Innate immune signaling in the pathogenesis of necrotizing enterocolitis.

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2013, Article ID 475415, 10 pages http://dx.doi.org/10.1155/2013/475415 Review Article Innate Immune Signaling in the Pathogenesis of Necrotizing Enterocolitis David J. Hackam,1 Amin Afrazi,1 Misty Good,2 and Chhinder P. Sodhi1 1 Division of Pediatric Surgery, Department of Surgery, Children’s Hospital of Pittsburgh and University of Pittsburgh School of Medicine, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA 2 Division of Newborn Medicine, Department of Pediatrics, Children’s Hospital of Pittsburgh and University of Pittsburgh School of Medicine, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Correspondence should be addressed to David J. Hackam; Received 10 March 2013; Revised 1 May 2013; Accepted 7 May 2013 Academic Editor: Philipp Henneke Copyright © 2013 David J. Hackam et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Necrotizing enterocolitis (NEC) is a challenging disease to treat, and caring for patients afflicted by it remains both frustrating and difficult. While NEC may develop quickly and without warning, it may also develop slowly, insidiously, and appear to take the caregiver by surprise. In seeking to understand the molecular and cellular processes that lead to NEC development, we have identified a critical role for the receptor for bacterial lipopolysaccharide (LPS) toll like receptor 4 (TLR4) in the pathogenesis of NEC, as its activation within the intestinal epithelium of the premature infant leads to mucosal injury and reduced epithelial repair. The expression and function of TLR4 were found to be particularly elevated within the intestinal mucosa of the premature as compared with the full-term infant, predisposing to NEC development. Importantly, factors within both the enterocyte itself, such as heat shock protein 70 (Hsp70), and in the extracellular environment, such as amniotic fluid, can curtail the extent of TLR4 signaling and reduce the propensity for NEC development. This review will highlight the critical TLR4-mediated steps that lead to NEC development, with a focus on the proinflammatory responses of TLR4 signaling that have such devastating consequences in the premature host. 1. Introduction Necrotizing enterocolitis (NEC) is a challenging disease to treat. While NEC may develop quickly and without warning, it may also develop slowly, insidiously, and to take the caregiver by surprise. In its most severe and extreme form, NEC is not particularly difficult to recognize; the premature infant with a grossly distended abdomen, bilious nasogastric aspirates, and maroon-colored stools can be readily considered to have NEC as a unifying explanation for his/her constellation of symptoms. In earlier stages of the disease, however, where the only symptoms may be feeding intolerance and mild hemodynamic instability, the diagnosis of NEC often cannot be made with high confidence or reliability, reflective perhaps of the fact that a variety of septic states can share features that overlap with NEC. Yet despite the inability to reliably diagnose NEC in these early stages, it is precisely at the earliest stages of the disease where an accurate diagnosis is most critical, as it is here that the ability to intervene may be expected to have the greatest potential for benefit before irreversible intestinal necrosis and overwhelming systemic sepsis occur. Given the relative imprecise nature of the diagnostic approaches for early stage NEC, scientists who investigate the molecular underpinnings of this disease and clinicians who take care of patients who suffer from it have focused their attention on gaining a greater understanding of the events that lead to its early development. In this regard, we and others have identified a necessary role for the innate immune lipopolysaccharide receptor toll like receptor 4 (TLR4) in the pathogenesis of NEC. In this review, we 2 will investigate the evidence that points to a role for TLR4 signaling in the pathogenesis of NEC, through its ability to promote intestinal injury and through its deleterious effects on intestinal healing in the premature host that together lead to the development of NEC. 2. Injury and Repair in the Intestinal Tract of the Premature Infant The intestinal mucosa of the premature infant exists in a state of constant injury and repair, which must be perfectly balanced in order to maintain homeostasis. Injury to the intestinal mucosa occurs during a variety of settings that may be present within the setting of prematurity, including hypoxia [1, 2], remote infection [3], and the administration of nonbreast milk infant formula [4]. We [5] and others [6] have shown that the initial injury to the small intestine primarily involves the loss of epithelial villi through apoptosis, which subsequently leads to the development of necrosis, a process that is consistent yet only incompletely explained. Loss of the epithelial barrier through apoptosis permits the translocation of bacteria and other antigens that are present within the lumen of the intestine, and which must normally be appropriately shielded from the immune system of the premature host in order to prevent the exaggerated inflammatory response, that is, typical of intestinal inflammatory conditions such as NEC [7, 8]. In response to the loss of epithelial continuity (which may be reflective of primary apoptosis or the early events that migh culminate in apoptosis), a multipronged healing program is initiated. Healing of the intestinal mucosa occurs initially through the process of enterocyte migration, which involves the movement of healthy enterocytes into the wounded area in order to provide a rapid seal, which limits the degree of bacterial translocation that can occur [9]. While enterocyte migration can facilitate the early steps that lead to intestinal restitution, these events are short lived and unlikely to have a long-lasting effect without the generation of new enterocytes, a process that occurs within the Crypts of Luberkuhn [10, 11]. The steps that regulate the proliferation of enterocytes from existing precursors have been well characterized in a series of thorough recent reviews [12, 13]. We have described that under conditions of prematurity, NEC is associated with a marked inhibition in both enterocyte migration and proliferation, which renders the host uniquely susceptible to further injury through the combined loss of both of the important reparative processes that are normally present within the intestine [5]. In the subsequent sections, the mechanisms by which enterocyte migration and proliferation are each impaired in the pathogenesis of NEC will be reviewed in further detail. 3. Activation of the Innate Immune Recept (...truncated)