Inflammatory signaling in NEC: Role of NF-κB, cytokines and other inflammatory mediators

Abstract

The pathogenesis of necrotizing enterocolitis (NEC) is complex and the exact etiology remains unknown. Clinically, the presentation and progression of NEC is variable and often difficult to predict. The majority of affected infants (>90%) are premature, and the following factors may play a role in NEC pathogenesis: 1) The immaturity of the intestinal barrier, the mucus layer, decreased Immunoglobulin A (IgA) and defensins; 2) an abnormal intestinal capillary blood flow due do the incomplete development of the intestinal microvasculature or due to the immature regulation of its vascular tone, causing insufficient substrate and O2 delivery to the intestinal epithelial cells; 3) abnormal bacterial colonization of the enteric tract triggering a mucosal pro-inflammatory response; and 4) immaturity of the immune system preventing normal control and killing of microbes, allowing them to penetrate the epithelium. Concomitantly, this immature immune system mounts an excessive production of inflammatory mediators which cause the recruitment of inflammatory cells such as neutrophils and subsequent tissue injury and necrosis. In order to investigate the pathogenesis of NEC, correlative studies have been conducted measuring different inflammatory mediators such as cytokines in the plasma or in the tissues resected from patients with NEC. However, these tissues are obtained at late stages of the disease when these are commonly necrotic, and therefore may not yield information about the early pathogenic events leading to NEC. As mechanistic studies obviously cannot be conducted in humans, animal models have been used. Studies on rats and mice have contributed to the discovery of several potentially important inflammatory mediators in the pathogenesis of NEC. In this chapter, the current evidence for the role of these inflammatory mediators is presented and a current unifying hypothesis regarding NEC pathogenesis is proposed.