components of the gastric refluxate. This review will highlight recent studies on the pathogenesis of reflux esophagitis and on reflux-related molecular reprogramming of esophageal squamous epithelial cells in the pathogenesis of Barrett's metaplasia.
反流性食管炎会损害正常衬于食管的鳞状上皮，并促使受损的鳞状上皮被巴雷特食管的肠化生所取代，而巴雷特食管是食管腺癌的癌前病变。因此，为了预防巴雷特化生和食管腺癌的发生，必须了解反流性食管炎的发病机制。我们已经报道，无论是在大鼠模型还是在人类中，反流性食管炎都是作为一种细胞因子介导的炎性损伤（即细胞因子“嘶嘶声”）而发生的，而不是像传统所认为的那样是一种腐蚀性化学损伤（即酸灼伤）。此外，反流会诱导缺氧诱导因子（HIF）-2α的激活，这会增强活化B细胞核因子κB（NF-κB）的转录活性，导致促炎细胞因子增加和T淋巴细胞迁移，这是这种细胞因子介导损伤的潜在分子机制。在一些个体中，反流性食管炎会伴有巴雷特化生愈合。产生这种肠化生的祖细胞的起源有多种可能性，包括食管、胃近端或骨髓的祖细胞。然而，在食管、胃或骨髓中通常不会发现肠细胞。因此，巴雷特肠化生的发生必须涉及祖细胞内关键发育转录因子的一些分子重编程，这一过程称为转分化，它可能由胃反流物中的有害成分引发。本综述将重点介绍关于反流性食管炎发病机制以及巴雷特化生发病机制中食管鳞状上皮细胞与反流相关的分子重编程的最新研究。
