The importance of pro-inflammatory signaling in neonatal necrotizing enterocolitis

Abstract

Despite modern medical advances, necrotizing enterocolitis (NEC) remains a significant cause of morbidity and mortality in neonatal intensive care units, affecting 10% of premature neonates born weighing less than 1500 g. Although many advances have been made in the understanding of NEC, the etiology and pathophysiology remain incompletely understood, and treatment is limited to supportive care. In recent years, many studies have evaluated the inflammatory cascade that is central to the disease process, and research is ongoing into strategies to prevent and/or ameliorate neonatal NEC. In this review, we examine the key points in the signaling pathways involved in NEC, and potential strategies for prevention and treatment of this dreaded disease.

Figure 1

Top panel: Treatment with PAF receptor antagonist WEB 2170 leads to a decrease in the incidence of NEC. Using our established neonatal rat model for NEC, animals were pretreated with WEB 2170, a PAF receptor antagonist, and then exposed to formula feeding, asphyxia, and bacterial colonization. In animals pretreated with WEB 2170, there was a marked reduction in the incidence of NEC (3/17 versus 14/18 in controls, p<0.001). Bottom panel: Supplementation with Bifidobacterium infantis rats leads to a reduction in the incidence of NEC. Using the same neonatal rat model, animals were treated with B. infantis, E. coli, or saline and then exposed to the NEC protocol. In animals exposed to B. infantis, there was a reduction in NEC to 7/24 versus 19/27 in controls and 16/23 in E. coli-treated animals (p<0.01).

Figure 2

Simplified schematic of TLR signaling. Following binding of ligand to TLR, the adaptor molecule Myd88 is recruited to the receptor complex. IL-1R associated protein kinases (IRAKs) and tumor necrosis factor receptor-associated factor 6 (TRAF6) are next recruited to this complex. IRAK-1 and TRAF6 then bind to transforming growth factor-beta-activated kinase (TAK-1), then the IκB kinase kinase (IKK) complex is activated, which leads to phosphorylation of IκB. IκB is then degraded, and this activates NFκB. NFκB is translocated to the nucleus where it upregulates the production of various inflammatory cytokines.

Figure 3

Formula supplementation with PUFA reduces the incidence of NEC. Using our established neonatal rat model of NEC, we have recently found that PUFA supplementation with AA and DHA, egg phospholipid, or DHA alone all lead to a decreased incidence of NEC compared with controls (p<0.01).

Figure 4

Formula supplementation with PUFA reduces PAF receptor mRNA expression. Using real-time quantitative RT-PCR, PAFR mRNA levels were measured. We found that within ileum and colon, PUFA supplementation in all groups led to a decrease in PAF receptor expression compared with control group (p<0.05)

Figure 5

PUFA supplementation reduces TLR4 gene expression in duodenum, jejunum, and ileum. TLR4 mRNA was measured using real-time quantitative RT-PCR. As shown in the figure, in groups supplemented with AA/DHA or egg phospholipid, there was a reduction in TLR4 gene expression in duodenum, jejunum, and ileum compared with controls (p<0.05).

Figure 6

NEC pathophysiology is a complex series of events leading to a final common pathway of inflammation. This figure demonstrates the proposed pathophysiology of NEC as it is understood currently, as well as potential protective effects of PUFA, probiotics and growth factors. Although much has been elucidated over many years of research, there are still multiple facets of NEC that are incompletely understood.