ABSTRACT
Activation of the lipopolysaccharide receptor toll-like receptor 4 (TLR4) in the intestinal epithelium plays a critical role in the pathogenesis of NEC. TLR4 activation leads to increased intestinal mucosal injury via apoptosis and necroptosis and decreased mucosal repair through reduced proliferation and migration. The translocation of bacteria through the injured barrier then activates TLR4 on the endothelium of the intestine, leading to a loss of eNOS and vasoconstriction. Breast milk is a powerful inhibitor of TLR4, explaining in part its protective effects against NEC. We have discovered a novel family of TLR4 inhibitors that prevent NEC in animal models and in human tissue ex vivo, raising the possibility that TLR4-specific therapies may offer hope for patients with this devastating disease.
