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* Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60614;
Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and
Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048
Bacteria are thought to contribute to the pathogenesis of necrotizing enterocolitis (NEC), but it is unknown whether their interaction with the epithelium can participate in the initiation of mucosal injury or they can act only following translocation across a damaged intestinal barrier. Our aims were to determine whether bacteria and intestinal epithelial TLR4 play roles in a well-established neonatal rat model and a novel neonatal murine model of NEC. Neonatal rats, C57BL/6J, C3HeB/FeJ (TLR4 wild type), and C3H/HeJ (TLR4 mutant) mice were delivered by Cesarean section and were subjected to formula feeding and cold asphyxia stress or were delivered naturally and were mother-fed. NEC incidence was evaluated by histological scoring, and gene expression was quantified using quantitative real-time PCR from cDNA generated from intestinal total RNA or from RNA obtained by laser capture microdissection. Spontaneous feeding catheter colonization or supplementation of cultured bacterial isolates to formula increased the incidence of experimental NEC. During the first 72 h of life, i.e., the time frame of NEC development in this model, intestinal TLR4 mRNA gradually decreases in mother-fed but increases in formula feeding and cold asphyxia stress, correlating with induced inducible NO synthase. TLR4, inducible NO synthase, and inflammatory cytokine induction occurred in the intestinal epithelium but not in the submucosa. NEC incidence was diminished in C3H/HeJ mice, compared with C3HeB/FeJ mice. In summary, bacteria and TLR4 play significant roles in experimental NEC, likely via an interaction of intraluminal bacteria and aberrantly overexpressed TLR4 in enterocytes.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants R01 HD37581 and R01 AI058128, the Jessica Jacobi Golder Endowment, and a grant from Mead Johnson Nutritionals.
2 Address correspondence and reprint requests to Dr. Michael S. Caplan, Professor of Pediatrics, The Evanston Hospital, 2650 Ridge Avenue, Evanston, IL 60201. E-mail address: mca113{at}northwestern.edu
3 Abbreviations used in this paper: NEC, necrotizing enterocolitis; CD, Crohn’s disease; CT, cycle threshold; DSS, dextran sodium sulfate; FFCAS, formula-feeding and cold/asphyxia stress; iNOS, inducible NO synthase; LCM, laser capture microdissection; MF, mother fed; PAF, platelet-activating factor; QRT-PCR, quantitative real-time RT-PCR; UC, ulcerative colitis.
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