Abstract
Background: Necrotizing enterocolitis (NEC) is the most common intestinal disease predominately of formula fed, premature babies. Epidermal growth factor (EGF) reduces the incidence of disease in a neonatal rat model of NEC. It has been suggested that increased mucosal permeability may play an important role in the pathogenesis of NEC. Claudin and occludin are the major structural and functional components of the tight junction barrier. These proteins may be altered in disease states. However, the role of tight junctions in NEC pathogenesis and EGF treatment is currently unknown.Objective: The aim of this study was to determine if EGF affects expression of tight junction genes and proteins in the ileum during the development of NEC.Methods: Neonatal rats, either dam fed (DF), milk formula fed (NEC), or fed with formula plus 500 ng/ml EGF (NEC+EGF) were exposed to asphyxia and cold stress to develop NEC. After 96 hours, ileal expression of claudin-3 and occludin were evaluated using Realtime-PCR, Western blot and immunohistochemistry.Results: Claudin-3 and occludin mRNA levels in the ileum were significantly increased 2–4 fold in NEC animals compared to DF animals (p<0.0001). Supplementation with EGF normalized mRNA expression to DF levels. Phosphorylated occludin was significantly decreased in NEC animals compared to DF animals (p<0.01) and EGF treatment increased expression to DF levels. Non-phosphorylated occludin was only present in NEC and NEC+EGF animals. Histological localization of claudin-3 and occludin proteins was disturbed in animals with NEC compared to DF animals. NEC animals had upregulated expression and disorganization of the tight junction proteins. EGF treatment resulted in localization of the proteins at the tight junction complex.Conclusion: The ability of EGF to normalize expression and localization of tight junction proteins may be one mechanism by which integrity of the mucosal barrier is maintained, thereby protecting the intestinal mucosa against NEC. The increased expression of mRNA and disorganization of protein in animals with NEC may represent a compensation for the inability to form functional tight junctions at the mucosal barrier.Supported by the APS Porter Physiology Fellowship (to J.C.) and NIH Grants HD-39657, HD-47237 (to B.D.)
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