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.