Discussion Brefeldin A Platelet activating factor plays an important role in the initiation and/or maintenance of mucosal inflammation and intestinal injury [10]. Although PAF has been implicated in numerous diseases involving mucosal inflammation, such as asthma [35], [36], peptic ulcer[37], Crohn’s disease [38], and ulcerative colitis [39], its pathogenic role is best established in neonatal necrotizing enterocolitis (NEC). We have shown that PAFR inhibition reduced the risk of NEC in a neonatal animal model using clinical risk factors for NEC (bacterial colonization, intestinal ischemia, and formula feeding) [5]. We have also shown that giving the PAF-degrading enzyme PAF-acetylhydrolase (PAF-AH) with enteral feedings prevents the initiation of experimental NEC in this rat model [7].

The intestine, particularly the distal small bowel, is at increased risk for PAF-induced inflammatory injury, since PAF-receptor gene is constitutively expressed at the highest level in the ileum compared to other organs [40]. Our previous studies have shown that the development of NEC in a rodent model is preceded and underlined by exaggerated enterocyte apoptosis [41] and that PAF is a potent inducer of enterocyte apoptosis in tissue culture [42]. However, while the role of PAF has been established in this NEC neonatal rat model, the mechanisms by which PAF contributes to NEC are not completely understood. TLRs are important in the protection of the host. They initiate the innate immune response modulate the adaptive immune response to bacteria and viruses.

TLRs recognize PAMPs that may derive either from bacteria, viruses or fungi and initiate signaling that results in expression and release of inflammatory cytokines. We and Cilengitide others [20], [22], [34], [43], [44] have shown that IEC of the mature, healthy small and large intestine express low levels of TLR4 and MD-2 and respond poorly to LPS, but TLR4 and MD-2 are abnormally upregulated in inflammatory bowel disease [34]. The very low level of expression of and subdued signaling via TLRs may represent an adaptation of IEC to prevent collateral tissue damage from an unnecessary inflammatory response to commensal organisms. Ongoing signaling between commensals and TLRs has an important beneficial effect on the maintenance of normal barriers in the intestine and enhances protection and repair from injury [45]. We have also demonstrated in an animal model of acute colitis using dextran sulfate sodium that TLR4, through the adapter protein MyD88, is important in the intestinal response to epithelial injury and limiting bacterial translocation [46]. We know that TLRs are expressed on fetal enterocytes [47].