Clark Jessica A, Doelle Sarah M, Halpern Melissa D, Saunders Tara A, Holubec Hana, Dvorak Katerina, Boitano Scott A, Dvorak Bohuslav
Department of Pediatrics, University of Arizona, Tucson, AZ 85724-5073, USA.
Am J Physiol Gastrointest Liver Physiol. 2006 Nov;291(5):G938-49. doi: 10.1152/ajpgi.00090.2006. Epub 2006 Jun 22.
Necrotizing enterocolitis (NEC) is the most common intestinal disease of premature infants. Although increased mucosal permeability and altered epithelial structure have been associated with many intestinal disorders, the role of intestinal barrier function in NEC pathogenesis is currently unknown. We investigated the structural and functional changes of the intestinal barrier in a rat model of NEC. In addition, the effect of EGF treatment on intestinal barrier function was evaluated. Premature rats were divided into three groups: dam fed (DF), formula fed (NEC), or fed with formula supplemented with 500 ng/ml EGF (NEC + EGF); all groups were exposed to asphyxia/cold stress to develop NEC. Intestinal permeability, goblet cell density, mucin production, and composition of tight junction (TJ) proteins were evaluated in the terminal ileum, the site of NEC injury, and compared with the proximal jejunum, which was unaffected by NEC. Animals with NEC had significantly increased intestinal paracellular permeability compared with DF pups. Ileal goblet cell morphology, mucin production, and TJ composition were altered in animals with NEC. EGF treatment significantly decreased intestinal paracellular permeability, increased goblet cell density and mucin production, and normalized expression of two major TJ proteins, occludin and claudin-3, in the ileum. In conclusion, experimental NEC is associated with disruption of the intestinal barrier. EGF treatment maintains intestinal integrity at the site of injury by accelerating goblet cell maturation and mucin production and normalizing expression of TJ proteins, leading to improved intestinal barrier function.
坏死性小肠结肠炎（NEC）是早产儿最常见的肠道疾病。尽管黏膜通透性增加和上皮结构改变与许多肠道疾病有关，但肠道屏障功能在NEC发病机制中的作用目前尚不清楚。我们在NEC大鼠模型中研究了肠道屏障的结构和功能变化。此外，还评估了表皮生长因子（EGF）治疗对肠道屏障功能的影响。将早产大鼠分为三组：由母鼠喂养（DF）、配方奶喂养（NEC）或用添加500 ng/ml EGF的配方奶喂养（NEC + EGF）；所有组均暴露于窒息/冷应激以诱发NEC。在NEC损伤部位的回肠末端评估肠道通透性、杯状细胞密度、黏蛋白产生以及紧密连接（TJ）蛋白的组成，并与未受NEC影响的空肠近端进行比较。与DF幼崽相比，患有NEC的动物肠道细胞旁通透性显著增加。患有NEC的动物回肠杯状细胞形态、黏蛋白产生和TJ组成发生改变。EGF治疗显著降低了肠道细胞旁通透性，增加了杯状细胞密度和黏蛋白产生，并使回肠中两种主要TJ蛋白（闭合蛋白和Claudin-3）的表达正常化。总之，实验性NEC与肠道屏障破坏有关。EGF治疗通过加速杯状细胞成熟和黏蛋白产生以及使TJ蛋白表达正常化来维持损伤部位的肠道完整性，从而改善肠道屏障功能。
