Park Jason Y, Zhang Xi, Nguyen Nathalie, Souza Rhonda F, Spechler Stuart J, Cheng Edaire
Esophageal Diseases Center, Department of Pathology, Children's Medical Center, Eugene McDermott Center for Human Growth and Development, and the University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Department of Pediatrics, Children's Medical Center, and the University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
PLoS One. 2014 Jul 2;9(7):e101391. doi: 10.1371/journal.pone.0101391. eCollection 2014.
Besides reducing gastric acid secretion, proton pump inhibitors (PPIs) suppress Th2-cytokine-stimulated expression of an eosinophil chemoattractant (eotaxin-3) by esophageal epithelial cells through acid-independent, anti-inflammatory mechanisms. To explore acid-inhibitory and acid-independent, anti-inflammatory PPI effects in reducing esophageal eosinophilia, we studied eotaxin-3 expression by the proximal and distal esophagus of children with esophageal eosinophilia before and after PPI therapy. In vitro, we studied acid and bile salt effects on IL-13-stimulated eotaxin-3 expression by esophageal epithelial cells.
Among 264 children with esophageal eosinophilia seen at a tertiary pediatric hospital from 2008 through 2012, we identified 10 with esophageal biopsies before and after PPI treatment alone. We correlated epithelial cell eotaxin-3 immunostaining with eosinophil numbers in those biopsies. In vitro, we measured eotaxin-3 protein secretion by esophageal squamous cells stimulated with IL-13 and exposed to acid and/or bile salt media, with or without omeprazole.
There was strong correlation between peak eosinophil numbers and peak eotaxin-3-positive epithelial cell numbers in esophageal biopsies. Eotaxin-3 expression decreased significantly with PPIs only in the proximal esophagus. In esophageal cells, exposure to acid-bile salt medium significantly suppressed IL-13-induced eotaxin-3 secretion; omeprazole added to the acid-bile salt medium further suppressed that eotaxin-3 secretion, but not as profoundly as at pH-neutral conditions.
In children with esophageal eosinophilia, PPIs significantly decrease eotaxin-3 expression in the proximal but not the distal esophagus. In esophageal squamous cells, acid and bile salts decrease Th2 cytokine-stimulated eotaxin-3 secretion profoundly, possibly explaining the disparate PPI effects on the proximal and distal esophagus. In the distal esophagus, where acid reflux is greatest, a PPI-induced reduction in acid reflux (an effect that could increase eotaxin-3 secretion induced by Th2 cytokines) might mask the acid-independent, anti-inflammatory PPI effect of decreasing cytokine-stimulated eotaxin-3 secretion.
质子泵抑制剂（PPIs）除了能减少胃酸分泌外，还可通过非酸依赖性抗炎机制抑制食管上皮细胞中Th2细胞因子刺激的嗜酸性粒细胞趋化因子（嗜酸性粒细胞趋化蛋白-3）的表达。为了探究PPIs在减少食管嗜酸性粒细胞浸润方面的抑酸作用和非酸依赖性抗炎作用，我们研究了食管嗜酸性粒细胞增多症患儿在接受PPI治疗前后食管近端和远端嗜酸性粒细胞趋化蛋白-3的表达情况。在体外，我们研究了酸和胆汁盐对食管上皮细胞中白细胞介素-13刺激的嗜酸性粒细胞趋化蛋白-3表达的影响。
在2008年至2012年期间于一家三级儿科医院就诊的264例食管嗜酸性粒细胞增多症患儿中，我们确定了10例仅接受PPI治疗前后均进行食管活检的患儿。我们将这些活检组织中的上皮细胞嗜酸性粒细胞趋化蛋白-3免疫染色与嗜酸性粒细胞数量进行了关联分析。在体外，我们测量了用白细胞介素-13刺激并暴露于酸和/或胆汁盐培养基中的食管鳞状细胞分泌的嗜酸性粒细胞趋化蛋白-3蛋白，同时添加或不添加奥美拉唑。
食管活检组织中嗜酸性粒细胞峰值数量与嗜酸性粒细胞趋化蛋白-3阳性上皮细胞峰值数量之间存在很强的相关性。仅在食管近端，PPIs可使嗜酸性粒细胞趋化蛋白-3的表达显著降低。在食管细胞中，暴露于酸-胆汁盐培养基可显著抑制白细胞介素-13诱导的嗜酸性粒细胞趋化蛋白-3分泌；在酸-胆汁盐培养基中添加奥美拉唑可进一步抑制嗜酸性粒细胞趋化蛋白-3的分泌，但不如在pH中性条件下抑制作用明显。
在食管嗜酸性粒细胞增多症患儿中，PPIs可显著降低食管近端而非远端的嗜酸性粒细胞趋化蛋白-3表达。在食管鳞状细胞中，酸和胆汁盐可显著降低Th2细胞因子刺激的嗜酸性粒细胞趋化蛋白-3分泌，这可能解释了PPIs对食管近端和远端作用不同的原因。在酸反流最严重的食管远端，PPI引起的酸反流减少（这一效应可能会增加Th2细胞因子诱导的嗜酸性粒细胞趋化蛋白-3分泌）可能掩盖了PPIs减少细胞因子刺激的嗜酸性粒细胞趋化蛋白-3分泌的非酸依赖性抗炎作用。
