Morphologic Alterations of the Enteric Nervous System and Deficiency of Non-Adrenergic Non-Cholinergic Inhibitory Innervation in Neonatal Necrotizing Enterocolitis

Abstract

Although damage to intramural nervous tissue should be expected in neonatal necrotizing enterocolitis (NNEC), as the pathology of NNEC is defined by substantial destruction of the bowel wall, only a few studies have considered its implication. Thus, the aim of the study has been to examine morphological alterations of the enteric nervous system (ENS) in intestinal segments affected by NNEC. Immunohistochemical methods allowed the demonstration of both neuronal and glial elements and the assessment of an altered localization of non-adrenergic non-cholinergic (NANC) inhibitory mediators within the intramural plexuses. Intestinal segments from patients with NNEC (n = 8) and control subjects (n = 3) were obtained and submitted to immunohistochemical examination incubating with antibodies against protein gene product (PGP) 9.5, protein S-100, vasoactive intestinal polypeptide (VIP) and nitric oxide synthase (NOS). The most severe damage of nervous tissue was found within the plexus mucosus and plexus submucosus internus. The ganglionated plexuses showed a loss ot both glial and nerve cells with various stages of cell deterioration and the formation of central lesions within the myenteric ganglia. The observed neuropathologic changes correspond to the group of acquired segmental hypoganglionosis. Specimens from patients with NNEC were also characterized by an absence of immunoreactive VIP and NOS in the plexus submucosus and within the circular muscle layer. The deficiency in NANC inhibitory innervation may contribute to the formation of functional obstructions following acute NNEC. Furthermore, it is likely that the neuropathological lesions induced in early stages of NNEC may result in dysfunctional intestinal motility facilitating intraluminal bacterial overgrowth and translocation, and therefore, possibly promote the self-perpetuating pathophysiologic cycle culminating in progressive NNEC. As an additional finding, two patients with NNEC showed typical features of intestinal neuronal dysplasia (IND). The association of NNEC and IND is reviewed in the literature and possible causalties are discussed.

Expression of a functional metabotropic glutamate receptor 5 on enteric glia is altered in states of inflammation

“…Disorganized and sponge like S-100b immunoreactivity has been described in biopsies from patients with necrotizing enterocolitis (Sigge et al, 1998), suggesting that the S100b changes that we have observed are due to the transmural nature of the TNBS inflammation. Again, no disorganization of GFAP was observed in the IL-10 2/2 mice and this difference could be the result of the chronicity of inflammation or the species.…”

Effect of Milk Formula Protein Content on Intestinal Barrier Function in a Porcine Model of LBW Neonates

“…In the former study, altered acetylcholine metabolism 8 (increase AChE expression and activity, decreased packaging and exocytosis of acetylcholine, alteration of ChAT expression…) was involved (31). Similarly, many studies reported a decrease in VIP-immunoreactive neurons during inflammation (33). Further studies are needed to investigate whether alteration of the nervous regulation of permeability is linked to an intestinal inflammatory state.…”

Inflammation-Induced Changes in the Chemical Coding Pattern of Colon-Projecting Neurons in the Inferior Mesenteric Ganglia of the Pig

“…Nitric oxide plays an important role in the protection of intestinal mucosa (Di and Krantis 2002;Konturek et al 2004). Moreover, NO has been shown to be involved in neuronal communication, regulation of blood flow and pressure, smooth muscle activity and intestinal motility, modulation of immunity, inflammatory reactions, and the regeneration of axons during injury (Grozdanovic et al 1994;Belai et al 1997;Sigge et al 1998;Bredt 1999;Balemba et al 2002). An increase in the number of neurons synthesizing NOS was observed under both "native" and experimental intestinally induced inflammation (Boughton-Smith et al 1993;Miller et al 1995;Miller and Sandoval 1999).…”