The work reviewed above indicates that activation of TLR4 within the intestine is deleterious to the host, through effects on intestinal barrier injury, repair, and bacterial translocation. The overriding concept that enterocyte TLR4 activation has negative effects on intestinal homeostasis is supported by work demonstrating that TLR4 plays an important role in protecting the host from the development of chemical-induced colonic inflammation through the maintenance of intestinal homeostasis and the production of cytoprotective factors (83) (84) (85) . However, subsequent studies have demonstrated that TLR4 may play a permissive role in the development of spontaneous colonic inflammation (86) , suggesting either that the net effects of TLR4 on intestinal inflammation are dependent on the specific disease process examined, the anatomic location of the disease process, or that the interaction with various downstream effectors influences the extent of intestinal inflammation that develops. It is noteworthy that the inflammation observed in NEC is predominantly localized to the small intestine as opposed to the colon (4,87), implying that the effects of TLR4 activation within small intestinal epithelial cells may lead to different effects than its role on the colonic epithelia. In support of this concept, it has been demonstrated previously that small intestinal enterocytes are more responsive to LPS than colonic enterocytes, due in part to differences in TLR4 expression and/or activity (88, 89) . Moreover, the increase in expression of TLR4 within the ileum that we have observed after exposure to hypoxia and endotoxin suggests that TLR4dependent signaling within the small bowel mucosa may be increased after exposure to these stressors. The combined effects of the enhanced baseline sensitivity of the small intestine to LPS, and the upregulation of TLR4 expression in the intestine may partially explain the observed effects of enterocyte TLR4 in the induction of NEC. In support of this possibility, Caplan et al. have recently demonstrated that TLR4 expressing mice are more susceptible to the development of NEC in a model of formula feeding and cold asphyxia through a mechanism involving the enhanced interaction with luminal bacteria (33) .